Phytochemical interventions of medicinal plants in the management of diabetes and obesity: A recent therapeutic overview

D’Souza Keith; Ketaki Apte; Vivek S. Kumawat; Ansh Chintamaneni; Meena Chintamaneni; Ujjawal Sharma; Bunty Sharma; Moyad Shahwan; Ginpreet Kaur; Damandeep Kaur; Hardeep Singh Tuli

doi:10.7324/JAPS.2025.217666

Abstract

Over the past four decades, the global surge in diabetes and obesity has given rise to the term “diabesity,” reflecting the strong connection between type 2 diabetes and obesity. This link is correlated with heightened risks of cardiovascular disease, hypertension, and stroke. In light of this escalating health crisis, medicinal plants and natural products, which have long been used in traditional medicine systems, have attracted growing interest for their potential to address diabetes and obesity. This review highlights scientific evidence from preclinical and clinical studies on the efficacy of medicinal plants in treating diabetes and obesity. It focuses on the phytoconstituent responsible for these benefits and supports their traditional therapeutic use while comparing with common therapeutic interventions. Additionally, the review delves into the mechanism of action through which these plants demonstrate their benefits and explores modern formulations that fuse traditional knowledge with current healthcare practices. As diabesity continues to rise globally, understanding the role of medicinal plants in managing this dual condition offers valuable insights into alternative and complementary approaches for comprehensive healthcare.

Keyword: AMPK PPAR anti-inflammatory anti-oxidant insulin resistance

Citation:

Keith D, Apte K, Kumawat VS, Chintamaneni A, Chintamaneni M, Sharma U, Sharma B, Shahwan M, Kaur G, Kaur D, Tuli HS. Phytochemical interventions of medicinal plants in the management of diabetes and obesity: A recent therapeutic overview. J Appl Pharm Sci. 2026;16(01):046-069. http://doi.org/10.7324/JAPS.2025.217666

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. INTRODUCTION

Cardiometabolic diseases (CMDs) encompass a variety of disorders that impair heart function and disturb the body’s physiological balance. This group includes conditions such as coronary artery disease, peripheral vascular disease, stroke, aneurysms, heart attacks, congestive heart failure, hypertension, and others [1,2]. Alarming statistics from the WHO underscore the gravity of CMDs as the primary global cause of mortality, claiming an estimated 17.9 million lives annually [3]. This distressing figure continues to climb, propelled by a myriad of risk factors. Age, sex, medications, and intricate interconnections such as lifestyles, genetics, and environmental influences collectively contribute to the surge in CMD-related fatalities. CMDs are not isolated events but rather complex outcomes of various factors converging to disrupt the cardiovascular and metabolic equilibrium. Lifestyle choices, including diet and physical activity, along with genetic predispositions and environmental conditions, play pivotal roles in the progression of these diseases [4–7].

The escalating prevalence of CMDs has brought about an unfortunate surge in global treatment costs, surpassing even the expenditures associated with cancer and diabetes treatments. This unwelcome reality has imposed a substantial economic burden, particularly affecting middle-income and lower middle-income families. The economic strain resulting from CMD treatment has become a pressing global concern in both health and pharmaceutical economics [8–11].

In response to this challenge, concerted efforts are underway to address the root causes and mitigate the risk factors associated with CMDs. A pivotal focus has been placed on tackling diabetes and obesity, recognized as two of the most critical and modifiable risk factors contributing to CMDs. By directing attention towards these specific factors, endeavors are being made to not only alleviate the economic impact but also enhance preventive strategies, ultimately promoting better global health outcomes [12].

In conducting this review, data were sourced from a variety of databases to ensure a comprehensive and robust analysis. PubMed was searched for peer-reviewed articles using keywords focusing on studies published within the last 5 years. ClinicalTrials.gov was used to gather information on ongoing and completed clinical trials relevant to the topic, prioritizing Phase II and III trials. Google Scholar and open-access journals were also utilized to identify additional research, including gray literature and open-access studies not covered in subscription-based databases. Manual searches of reference lists from key studies were performed to capture additional relevant literature. All articles were screened based on inclusion criteria such as relevance, study design, and quality of data.

2. DIABETES AND OBESITY

Diabetes manifests as a family of metabolic disorders distinguished by either insufficient insulin secretion (type 1 diabetes mellitus or T1DM) or resistance to insulin (type 2 diabetes mellitus or T2DM), resulting in high systemic glucose levels alternatively called hyperglycemia [13]. This global health challenge has evolved into an epidemic, claiming over 1.5 million lives, particularly impacting individuals under the age of 70. Projections indicate a worrisome trajectory in the soaring global costs associated with diabetes [14].

The occurrence of type 2 diabetes mellitus (T2DM) is influenced by a constellation of factors, including lifestyle choices, dietary habits, levels of physical activity also including an individual’s age and gender. Notably, both T1DM and T2DM carry an augmented risk of being genetically inherited, adding a layer of complexity to their etiology [15–18].

The pathophysiology of T2DM is intricately tied to the malfunctioning or destruction of β-cells and the inhibition of their signaling pathways, potentially influenced by various genetic linkages [19–21]. Currently, oral anti-diabetic drugs like metformin and sitagliptin are available, but lifestyle modifications remain efficacious in managing diabetes [22]. While the direct connections between diabetes and CMDs are not entirely elucidated, factors such as obesity significantly escalate the risk of CMDs [23].

The pathogenesis of T2DM involves intricate mechanistic pathways, with a prominent association with hyperlipidemia and obesity. These factors spark a deluge of events leading to complications such as reactive oxygen species mediated oxidative stress and low-grade inflammation, ultimately culminating in cardiac ailments like arteriosclerosis [24,25]. Another significant pathway implicated in diabetes progression is the tyrosine-serine Protein Kinase C (PKC) pathway, which induces redox stress, contributing to microvascular complications [26].

Additionally, the interaction of sugars with proteins at their freely available amino groups gives rise to Schiff bases, resulting in a rearrangement to form more stable products known as Amadori products, also known as advanced glycation end-products (AGEs). The prevalence of AGEs further exacerbates microvascular complications in diabetes [27]. This multifaceted interplay of hyperlipidemia, obesity, oxidative stress, inflammation, PKC pathway activation, and theformation of AGEs collectively underscores the intricacies of T2DM progression and its associated complications (Fig. 1).

Figure 1. Complications in diabetes mellitus. Lipid accumulation resulting in hyperlipidemia can cause arteriosclerotic plaques. Increased inflammatory markers (IL-6, TNF-α), oxidative damage, and advanced glycation end products (AGEs) contribute to vascular remodeling. Adapted from Poznyak et al. [40].

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Obesity is defined as an “abnormal buildup of fat that can negatively affect wellness” and occurs when calorie consumption exceeds energy expenditure [28]. In India, data from the National Family Health Surveys (NFHS-4 and NFHS-5) indicate a notable rise in the number of overweight or obese women, rising from 20.6% to 24%. Similarly, the prevalence of obese or overweight men has risen from 18.9% to 22.9% [29,30]. Multiple factors contribute to obesity, including dietary patterns, environmental influences, sedentary lifestyles, social dynamics, and genetic predispositions [31–33].

Population studies emphasize the pivotal roles of dietary habits and physical involvement in the genesis of obesity, with genetic factors together with environmental elements intertwining to characterize it as a modern epidemic. The complexity of these interactions complicates treatment strategies, necessitating a nuanced and multifaceted approach to address the rising epidemic of obesity and its associated health risks. Obesity is frequently associated with a state of low-grade inflammation, a condition that underlies many of its detrimental effects on the cardiovascular system [34]. Additionally, endocrine imbalances, such as hyperthyroidism, Cushing’s syndrome, and resistance to leptin effects, contribute to the pathogenesis of obesity [35]. This condition, in turn, acts as a significant risk factor for diabetes, dyslipidemia, and insulin resistance, exacerbating the impact on CMDs [36,37]. The strong association between obesity and hypertension, a prevalent CMD, further emphasizes the profound influence of obesity on cardiovascular health and its related complications [38]. Various treatment strategies are currently available for obesity, ranging from lifestyle modifications and dietary therapy to pharmacotherapy, gene therapy, and surgical interventions. Notably, pharmacotherapy has garnered high acceptance rates among patients, offering a viable avenue for addressing obesity and its associated health challenges. This multifaceted approach acknowledges the intricate interplay of factors contributing to obesity, recognizing that effective intervention necessitates a comprehensive understanding of both its origins and its far-reaching consequences on overall health [39].

3. PATHWAYS INVOLVED IN DIABETES AND OBESITY

The AMPK pathway serves as the primary regulator of energy metabolism, finely tuned by the adenosine monophosphate (AMP)/adenosine triphosphate ratios. Elevated AMP levels, induced by factors such as exercise or other stimuli, activate the pathway through LKB1, initiating a cascade that controls secondary messengers pivotal in the metabolism of glucose and lipids. Activation leads to upregulating secondary messengers like TBC1D1 and TBC1D4, culminating in increased GLUT4 expression and enhanced glucose uptake (Fig. 2). Conversely, inactivation results in hyperglycemia [41].

Figure 2. Activation of AMPK signaling pathway resulting in increased levels of LBC1D1 and LBC1D4 which up-regulate the expression of GLUT-4 essential in cells glucose uptake.

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This pathway also is essential in modulating lipid levels in obesity. It downregulates acetyl-CoA carboxylase (ACC), resulting in a decrease in the synthesis of fatty acids, and concurrently upregulates desnutrin/adipose triglyceride lipase (ATGL) [42]. Desnutrin/ATGL, a key player in adipose lipolysis, catalyzes the initial step in the breakdown of fats, contributing significantly to the regulation of lipolysis (Fig. 3) [43].

Figure 3. Activation of AMPK to induce ACC which aids in the conversion of acetyl-CoA to FFA for triglycerides. The induction of ATGL prevents the breakdown of triglycerides.

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Another pivotal molecular pathway is the PPAR pathway, featuring a family of nuclear receptors. PPARs operate through dual mechanisms: activating genes responsible for glucose and lipid metabolism while concurrently repressing inflammatory pathways, notably NFκB, commonly implicated in obesity-related inflammation (Fig. 4). Understanding these intricate molecular pathways provides valuable insights into potential targets for interventions aimed at regulating glucose and lipid metabolism and mitigating the inflammatory aspects associated with obesity [44,45].

Figure 4. PPAR-Υ can function by multiple pathways—(1) once bound to a ligand it heterodimers with the RXR element to serve as a promoter to the genes that help to maintain glucose and lipid homeostasis and (2) on its own can inhibit the NF-kB pathway.

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As the search for new molecules for the treatment and mitigation of obesity and diabetes has slowed down the focus is shifting towards the various traditional systems of medicines and herbal preparations [46,47]. Phytopharmaceuticals have increased patient tolerance with fewer side effects. Over a quarter of the pharmaceuticals are phyto-derived explaining their increase in its share in the pharmaceutical industry expected to be reaching 550 billion dollars in 2030 [48–50].

4. MEDICINAL PLANTS IN PRE-CLINICAL AND CLINICAL TRIALS

4.1. Bitter Melon/Karela (Momordica charantia L.)

4.1.1. Mechanism of action

Bitter melon, popularly referred to as “Karela” in India, has long been renowned for its hypoglycemic effects. Its leaves, stem, and fruits offer many medicinal benefits with its powder form available commercially as a nutraceutical. It is rich in various micronutrients (vitamins and minerals) supporting general metabolic health, and along with various other alkaloids, saponins, flavonoids, and terpenes constitute the main bioactive compounds in bitter melon [51]. Momordica charantia polysaccharides (MCP) are a group of heteropolysaccharides present in M. charantia that exert hypoglycemic effects by various mechanisms, particularly it demonstrates immunomodulatory activity by regulating Th1 and Th2 cells, protecting and repairing impaired pancreatic β-cells. It also may serve as an inhibitor for intestinal α-glucosidase blocking the absorption of glucose into the systemic circulation. At skeletal muscle levels, it may stimulate the uptake of glucose by increasing GLUT-4 expression in a dose-dependent fashion [52].

Cucurbitane-type saponin glycosides are another major bioconstituent in M. charantia. Amongst these, the triterpenoid saponin Momocharin (charantin) is believed to be the primary hypoglycemic agent. It shows insulin-like effects such as upregulating the expression of GLUT-4 in skeletal muscle and IRS-1 in the liver cells [53]. Polypeptides in the plant are highly sought-after phytoconstituents due to their multiple activities. Polypeptide-k isolated from the seeds of the plant demonstrated the ability to inhibit both α-glucosidase and α-amylase [54]. Another novel peptide, mcIRBP-1, is a gastric receptor peptide shown to bind at a site on the insulin receptor different from insulin and activate it. Furthermore, it is shown to activate Akt pathways where it phosphorylates and inactivates Protein tyrosine phosphatase 1B, an enzyme responsible for desensitizing insulin receptors [55].

Research indicates that Karela extract selectively inhibits 11β-hydroxysteroid dehydrogenase1 in a dose-progressive fashion and prevents visceral fat deposition. Inhibition of the enzyme also results in suppressing phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, key enzymes in hepatic gluconeogenesis. This causes decreased bioenergetics in cells, triggering stress conditions that activate AMPK [56]. The anti-obesity potential of M. charantia stems from its ability to suppress the various pathways linked with lipid homeostasis namely PPAR and Sterol regulatory element binding proteins (SREBP) pathways [57]. Inhibiting PPAR is well known for targeting obesity and reducing fat accumulation; while SREBP inhibition is an epigenetic modification that targets cholesterol homeostasis, reducing levels of triglycerides and cholesterol which allows managing hyperlipidemia [58].

4.1.2. Pre-clinical studies

Momordica charantia juice has been investigated for both the prophylaxis and treatment of T2DM in Streptozotocin (STZ)-induced diabetic rats. Notably, prophylactic administration was found to be more effective in preventing pancreatic β-islet degradation, primarily due to its potent antioxidant properties, which significantly reduced malonyl aldehyde (MDA) levels. This suggests that M. charantia extract can delay the onset of diabetes by protecting pancreatic cells from oxidative damage. Furthermore, treatment with M. charantia juice led to a significant reduction in blood glucose levels and lipid parameters, including triglycerides (TG), total cholesterol (TC), and low-density lipoprotein (LDL), highlighting its potential role in metabolic regulation [59]. To further enhance its therapeutic efficacy, Olusola Olalekan Elekofehinti developed M. charantia-silver nitrate nanoparticles, which demonstrated superior glucose-lowering and lipid-regulating effects compared to conventional extracts. These nanoparticles not only improved antioxidant defense but also offered a key advantage in epigenetic modulation, leading to enhanced insulin secretion. Unlike traditional delivery systems, which often result in suboptimal insulin release, this nanoformulation improved systemic insulin availability, making it a promising approach for more effective diabetes management [60].

The studies incorporated here highlight the vast potential of M. charantia bioactive compounds. Liu et. al. [52] extracted MCP from M. charantia and administered it to T1DM rats, where it reduced the fasting blood glucose (FBG) levels with a progressive loss in body weight after the 12-week period. Further analysis revealed that MCP was able to lower cytokines (TNFα and IL-6) by NF-kB suppression and neovascularization by vascular endothelial growth factor (VEGF) downregulation in the eye, which proved beneficial in mitigating the risks of diabetic retinopathy, a common complication in older patients [61]. Bitter melon powder demonstrated the ability to also improve the gut microbiome, particularly the short chain fatty acids (SCFAs) producing microbes—Blautia, Lactococcus, and Allobaculum. SCFA like butyrate and propionate help prevent gut inflammation as seen in obesity. SCFA has a beneficial role in preventing glucose spikes and regulating cholesterol and blood pressure levels in CMD. It also decreased lipopolysaccharide-binding protein (LBP), a potential biomarker for inflammation and insulin resistance [62]. mcIRB-19 was analyzed to decrease blood glucose levels and it showed positive effects and together with its other insulin mimetic activities, it reduced inflammation and immune reactions at the nephron level to decrease the incidence of diabetic nephropathy [62] (Table 1).

Table 1. Pre-clinical trials of M. charantia and its phytoconstituents.

No.	Animal model	Period of study	Study design and method	Outcomes	Reference to study
1	STZ-induced Wistar rats	21 days	Group 1—Normal control Group 2—Diabetic control Group 3—14 days M. charantia juice + induce diabetes and continue treatment for 21 days. Group 4—21 days treatment in diabetic rats.	↓FBG ↓TG ↓TC ↓LDL ↓MDA	[59]
2	STZ-induced Wistar rats	11 days	Group 1—Normal control Group 2—Diabetes control Group 3—M. charantia nanoparticles (50 mg/kg). Group 4—silver nitrate (10 mg/kg). Group 5—Metformin (100 mg/kg). Group 6—M. charantia aqueous extract (100 mg/kg).	↓FBG ↑insulin secretion ↓TG ↓TC ↓LDL	[60]
3	STZ-induced Sprague Dawley rats	12 weeks	Group 1—Normal control receiving sodium citrate. Group 2—Diabetic control receiving sodium citrate. Group 3—Diabetic group receiving 500 mg/kg b.w. of MCP	↓FBG ↓Total body weight ↓TNFα, IL-6 ↓Neovascularization VEGF	[61]
4	Sprague Dawley rats	8 weeks	Group 1—Normal fed diet (NFD) Group 2—High fat diet (HFD) Group 3—High fat diet + 400 mg/kg b.w. bitter melon powder	↓FBG ↓LBP ↑SCFA producing gut microbiome	[62]
5	db/db mice models	12 weeks	Group 1—Control group Group 2—mcIRB19 treated group	↓FBG ↓HbA1c ↓renal vasculature leakage ↓Nf-kB	[63]

4.1.3. Clinical studies

mcIRB19 was further extended to human trials in DM patients, which received 600 ppm of peptide daily. After 3-month intervention, the FBG and HbA1c levels were significantly lower than those of the control group. It also demonstrated lower TG and blood urea nitrogen (BUN); the latter associated with diabetic nephropathy. Although the study showed promising effects in lowering FBG, the study didn’t fully exclude the effect of patients’ hypoglycemic medications and further analysis would be required to study the other effects too [64].

In a study comparing bitter melon vs oral hypoglycemic glibenclamide, it was found that bitter melon at 2–4 g was not very effective just alone when compared to glibenclamide. However, significant and better results were found in lowering TC to high-density lipoprotein (HDL) ratio in the 4 g bitter melon treated group, highlighting the antiatherogenic risk of the plant [65]. The combination studies of M. charantia extract were studied with oral hypoglycemics metformin and glibenclamide. It was found that the combination of half doses of metformin and glibenclamide with M. charantia extract was more pronounced in lowering FBG and post-prandial glucose by 10%–21%, respectively, than full doses of metformin and glibenclamide without extract underscoring the augmented hypoglycemic effect of M. charantia with various anti-diabetic drugs [66].

In the context of treating cardiovascular complications of diabetes and obesity, M. charantia extract was found to reduce LDL levels significantly even in healthy personal mostly attributed to its fiber content, which was confirmed by normal HDL and TG levels. Even at low doses of 300 mg/day, it was effective but the small sample size may warrant for additional studies [67]. Another study focused on polyethylene glycol (PEG) microspheres laded with M. charantia demonstrated that it reduced the viscosity of blood in hyperglycemic patients. In individuals with diabetes, blood viscosity is often elevated, potentially increasing the risk of cardiovascular complications and microvascular damage. While PEGylation itself cannot lower blood viscosity, the M. charantia fraction may exert these effects via insulin mimetic or anti-oxidant potential [68] (Table 2).

Table 2. Clinical trials of M. charantia and its phytoconstituents.

Sr. No.	Number of participants	Period of study	Trial design and treatment mode	Outcomes	Reference to study
1	142 T2DM patients	3 months	Group 1—Placebo control Group 2—300 mg bitter melon powder capsules containing 300 ppm mcIRBP-19 peptide given twice a day before meals.	↓FBG ↓HbA1c ↓TG ↓BUN	[64]
2	15 T2DM patients	2 weeks	Group 1—0.5 g metformin Group 2—5 mg glibenclamide Group 3—0.5 g metformin + 5 mg glibenclamide. Studied for 1 week and the dose was reduced to half and combined with 200 mg M. charantia extract	↓FBG and post prandial glucose were reduced more with M. charantia extract combination at half dose of oral hypoglycemic	[65]
3	95 T2DM patients	2 weeks	Group 1—Bitter melon powder 2 g/day Group 2—Bitter melon powder 4 g/day Group 3—Glibenclamide 2.5 mg/day	↓FBG but lower than glibenclamide ↓TC/HDL ratio was more significant than glibenclamide ↓Systolic blood pressure	[66]
4	47 Healthy Adults	30 days	Group 1—Placebo control Group 2—300 mg/day bitter melon extract divided into three doses	↓LDL No changes in HDL and TG	[67]
5	56 Normoglycemic and 26 Hyperglycemic volunteers	_	Blood from both groups was incubated with PEG-M. charantia microspheres at 37⁰C for 30 minutes	↓blood viscosity	[68]

**4.2. Barberry (Berberis vulgaris)**

4.2.1. Mechanism of action

Barberries are the fruits of B. vulgaris which have a long-standing role in the treatment of various cardiovascular disorders. It is rich in flavonoids, lignans, coumarins, and terpenes that play a role in providing anti-oxidant and anti-inflammatory effects but its true value lies in its alkaloids namely the Isoquinoline class which includes berberine, berbamine, palmatine, and jatrorrhizine [97]. Polyphenols in barberry have potent anti-oxidant activity to prevent lipid peroxidation in CMD as well as some Angiotensin-converting enzyme inhibitory activity to lower hypertension [98].

Berberine is the most sought-after candidate for this species. It can effectively activate the AMPK pathway, leading to improved glucose control and reduced lipid accumulation [99]. Moreover, it can non-competitively inhibit α-amylase and competitively inhibit α-glucosidase to prevent absorption of glucose from the brush border epithelium of the intestine [100]. Finally, it prevents hepatic gluconeogenesis, a feature attributed to the inhibition of PEPCK and G6Pase [101] which when coupled with decreased expression of PPAR-Υ and SREBP prevents adipocyte differentiation and results in weight loss thereby averting obesity and its complications [102].

Palmatine and Jatrorrhizine were also effective by similar mechanisms. They caused increased metabolism in adipocytes by epigenetic modulation downregulating FAS and preventing cholesterol synthesis and absorption. Jatrorrhizine showed the most potent epigenetic regulation than the other two alkaloids and had more pronounced effects in treating hyperlipidemia [103,104].

Beyond its effects on metabolism, berberine demonstrates potential in heart health. It inhibits potassium channels and elevates calcium levels, positioning itself as a treatment candidate for heart failure [105]. Berberine also exhibits noteworthy anti-arrhythmic and anti-platelet aggregation activities, emphasizing its broad therapeutic potential in cardiovascular conditions [111, 112].

4.2.2. Pre-clinical studies

Berberine demonstrated a significant reduction in FBG levels in diabetic rats, though its efficacy was lower than that of the reference drug, glibenclamide. Additionally, the combination of berberine and glibenclamide exhibited limited synergistic effects in lowering FBG than stand-alone; however, it contributed to enhanced antioxidant activity by increasing the expression of SOD and CAT [69]. At higher doses (above 100–200 mg/kg b.w.), berberine effectively reduced inflammation by inhibiting Toll-like receptor 4 (TLR4) and NF-kB signaling in podocytes, thereby playing a protective role in mitigating the progression of diabetic nephropathy [70]. These anti-oxidant and anti-inflammatory effects of berberine can also help to prevent early apoptosis in Muller cells (retinal glial cells) to prevent diabetic retinopathy [71].

Berberine suffers from low bioavailability which often limits its potential to treat metabolic syndrome. Wang et al. [72] prepared a co-crystal of berberine-ibuprofen which demonstrated potentiated effects such as improved fat metabolism and decreased insulin resistance leading to weight loss in db/db mice. Moreover, it inhibits Nf-kB more strongly than berberine alone reducing pro-inflammatory cytokines and low-grade inflammation [72].

In the realm of non-alcoholic fatty liver disease (NAFLD), berberine was found to inhibit microsomal triglyceride transfer protein (MTTP) and LDL receptor expression which lowered the lipid accumulation in the liver as demonstrated by reduced aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. This also results in significantly reducing the levels of TC, TG, and LDL [73] (Table 3).

Table 3. Pre-clinical trials of B. vulgaris and its phytoconstituents.

Sr. No.	Animal model	Period of study	Study design and method	Outcomes	Reference to study
1	STZ-induced ICR diabetic rats	2 weeks	Group 1—Control rats Group 2—Glibenclamide treated 10 mg/kg Group 3—Berberine treated 100 mg/kg Group 4—Glibenclamide 10 mg/kg and Berberine treated 100 mg/kg	↑SOD and CAT ↓FBG in groups 2-4	[69]
2	STZ-induced Sprague-Dawley rats	8 weeks	Group 1—Normal control Group 2—Diabetic control Group 3—50 mg/kg b.w. Berberine. Group 4—100 mg/kg b.w. Berberine. Group 5—200 mg/kg b.w. Berberine.	↓FBG ↓creatine and BUN ↓IL-1β, IL-6, and MCP-1	[70]
3	STZ-induced Sprague-Dawley rats	8 weeks	Group 1—Diabetic control Group 2—100 mg/kg b.w. Berberine. Group 3—200 mg/kg b.w. Berberine.	↓Apoptosis of Muller cells. ↑SOD and CAT ↓Nf-kB signaling	[71]
4	db/db mouse	5 weeks	Group 1—Normal control. Group 2—150 mg/kg b.w. Berberine Group 3—75 mg/kg b.w. Berberine-ibuprofen co-crystals Group 4—150 g/kg b.w. Berberine-ibuprofen co-crystals	↓FBG ↓TG ↓LDL ↑HDL ↓TNFα, IL-6 and MCP-1	[72]
5	Sprague-Dawley rats	8 weeks	Group 1—NFD rats Group 2—HFD rats Group 3—HFD + vehicle-treated Group 4—HFD + 100 mg/kg b.w. berberine	↓TC ↓TG ↓LDL ↓AST and ALT ↓MTTP and LDL receptors	[73]

4.3. Clinical studies

Berberine is as effective in increasing insulin receptor expression when compared to hypoglycemic drugs such as metformin and rosiglitazone which results in a reduction of FBG. When compared to these two drugs it was more effective in lowering TG and TC levels in hyperlipidemia. When combined with metformin, the FBG and HbA1c levels decreased further than monotherapy and LDL levels were also significantly lower than baseline [117,118].

While studying the lipid-lowering effects of berberine, Zhao et al. [73] reported that berberine effectively lowered TC and LDL levels while it increased testosterone levels in men. Significant levels of testosterone are associated with a lower risk of CMD. This study however doesn’t fully represent the anti-atherogenic effects of berberine namely as the subject selection didn’t include patients of T2DM or known cardiovascular disorders and secondly didn’t consider women in the study and their hormonal interactions [74]. Kong et al. [75] combined berberine with Simvastin—an HMG-CoA reductase inhibitor; the anti-lipid profile included the reduction of LDL and TG; the latter being reduced due to upregulation of hepatic LDL receptors. It also showed to decrease fat accumulation and risk of steatohepatitis [75].

Yan et al. [76] conducted a multicentre parallel randomized control trial of berberine for NAFLD. Berberine along with lifestyle improvement was found to be more effective than lifestyle modification alone and pioglitazone treatment. It lowered liver fat content and systemic levels of TC, TG, and LDL while significantly lowering the FBG. Though the exact mechanism is not fully elucidated, epigenetic modulation in lowering MTTP and LDL receptors is often given the credit [76] (Table 4).

Table 4. Clinical trials of B. vulgaris and its phytoconstituents.

Sr. No.	Number of participants	Period of study	Trial design and treatment mode	Outcomes	Reference to study
1	97 T2DM patients	2 months	Group 1—1 g Berberine per day Group 2—1.5 g Metformin per day. Group 3—4 mg rosiglitazone per day	↑insulin receptors ↓FBG ↓TG	[72]
2	84 T2DM patients	3 months	Group 1—500 mg berberine/3 times a day Group 2—500 mg metformin/3 times a day Group 3—500 mg berberine/3 times a day + continue original anti-diabetic therapy.	↓HbA1c ↓TC ↓LDL ↓insulin resistance	[73]
3	80 hyperlipidemic patients	12 weeks	Group 1—Berberine treated (500 mg twice/day) Group 2—Placebo treated (500 mg twice/day)	↓TC ↓LDL	[74]
4	63 hypercholesteremia patients	2 months	Group 1—1 g/day Berberine Group 2—20 mg/day simvastatin Group 3—combination of berberine and simvastatin.	↓TC ↓LDL ↑Testosterone	[75]
5	184 NAFLD patients	16 weeks	Group 1—lifestyle improvement. Group 2—15 mg/day pioglitazone + lifestyle improvement. Group 3—0.5 g/ 3 times a day before meals berberine + lifestyle improvement.	↓FBG ↓TC ↓TG ↓LDL ↓AST and ALT ↓Hepatic fat content	[76]

4.4. Brown algae (Phaeophyceae)

4.4.1. Mechanism of action

Marine ecosystems are a rich source of bioactive compounds, brown seaweeds such as Laminaria japonica and Undaria pinnatifida, stand out for their diverse therapeutic potential. Traditionally consumed for their nutritional value, they have recently drawn scientific attention to their role in metabolic health. The key phytoconstituents—fucoxanthin, fucoidans, phlorotannins, alginates, and bromophenols—work through multiple mechanisms to support glucose regulation, lipid metabolism, and inflammation control.

Fucoidan, a sulfated polysaccharide contributes to metabolic balance by preventing inflammation via the Nf-kB pathway and anti-oxidant potential protecting oxidative damage to β-cells, which in turn improves insulin secretion; fucoidans are also responsible for insulin-sensitizing actions due to activation of P13K/Akt pathway in cells [119].

Fucoxanthin, a carotenoid found in brown seaweeds, promotes fat metabolism by activating uncoupling protein-1 (UCP1) in white adipose tissue, shifting it toward a more energy-burning state. It also regulates AMPK and PPAR-γ, improving insulin sensitivity and reducing fat accumulation. By enhancing GLUT4 expression, fucoxanthin facilitates glucose uptake, helping to stabilize blood sugar levels [120,121].

Phlorotannins like eckol and dieckol, a unique class of polyphenols found in brown algae, support glycemic control by inhibiting α-glucosidase and α-amylase, enzymes involved in carbohydrate digestion [127]. This results in a slower release of glucose into the bloodstream, preventing rapid spikes in blood sugar. Phlorotannins also help regulate fat metabolism by downregulating SREBP-1c and FAS, genes involved in lipid synthesis [128].

Sterols also contribute to these metabolic effects. One such sterol majorly found in brown algae is fucosterol which by inhibition of pancreatic lipase is able to prevent breakdown and absorption of dietary fats [129]. It also is known to reduce lipid accumulation in adipocytes namely by PPARΥ and CEBPα downregulation [130]. Research also indicates the anti-diabetic potential of these sterols by improving insulin sensitivity by inhibiting PTP-1B expression [131].

4.4.2. Pre-clinical studies

The various phytoconstituent effects have been summarized here in general. Fucoidans were able to exert protective effects on the β islet cells effectively improving insulin production. The study also revealed the role of fucoidan in improving GLP-1 levels which improved insulin secretion via AMPK and Sirt expression [77].

Zhang et al. [78] studied the various pathways of fucoxanthin in diabetes while comparing its effects to metformin. Like metformin fucoxanthin was able to lower FBG levels while modulation insulin secretion in a dose-dependent fashion. Fucoxanthin supplementation also showed positive effects on the lipid profile such as lowering TG and TC levels while decreasing the body weight making it beneficial in obesity. Fucoxanthin was shown to act via a multitude of pathways including the inactivation of PEPCK and G6Pase in the liver and activating GSK3β to inhibit gluconeogenesis [78]. Sun et al. [79] studied the anti-inflammatory effects of fucoxanthin in treating obesity. While the decrease in lipid parameters was significant like the previous study, fucoxanthin supplementation resulted in a decreased incidence of hepatic steatosis. The main reason believed was the gut microbiome regulation by downregulating Firmicutes and upregulating Bacteroidetes. This helped to maintain a beneficial gut microbiome producing SCFA preventing intestinal inflammation and control of lipid parameters [79].

Phlorotannins from Sargassum linifolium were screened for their antidiabetic potential. The major effect was to reduce the oxidative stress resulting in the protection of the β-islet cells. Insulin sensitivity was improved via AMPK activation while the lipid levels of TG and TC were concurrently lowered [80]. Fucosterol was examined in diabetic control by Yeon Sil Lee et al. where it lowered the FBG and inhibited glycogenolysis in the liver. Hyperglycemia converts excessive glucose to sorbitol via the polyol pathway which is responsible for neuro and nephropathies in diabetes complications. When compared to the aldose reductase inhibitor epalrestat, it was shown to decrease the sorbitol levels significantly in the lenses which could turn out useful in diabetic retinopathy but the insignificant decrease in sorbitol accumulation in RBC and sciatic nerves warrants for more comprehensive studies for longer durations [81] (Table 5).

Table 5. Pre-clinical trials of various Brown algae and its phytoconstituents.

Sr. No.	Animal model	Period of study	Study design and method	Outcomes	Reference to study
1	C57BL/6 mice	6 weeks	Group 1—Normal control Group 2—Diabetic control Group 3—Diabetic group treated with 300 mg/kg b.w. fucoidan	↓FBG ↑insulin levels ↑GLP-1 activation ↑β-cell proliferation.	[77]
2	C57BL/KsJ-db/db mice	6 weeks	Group 1—Normal control Group 2—0.2%w/w fucoxanthin Group 3—0.4%w/w fucoxanthin Group 4—0.02% w/w Metformin	↓body weight ↓FBG ↑insulin sensitivity ↓TC and TG ↓gluconeogenesis	[78]
3	C57BL/6J mice	12 weeks	Group 1—NFD control Group 2—HFD control Group 3—HFD + 0.05%w/w fucoxanthin Group 4—HFD + 0.1%w/w fucoxanthin	↓body weight ↓LDL ↑HDL ↓ Firmicutes ↑Bacteroidetes	[79]
4	STZ-induced Wistar rats	4 weeks	Group 1—Normal untreated group. Group 2—Normal treated with 60 mg/kg b.w. phlorotannins Group 3—Diabetic untreated group. Group 4—Diabetic treated with 60 mg/kg b.w. phlorotannins	↓FBG ↓TC ↓TG ↑β-cell proliferation.	[80]
5	STZ-induced Sprague Dawley rats	1 day	Group 1—Normal control Group 2—Epalrestat 50 mg/kg b.w. Group 3—Fucosterol 30 mg/kg b.w.	↓FBG ↓glycogenolysis ↓sorbitol accumulation in lenses	[81]

4.4.3. Clinical studies

Kombu or Japanese kelp (Laminaria japonica) is one of the most emerging nutraceuticals in this category due to its rich source of carotenoids and polyphenols. Supplementation of kelp powder was shown to decrease the body fat percentage in Japanese obese men while in women it didn’t demonstrate significant results when compared to control due to strong hormonal regulation already contributing to lower fat percentages. However, kelp powder lowered the serum levels of TC namely LDL in both groups decreasing atherogenic risk [82]. A polyphenol-rich extract of Ascophyllum nodosum indicated a modest decrease in lymphocyte DNA damage in obese individuals. Plasma and urine analysis studies identified various metabolites of phlorotannins such as pyrogallols, phloroglucinols, and eckol derivatives highlighting their role in preventing oxidative DNA damage commonly linked with obesity [83].

Fucoxanthin administration in patients with metabolic syndrome demonstrated lower BMI and waist circumference levels. It also showed a positive impact in lowering hypertension often linked with these disorders and triglyceride levels. It also showed improved insulin secretion often linked to its β-islet protective activity [84]. When combined with low molecular weight fucoidans, fucoxanthin demonstrated excellent hepatoprotective activity mainly via reducing oxidative damage and cytokine-induced inflammation in hepatocytes. Enhanced leptin and adiponectin expression due to this combination results in better fat expenditure in adipocytes and decreased insulin resistance as demonstrated by lower FBG, TG, and TC levels [85]. Xanthigen, a combination of fucoxanthin and pomegranate seed oil was screened in NAFLD patients. 300 mg pomegranate seed oil + 2.4 mg fucoxanthin dose showed the most significant beneficial effects such as improving the resting state energy expenditure compared to placebo. The anti-oxidative and anti-inflammatory activities of both constituents showed improved synergistic activity to serve as hepatoprotective [86] (Table 6).

Table 6. Clinical trials of various brown algae and its phytoconstituents.

Sr. No,	Number of participants	Period of study	Trial design and treatment mode	Outcomes	Reference to study
1	48 overweight participants	8 weeks	Group 1—Placebo control Group 2—500 mg tablets containing kelp powder given 30 times a day.	↓BMI ↓body fat ↓LDL	[82]
2	80 overweight participants	24 weeks	Group 1—Placebo control Group 2—400 mg Seaweed polyphenol capsules	↑antioxidative activity ↓obesity-induced DNA damage	[83]
3	28 patients with metabolic syndrome	90 days	Group 1—Magnesium stearate capsules Group 2—12 mg fucoxanthin capsules before breakfast.	↑insulin secretion ↓TG ↓BP ↓BMI and waist circumference	[84]
4	42 NAFLD patients	24 weeks	Group 1—Placebo control Group 2—Treatment group (825 mg low molecular weight fucoidan + 825 mg fucoxanthin)	↓FBG ↓TC and TG ↑hepatocytes protection ↑leptin and adiponectin expression	[85]
5	113 non-diabetic NAFLD patients and 38 with normal fat liver	16 weeks	Divided into 11 groups with placebo control and increasing doses of fucoxanthin and pomegranate seed oil.	↓BMI and waist circumference ↓liver fat and enzyme activity ↑resting state energy expenditure	[86]

**5. BLACK CUMIN SEEDS/KALONJI (NIGELLA SATIVA)**

5.1. Mechanism of action

Nigella sativa, commonly known as Kalonji or black cumin, stands out due to its rich phytochemical profile. Traditionally valued in various healing systems, this tiny black seed harbors a powerful blend of bioactive compounds including terpenes such as thymoquinone (the major constituent), isoquinoline alkaloids like nigellidine and nigellimine, saponins, and polyphenols [135].

Thymoquinone (TQ) and its derivatives, thymohydroquinone and dithymoquinone, are powerful activators of the Nrf2 pathway, enhancing cellular antioxidant defenses by upregulating catalase and glutathione. This antioxidant boost plays a crucial role in mitigating oxidative stress and inflammation, key contributors to metabolic dysfunction. Additionally, these compounds effectively suppress the TLR4 signaling pathway, reducing pro-inflammatory cytokine production. This dual mechanism not only protects pancreatic β-cells, thereby enhancing insulin secretion but also helps regulate hepatic glucose metabolism by inhibiting gluconeogenesis. Furthermore, their activation of the AMPK pathway enhances insulin sensitivity and promotes glucose uptake in cells [136,137]. Moreover, it contributes to its anti-obesity effects by inhibiting adipocyte differentiation, lipid accumulation, and downregulating PPARΥ [138]. Enomoto et al. [139] analyzed the methanolic portion of N. sativa which revealed various terpenes such as 2-(2-methoxypropyl)-5-methyl-1,4-benzenediol, thymol carvacrol which showed fibrinolytic activity comparable or higher that aspirin, a useful characteristic to treat thrombosis in CMDs [139].

Nigella sativa also contains triterpenoid saponins hederagenin, and α -hederin, which have a beneficial role in preventing autophagy in cancer cells. Recently it has also been noted that these saponins can upregulate UCP-1 expression via PPAR-Υ modulation to promote thermogenesis and browning in 3T3L1 adipocytes [140]. Nigella sativa oil is now regarded as a functional oil due to its high contents of omega 3 polyunsaturated fatty acids (PUFA) such as linoleic acids and a few others in marginal quantities. These PUFAs are often linked to lower insulin resistance and LDL and TG levels preventing arteriosclerosis risk [141,142].

5.1.1. Pre-clinical studies

The effects of N. sativa have been compared to standard metformin treatment. It was found that 0.5 ml/kg N. sativa oil was more effective than its aqueous extract and metformin treatments in reducing FBG and HbA1c levels as well as lipid profiles of TG, TC, and LDL [87]. Ayaz et al. [88] reported that N. sativa oil was more of a nephroprotective than vitamin E and metformin supplementation as shown by the lower BUN levels. N. sativa oil downregulated apoptotic proteins like Bax, caspase-3, and caspase-9 while upregulating anti-apoptotic Bcl-2 indicating its role in preventing diabetic nephropathy complications [88]. Esmail et al. [89] studied the effects of three drugs namely atorvastatin, L-carnitine, and N. sativa oil in reducing hepatic-induced injury in NAFLD. Both N. sativa and L-carnitine decreased body weight reducing visceral fat deposition. Histopathological analysis of the liver highlighted that N. sativa was able to prevent hepatic injury better than atorvastatin possibly via the anti-inflammatory and anti-oxidant activities often attributed to thymoquinone. This could open the doors for a combination of N. sativa and L-carnitine in the future for the treatment of NAFLD [89].

Thymoquinone supplementation effectively ameliorated diabesity parameters in HFD rats. It is shown that it reduced C/EBP-α and SREBP expression similar to orlistat (an anti-hyperlipidemic drug as pancreatic lipase inhibitor) reducing fat accumulation and body weight. This is often associated with reduced FBG and improved AMPK signaling. The plasma lipid profile was also lower than the orlistat treatment group [90]. Thymoquinone often suffers from low bioavailability limiting its effects. Rani et al. [91] prepared various doses of thymoquinone-nanocapsules and compared it with metformin-nanocapsules. The drug release profile of thymoquinone was greatly increased due to increased solubility and permeability. When compared to metformin-nanocapsules it was equivalent to reducing FBG but had a more pronounced effect than the latter to decrease levels of C, TG, and LDL while significantly increasing HDL cholesterol [91] (Table 7).

Table 7. Pre-clinical trials of N. sativa and its phytoconstituents.

Sr. No.	Animal model	Period of study	Study design and method	Outcomes	Reference to study
1	STZ-induced Albino rats	2 months	Group 1—Normal control Group 2—Diabetic control Group 3—Diabetic rats + Metformin 8.5 mg/kg IP Group 4—Diabetic rats + N. sativa oil 0.5 ml/kg IP Group 5—Diabetic rats + Aqueous extract of N. sativa 3 mL/kg IP	↓FBG ↓HbA1c ↓TG ↓LDL ↓TC	[87]
2	Wistar Albino rats	8 weeks	Group 1—Normal control Group 2—Diabetic control Group 3—Diabetic rats + Metformin 100 mg/kg b.w. Group 4—Diabetic rats + Vitamin E 100 mg/kg b.w. Group 5—Diabetic rats + N. sativa oil 2.5 ml/kg	↓Blood urea nitrogen ↓Bax ↓caspase-9 ↑Bcl-2	[88]
3	Male Wistar rats	12 weeks	Group 1—Normal control Group 2—HFD control Group 3—HFD + –N. sativa oil-treated diabetic group Group 4—HFD + atorvastatin treated Group 5—HFD + L-carnitine treated	↓body weight ↓hepatic steatosis and hepatic injury	[89]
4	Sprague Dawley rats	18 weeks	Group 1—NFD rats Group 2—HFD control Group 3—HFD + 20 mg/kg b.w. thymoquinone Group 4—HFD + 40 mg/kg b.w. thymoquinone Group 5—HFD + 5 mg/kg b.w. orlistat	↓FBG ↑AMPK ↓body weight ↓SREBP ↓ C/EBP-α ↓ TC, TG, and LDL	[90]
5	Wistar rats	21 days	Group 1—Normal control Group 2—Diabetic control Group 3—Metformin 150 mg/kg Group 4—Metformin nanocapsules 80 g/kg Groups 5–7—Thymoquinone (20, 40, and 80 mg/kg) Groups 8–10— Thymoquinone nanocapsules (20, 40, and 80 mg/kg) Group 11—Empty nanocapsules shells	↑bioavailability ↓FBG ↓LDL ↓TG ↓TC ↑HDL	[91]

5.1.2. Clinical studies

Limited clinical studies have been conducted on N. sativa for diabetes and obesity but the current trials demonstrate the potential of this plant. In comparison with lifestyle modification and metformin treatment in pre-diabetic patients N. sativa was statistically equivalent to metformin in lowering the FBG levels and improving the Sirt-1 expression leading to improved insulin secretion. The lipid profile of only N. sativa was found to be significant than the other two groups lowering TG, TC, and LDL while also significantly elevation HDL [92]. Ansari et al. [93] studied the effects of N. sativa oil supplementation in chronic kidney disease patients in comparison with conservative management treatment (insulin, torsemide, telmisartan, iron, calcium, vitamin D3, and erythropoietin). Nigella sativa significantly decreased FBG and BUN nitrogen levels. Compared to control, it also improved the GFR and urine output levels and maintained serum electrolytes of Na⁺, K⁺, and Ca²⁺ at normal physiological levels [93]. Seyed-Ali Khodaie et al. [94] studied the effects of N. sativa ointment on treating peripheral neuropathy. After receiving the treatments, the patients were asked to fill out a michigan neuropathy screening instrument questionnaire to assess their pain. The results revealed a greater relief in the N. sativa group than in gabapentin to alleviate the symptoms of leg cramps, skin prickling, foot numbness, and pain during walking. While the study showed effects in alleviating symptoms, the study still requires further investigations into the mechanisms and biochemical parameter changes to explain the effects [94].

Razmpoosh et al. [95] conducted two separate clinical trials to demonstrate the cardio-beneficial properties of N. sativa in overweight and obese women. Nigella sativa significantly lowered leptin LDL, TC, and TG levels, reducing lipid accumulation and improving cardiovascular health. Additionally, it downregulated pro-inflammatory cytokines IL-6 and IL-1β, mitigating systemic inflammation and endothelial dysfunction. The reduction in systolic BP further contributed to cardiovascular protection, alleviating hypertension-related risks. These findings highlight the potential of N. sativa in promoting heart health through lipid regulation, anti-inflammatory effects, and blood pressure control [95,96] (Table 8).

Table 8. Clinical trials of N. sativa and its phytoconstituents.

Sr. No.	Number of participants	Period of study	Trial design and treatment mode	Outcomes	Reference to study
1	117 pre-diabetic patients	6 months	Group 1—Lifestyle modification. Group 2—Metformin 500 mg twice a day. Group 3—N. sativa oil 450- mg capsule twice a day.	↓FBG ↓TC, TG, and LDL ↑HDL ↑SIRT expression	[92]
2	63 chronic kidney disease patients in stages 3 and 4	12 weeks	Group 1—Conservative treatment Group 2—Conservative treatment + N. sativa oil 2.5 ml/day	↓FBG ↓BUN ↑GFR and urine output Normal physiological ion concentrations	[93]
3	120 neuropathic patients	8 weeks	Group 1—Placebo control Group 2—N. sativa ointment 10%w/w Group 3—300 mg gabapentin	↓pain, numbness, and alternate sensations.	[94]
4	46 overweight or obese women	8 weeks	Group 1—Placebo control. Group 2—2000 mg N. sativa/day	↓TC, TG, and LDL ↓leptin ↓IL-1β ↓IL-6	[95]
5	39 overweight or obese women	8 weeks	Group 1—Placebo control. Group 2—2000 mg N. sativa/day	↓TC, TG, and LDL ↓Systolic BP	[96]

6. HOLY BASIL (OCIMUM SANCTUM)

6.1. Mechanism of action

Ocimum sanctum, also known as Holy Basil is regarded as the Queen of Herbs with anti-inflammatory, antidiabetic, antimicrobial, hepatoprotective, radioprotective, neuroprotective, anticancer, and notably, mosquito repellent properties, being some of its many roles. Its leaves contain various phytoconstituents including but not limited to eugenol, caryophyllene, ursolic acid, rosmarinic acid, and flavonoids. Due to its antioxidant nature, an extract of O. sanctum helps to increase the insulin sensitivity in pancreatic cells [143]. Even though its exact mechanism is still unclear, the antiglycemic effect of O. sanctum can be attributed to its role in the stimulation of pancreatic beta cells by modification of the passage of intracellular calcium. Eugenol present as 67%–73% of the composition of the leaf constitutes to be a major component showing alpha-glucosidase inhibition activity. It prevents the glucose moiety in the body from binding to serum albumin protein. A supporting action in diabetes management is its antioxidant character as it upregulates enzymes such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase in addition to being a potent free radical scavenger [144].

Orientin and vicenin are two flavonoids in Holy Basil, beneficial as antioxidants, using the same mechanism of targeting harmful free radicals and providing cellular defense against radiation. As a cell protectant, it acts on human erythrocytes in a dose-dependent manner to prevent oxidative stress-induced damage. Its function as an antioxidant allows a broad application in diseases such as colon cancer by peroxidation and neutralization of the carcinogen dimethyl hydrazine. Orientin has a vast unexplored potential in neuroprotection owing to its antioxidant, anti-inflammatory, and radioprotective properties. It has shown significant improvement in trials against neurodegeneration-associated pain, by inhibition of interleukins 1 and 6 and also shows an effect on various pathways such as TLR-4 and NF-KB [145]. Ocimum sanctum can be made into various formulations in order to improve the bioavailability, and ease of administration, reduce chances of drug-herb or her-herb interaction, or for a targeted release mechanism. A lyophilized leaf powder of Tulsi produced a pronounced effect on the blood glucose levels, HbA1c, and other biochemical parameters when compared with the control and glibenclamide-treated rats. The researchers concluded that the effect of O. sanctum may not be due to the action of a single phytocompound but in turn, a synergistic effect of multiple phytochemicals present either in a single plant or a structured combination of several herbal agents [146]. Silver nanoparticles of O. sanctum and Ocimum basilicum using its aqueous leaf extracts were tested in vitro for antidiabetic activity by Malapermal et al. [147] phytotherapy is preferred over synthetic alternatives, due to the outcome being similar to the chemical counterparts, but without the side effects. Both plants exhibit higher alpha-amylase inhibitory activity, paired with the technologically advanced nanoparticle delivery will aid in its faster transport across cell membranes and may exhibit a sustained effect in the body. Additionally, the green synthesis of a medicinally active phytocompound eliciting an euglycemic response paves a path for cheaper and more beneficial treatment options for hyperglycemia [147].

6.1.1. Pre-clinical studies

An extract of O. sanctum administered to alloxan-induced diabetic albino rats showed that it successfully reduced the peak glucose levels in glucose-fed hyperglycemic animals [148]. Streptozocin-induced type 1 type 2 diabetic rats with obesity and insulin resistance were tested for oral glucose resistance, gut motility and absorption, glucose uptake, disaccharide, and antioxidant activity after administration of O. sanctum by in situ perfusion. According to a study by Hannan et al. [106] preclinical trials of nicotinamide and streptozocin-induced diabetic rats showed a positive response to tulsi extract. Several comparative studies have been conducted to measure the effectiveness of allopathic medication in conjunction with traditional and herbal sources. The antidiabetic effect of OS on measuring rat cells for serum and glucose contents concluded that glucose secretion and insulin levels in 3T3-L1 cells were increased. This represents that OS can be successfully used in diabetes management as an adjunct to chemotherapy [106]. OS also contributes to antidyslipidemic effects in addition to hyperglycemia. To ascertain and quantify this, Suanarunsawat and Songsak [107] conducted a study where alteration of elevated blood glucose levels was observed after 3 weeks of treatment with OS. 2% white dietary O. sanctum was administered to STZ-induced diabetic rats. Serum triglyceride, total cholesterol, HDL-cholesterol, LDL-cholesterol, serum AST, serum ALT, and creatinine levels were examined. It normalized the lipid profile and creatinine, and reduced the elevated ALT and AST levels. The action of O. sanctum improves glucose regulation in type 2 diabetic rats by delaying carbohydrate digestion and enhancing insulin circulation in the body. OS supplementation either before or after diabetic induction can reverse dyslipidemia and glomerular filtration. Thus, pretreatment of subjects with white OS can be a therapeutic addition to antidiabetic treatment options [107]. Delayed wound healing is a common occurrence in diabetic patients, leading to oxidative stress and inefficient collagen synthesis. The wound healing capacity of diabetic rats was examined after administration of 400 mg/kg OS ethanolic extract. Antioxidant, free radical, inflammatory markers as well as serum blood glucose and cholesterol testing of granulated wound ulcer tissue was performed. Examination of wound ulcers of albino rats treated with OS not only reduced the blood glucose levels but also aided in wound healing. OS increased antioxidant activity and reduced inflammation and oxidative damage in order to enhance wound healing. OS promotes the formation of connective tissue and antioxidant action, concurrently decreasing blood glucose levels [108]. A combination therapy of traditional alternatives with drugs for diabetes has shown a lot of promise. OS is to be used synergistically with gliclazide poses to be an effective treatment option. A comparison of OS-supplemented alloxan-induced diabetic rats on gliclazide with rats on monotherapy of gliclazide or OS was conducted by Ramzan et al. [109] Biochemical and histopathological examination of pancreatic and liver tissues for anti-hyperglycemic effect was conducted for alloxan-induced diabetic rats. Assessment of blood glucose levels, lipid profile, and tissue contents showed a marked improvement in insulin secretion and islet cells. The antioxidant activity of OS in conjunction with gliclazide was effective in ameliorating oxidative stress-mediated damage to the liver. Use of OS as an adjunct to first-line gliclazide achieved sustained hypoglycemic effect [109]. Ocimum sanctum extract was administered at 200 mg/kg for the diabetic group to examine immunohistochemical and structural changes in the kidneys. Assessing the effect of OS on the liver pathology led to an enhanced understanding of the role of inflammatory cytokines in diabetic patients. This is one of the leading causes of diabetic nephropathy, with various levels of OS being deposited at particular junctures in the kidney as time progressed. OS reduced kidney damage that normally occurs in diabetic rats, showing an influence on IL-1B secretion. IL-1B levels were lower in the OS-treated group as compared to the diabetic group, affirming its involvement as an anti-diabetic agent [110] (Table 9).

Table 9. Pre-clinical trials of O. sanctum and its phytoconstituents.

Sr. No.	Animal model	Period of study	Study design and method	Outcomes	Reference to study
1	Male Long-Evans rats (14 weeks old, weighing180–220 g)	28 days	Group 1—Placebo control Group 2—Type-1 diabetes-induced rats Group 3—Type-2 diabetes-induced rats	↑glucose transport ↓Intestinal disaccharide activity ↓glucose absorption ↑Total antioxidant status ↓Fasting serum glucose	[106]
2	Male Wistar rats weighing between 180 and220 g	6 weeks	Group 1—Placebo control Group 2—2% dietary OS Group 3—2% dietary OS before induction of experiment	↓blood glucose on pretreatment ↓elevated AST and ALT	[107]
3	Inbred Charles-Foster albino rats (160–180 g) and Swiss albino mice (20–25	10 days	Group 1—Diabetic rats	↑collagen turnover and stabilization ↑breaking strength of healed wounds ↓blood glucose ↓cholesterol ↑wet tissue weight ↑protein per gram tissue ↓triglycerides	[108]
4	Forty-two male Wistar rats of body weight 170–200 g	21 days	Group 1—(NC) normal saline for placebo Group 2—OSE given to healthy rats (N+OSE) Group 3—(DC) normal saline to diabetic rats Group 4—(D+G) gliclazide to diabetic rats Group 5—(D+OSE) OSE to diabetic rats Group 6—(D+G+OSE) OSE and gliclazide to diabetic rats	↑body weight ↑glucose metabolism in the liver ↓lipids and triglycerides ↑ serum glucose and HbA1c ↓bilirubin ↓elevated AST and ALT ↓oxidative stressors ↓tissue necrosis ↑ pancreatic islet, liver, and regenerating cells	[109]
5	40 male rats, aged 4 to 5 months weighing 200–300 g	14 days	Group 1—control Group 2—Sham group Group 3—OS to healthy rats Group 4—diabetes-induced rats Group 5—OS to diabetic rats	↓IL-1B immunoreactivity ↑ blood glucose ↓degeneration of kidney tissue	[110]

6.1.2. Clinical studies

Ocimum sanctum acted as a successful adjuvant when administered with oral hypoglycemic agents by reducing the safety profile of the treatment. The incidence of hypoglycemic episodes in the test group receiving the combination therapy was significantly lower than that in the control group. This affirms that O. sanctum shows synergistic effects when administered with prescription medication when recommended to a moderately diabetic patient [149]. A study was carried out to ascertain the efficacy of OS in addition to glibenclamide as an anti-hyperglycemic agent. Glibenclamide is a sulfonylurea which stimulates the release of insulin from the pancreas. When administered in conjunction with OS 250 mg capsule to a diabetic patient, lowered the HBA1c levels in both fasting and post-prandial testing as compared to glibenclamide alone. Haemoglobin and fasting blood glucose showed better and long-term control of glycemic levels in patients. Significant prolonged glycemic control during the study as well as during follow-up checks proves this combination therapy to show fewer hypoglycemic cases and sustained control over diabetes [113]. A study by Satapathy et al. [114] tackles the obesity epidemic by proposing the inclusion of Tulsi capsules twice a day for overweight patients. A randomized, parallel-group, open-label pilot study was designed for obese subjects to evaluate the role of O. sanctum. Twice daily supplementation of OS capsules led to significant improvement in body weight, BMI, plasma insulin levels, and other biochemical parameters. Thus, O. sanctum stands to be an easily available, cost-effective, and beneficial constituent for obesity treatment, with lowered side effects [114]. The effect of several medicinal aqueous extracts including Ocimum sanctum was studied to assess its antihyperlipidemic and anti-diabetic effect on diabetic patients in Bengal. An aqueous extract of tulsi lowered not only the total cholesterol and LDL but also significantly increased the HDL levels in the patients of rural Bengal, exhibiting excellent anti-diabetic and hypolipidemic effects. Thus, OS significantly reduced both glycemic and lipidemic levels in the patients [115]. Kochhar et al. [116] studied the effect of tulsi and neem, as monotherapy and in combination to alleviate diabetic symptoms and blood pressure in non-insulin dependent males who were diagnosed with diabetes. The study findings included positive markers where diabetic symptoms such as polydypdia, polyphagia, tiredness, frequent urination were significantly reduced in all treated groups. Blood pressure reduction and diabetic symptoms observed and reported by the patient indicated a positive change after neem and tulsi supplementation [116] (Table 10).

Table 10. Clinical trials of O. sanctum and its phytoconstituents.

Sr. No.	Number of participants	Period of study	Trial design and treatment mode	Outcomes	Reference to study
1	60 patients with T2DM	90 days	Group 1—glibenclamide administered to diabetic patients Group 2—glibenclamide with OS treatment for diabetic patients	↓fasting blood sugar ↓post prandial mean blood glucose level ↓HbA1c ↓hypoglycemic episodes	[113]
2	30 over-weight participants (BMI > 2) Age group - 17–30 years	8 weeks	Group 1—250 mg tulsi extract capsule Group 2—no intervention	↑HDL-C ↓lipids and triglycerides ↓BMI ↓plasma insulin	[114]
3	20 type 2 diabetic patients	2 months	Group 1—Tulsi aqueous extract Group 2—control	↑HDL-C ↓fasting blood sugar ↓total cholesterol ↓LDL	[115]
4	90 non-insulin dependent male diabetic subjects in the age group of 40–60 years	3 months	Group 1—Tulsi powder Group 2—neem powder Group 3—mixture of tulsi and neem powder in a capsule form	↓blood pressure ↓diabetic symptoms	[116]

6.2. Curry leaves (Murraya koenigii)

6.2.1. Mechanism of action

This medicinal herb functions as an antidiabetic agent by facilitating the uptake and breakdown by cells when either glycogenesis increases or gluconeogenesis/glycogenolysis is reduced. Murraya koenigii contains carbazole alkaloid, which has proven anti-hyperglycemic and anti-hyperlipidemic activity [122]. Another study by Dineshkumat et al. [115] has isolated the carbazole alkaloid, called mahanimbine, responsible for the antioxidant activity and pancreatic beta-cell protective activity, exhibiting a therapeutic benefit for a diabetic body. Additionally, it showcases a free radical scavenging activity which is essential in regulating insulin levels and preventing insulin resistance in the body.

6.2.2. Pre-clinical trials

In an effort to understand the effect of M. koenigii on histopathological and biochemical changes in the kidneys and pancreas of diabetic rats, a study was conducted in Malaysia by Al-Ani et al. [122] The pathological changes in pancreatic islet cells and kidneys of diabetic rats were reversed after treatment with MK extract. Aqueous extract of MK led to a dose-independent fall in glucose levels, and improvement in islet morphology associated with an increase in body weight. It was responsible for a significant lowering in the blood glucose levels in treated rats as compared to the control group. This therapy displayed hypoglycemic as well as hepatoprotective effects [122]. Comparison of the effect of Murraya koenigii on STZ-induced diabetic rats with a well-known glibenclamide treatment for hyperglycemia showed a decrease in blood glucose and an increase in blood insulin levels by MK. This can be attributed to the improved action of the beta cells of islets of Langerhans to release insulin. Administration of an aqueous extract of curry leaves to STZ-induced diabetic rats showed a better response than the glibenclamide-tested group. It also showed a positive effect on levels of hemoglobin which usually decrease in a diabetic patient. The antihyperglycemic property of MK has also resulted in enhancing the levels of a protein related to a decrease in proteolysis and an increase in protein synthesis due to an increase in insulin levels. Creatinine, uric acid levels, and other metabolic factors affecting kidney function were reported to be high in diabetic rats, which were lowered after the administration of the extract. Thus, MK has shown an all-round enhanced activity as a diabetogenic agent [123]. Diabetes-induced rabbits were tested for blood glucose levels after administration of tolbutamide and MK extract in respective groups for comparison of the effect of M. koenigii on alloxan-induced diabetic rabbits for hyperglycemia. The aqueous extract of MK showed a marked lowering of blood sugar levels in just 4 hours, with a 300 mg/kg dose showing a response identical to the drug tolbutamide, and holds promise in its role as an anti-diabetic agent. Thus, MK is an effective and promising diabetogenic agent, which can be recommended as an adjunct dietary therapy for the treatment of hyperglycemia [124]. Mahanimbine is a carbazole alkaloid, especially found in M. koenigii plant leaves. Estimation of biochemical parameters for the antihyperglycemic role of mahanimbine obtained from MK leaves was performed by Dineshkumar et al. Pre-treatment and post-treatment blood samples were compared, where the effect of mahanimbine showed significantly lowered fasting blood glucose, triglycerides, LDL, and total cholesterol. Delayed degradation of complex carbohydrates by inhibition of alpha-amylase and alpha-glucosidase activity is an avenue for managing post-prandial hyperglycemia is exhibited by mahanimbine. Mahanimbine extract can be used in individuals with an imbalanced lipid profile and cardiovascular complications, who are diabetic patients due to its antihyperglycemic and antihyperlipidemic properties [125]. Bhupatiraju et al. [126] conducted a trial for the evaluation of behavioral and biochemical parameters of diabetes-induced cognitive disability models of rats on the administration of M. koenigii. Improved memory and learning in diabetic rats as well as spontaneous motor activity indicates a nootropic effect due to the interaction of various phytoconstituents such as flavonoids, anthocyanin glycosides, triterpenoids, and phytosterols. A 400 mg/kg dose of MK extract exhibited a comparative effect with the synthetic complex donepezil, and thus can be utilized as a potent adjuvant in the treatment of neurodegenerative diseases in a diabetic patient. A concurrent increase in body weight of the animal in all studies on administration of a hypoglycemic agent follows the mechanism which enhances glucose metabolism. Long term chronic use of MK ethanolic extract may play a role in preventing cognitive decline and reducing oxidative damage in the diabetic nervous system [126] (Table 11).

Table 11. Clinical trials of M. koenigii and its phytoconstituents.

Sr. No.	Animal model	Period of study	Study design and method	Outcomes	Reference to study
1	Thirty healthy adult male Sprague Dawley rats	30 days	Group 1—(NC1) control Group 2—(NC2) 400 mg/kg MK Group 3—(DC) diabetic control Group 4—(MK-200) 200 mg/kg MK Group 5—(MK-400) 400 mg/kg MK	↑islet cell histology ↑reversal of body weight loss ↓blood glucose ↓oxidative stress ↑ renal function	[122]
2	Male albino Wistar rats weighing about 160–180 g	30 days	Group 1—control Group 2—diabetic control Group 3—200 mg/kg MK to diabetic rats Group 4—glibenclamide to diabetic rats	↑protein levels ↓blood glucose ↓ blood urea, uric acid, and creatinine ↑Body weight ↑ insulin level	[123]
3	Male Albino rabbits Weight - 1.00–1.5 kg	6 hours	Group 1—control Group 2—diabetic control Group 3—200 mg/kg MK to diabetic rats Group 4—300 mg/kg MK to diabetic rats Group 5—400 mg/kg MK to diabetic rats Group 6—tolbutamide to diabetic rats	↑glucose tolerance ↓blood glucose	[124]
4	Adult male Wistar Rats (weighing 150–200 g)	30 days	Group 1—control Group 2—diabetic control Group 3—50 mg/kg mahanimbine to diabetic rats Group 4—100 mg/kg mahanimbine to diabetic rats Group 5—0.50 mg/kg glibenclamide to diabetic rats	↑potentiation of insulin ↓fasting blood sugar ↓lipid profile ↓poat prandial hyperglycemia ↑ alpha-amylase and alpha-glucosidase inhibition	[125]
5	Adult Wistar Albino rats weight - 150–250 grams	30 days	Group 1—control Group 2—diabetic control Group 3—donepezil to diabetic rats Group 4—200 mg/kg ethanolic extract of MK to diabetic rats Group 5—400 mg/kg ethanolic extract of MK to diabetic rats Group 6—200 mg/kg aqueous extract of MK to diabetic rats Group 6—400 mg/kg aqueous extract of MK to diabetic rats	↑memory and learning ↓fasting blood sugar ↓lipid profile ↓oxidative injury ↑spontaneous motor activity	[126]

6.3. Clinical trials

A controlled randomized trial to determine the therapeutic potential of the capsule of curry leaf extract in the regulation of blood glucose levels and HbA1c in diabetic patients focusing on the female diabetic population showed a consistent result as that of previous animal trials taken place, with a significant improvement in HbA1c levels followed by random blood sugar levels and fasting blood sugar levels. The study also measured the high magnesium content in the curry leaves, which may have made a contribution to regulating insulin function. The results denoted a long-term decrease in HbA1c levels and reduced elevated fasting glucose levels [132]. Curry leaves being a natural source of carbazole alkaloids, pose to be a highly helpful alternative to allopathic medicines which cause complications in later stages due to damage to kidneys and liver. In this study, on observing the blood sugar among diabetic patients before and after their treatment with curry leaves powder, it was concluded that consumption of curry leaves has successfully reduced the blood sugar levels without any side effects [134]. Jadhav and Dhudum [133] assessed fasting blood sugar and post-prandial blood sugar in diabetic patients by treating them with 12 g of curry leaves powder. Descriptive and inferential statistics determined a significant difference in the average levels of sugar before and after the administration of MK powder [133] (Table 12).

Table 12. Clinical trials of M. koenigii and its phytoconstituents.

Sr. No

Number of participants

Period of study

Trial design and treatment mode

Outcomes

Reference to study

45 women

45 days

Group 1—control

Group 2—curry leaves extract 5 mg/kg

Group 3—curry leaves extract 10 mg/kg

↓fasting blood sugar

↓random blood sugar level

↓HbA1c levels

[132]

60 patients

20 days

Group 1—control

Group 2—curry leaves extract 5 mg/kg

Group 3—curry leaves extract 10 mg/kg

↓fasting blood sugar

↓Post-prandial blood sugar

[133]

70 patients

30 days

Group 1—diabetic control

Group 2—curry leaves powder for diabetic patients

↓post prandial sugar level

[134]

7. FUTURE PROSPECTIVES

Regulatory challenges, quality control, and standardization are critical hurdles in the clinical adoption of medicinal plant formulations. The variability in bioactive compound composition due to differences in plant species, geographical location, harvesting conditions, and extraction methods complicates standardization [150]. Regulatory bodies such as the FDA and EMA require stringent quality assurance, including batch-to-batch consistency, stability, and safety evaluations, yet the lack of globally harmonized guidelines leads to discrepancies in approval processes across regions. Additionally, the presence of contaminants, adulterants, and variable potency necessitates robust analytical techniques, such as high-performance liquid chromatography and mass spectrometry, to ensure quality control [151]. Establishing pharmacopeial standards and good manufacturing practices for herbal medicines is essential to enhance their reliability, safety, and therapeutic efficacy, ultimately facilitating their integration into mainstream healthcare [152].

Combining phytochemicals with conventional anti-diabetic and anti-obesity drugs offers a multi-targeted approach that enhances therapeutic efficacy, enables dose reduction, and minimizes side effects. Preclinical and clinical studies have demonstrated significant benefits, including the ability of M. charantia to reduce the required dosage of hypoglycemic agents, to synergistic combinations of phytoconstituents, such as thymoquinone and L-carnitine, in NAFLD. Beyond these examples, bioactive compounds such as berberine, fucoxanthin, and polyphenols have been reported to improve insulin sensitivity, regulate lipid metabolism, and exert anti-inflammatory effects when combined with standard pharmacotherapies, offering a more holistic strategy for metabolic disease management.

Beyond their synergistic potential with conventional drugs, these phytochemicals also hold promise as standalone nutraceuticals for metabolic health. These plant-derived bioactives have demonstrated glucose-lowering, lipid-regulating, and anti-inflammatory properties, making them viable options for individuals seeking natural alternatives or adjuncts to pharmaceutical interventions. Their ability to modulate key metabolic pathways, enhance mitochondrial function, and support gut microbiota balance underscores their potential as preventive and therapeutic agents in diabetes and obesity management. However, optimizing bioavailability and understanding long-term safety remain critical areas for further research.

8. CONCLUSION

Medicinal plants stand as a reservoir of diverse phytoconstituents, each endowed with a broad spectrum of functions that hold significant promise in healthcare. The ongoing exploration of these botanical wonders is marked by a surge in both pre-clinical and clinical trials, aiming to unravel the therapeutic potential of various phytochemicals in managing an array of diseases and disorders. However, it remains crucial to acknowledge that, despite their natural origins, herbal medicines are not exempt from side effects, necessitating a judicious approach to their utilization.

The relentless pursuit of understanding and harnessing the healing properties of medicinal plants has led to a continuous influx of herbal drugs into the pharmaceutical market. This expanding repertoire of phyto-therapies enriches the options available for healthcare practitioners and patients alike. With each new herbal remedy that undergoes scrutiny and validation, the compendium of plant-based treatments grows, offering a diverse array of alternatives in the pursuit of holistic health.

In parallel with the utilization of well-known herbal remedies, concerted efforts are underway to extract and investigate newer combination therapies of phytochemicals, further diversifying the pharmacological arsenal derived from nature. This ongoing exploration is fueled by the recognition that the untapped potential of medicinal plants extends beyond the compounds already familiar to us. As science delves deeper into the intricate biochemistry of these botanical sources, novel phytoconstituents are identified, paving the way for innovative therapeutic interventions.

As we move forward, a thoughtful, science-backed approach to phytotherapy will ensure that these age-old remedies continue to offer safe, effective, and accessible options in the evolving landscape of medicine

9. LIST OF ABBREVIATIONS

AGE, Advanced Glycation End products; ALT, Alanine Aminotransferase; AMP, Adenosine monophosphate; AMPK, Adenosine Monophosphate Kinase; AST, Aspartate Aminotransferase; BUN, Blood urea nitrogen; C/EBP-α, CCAAT/Enhancer binding protein alpha; CAT, Catalase; CMD, Cardiometabolic disorders; FAS, Fatty acid synthase; FBG, Fasting blood glucose; G6Pase, Glucose-6-Phosphatase; GSH, Glutathione; HbA1c, Glycated hemoglobin; HDL, High-density lipoprotein; IL-6, Interleukin-6; LDL, Low-density lipoprotein; MAD, Malonyl aldehyde; MCP, Momordica Charatin polysaccharide; MK, Murraya koenigii; NAFLD, Non-Alcoholic fatty liver disease; NF-kB, Nuclear Factor Kappa B; OS, Ocimum sanctum; PEPCK, Phosphoenolpyruvate carboxykinase; PPAR, Peroxisome proliferator-activated receptors; PTP-1B, Protein Tyrosine Phosphatase 1B; ROS, Reactive oxygen species; SBP, Systolic blood pressure; SCFA, Short-chain fatty acids; SOD, Superoxide dismutase; SREBP, Sterol regulatory element binding protein; STZ, Streptozocin; T2DM, Type 2 diabetes mellitus; TC, Total cholesterol; TG, Triglycerides; TNF-α, Tumor necrosis factor-alpha; UCP-1, Uncoupling protein 1

10. AUTHOR CONTRIBUTIONS

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. All the authors are eligible to be an author as per the International Committee of Medical Journal Editors (ICMJE) requirements/guidelines.

11. CONFLICTS OF INTEREST

The authors report no financial or any other conflicts of interest in this work.

12. FINANCIAL SUPPORT

There is no funding to report.

13. ETHICAL APPROVALS

This study does not involve experiments on animals or human subjects.

14. DATA AVAILABILITY

All data generated and analyzed are included in this research article.

15. PUBLISHER’S NOTE

All claims expressed in this article are solely those of the authors and do not necessarily represent those of the publisher, the editors and the reviewers. This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.

16. USE OF ARTIFICIAL INTELLIGENCE (AI)-ASSISTED TECHNOLOGY

The authors declare that they have not used artificial intelligence (AI)-tools for writing and editing of the manuscript, and no images were manipulated using AI.

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