Recent discovery of plant-derived anti-diabetic natural products

Carpino P.A., Goodwin B.

C. Hardman T., Rutherford P., W. Dubrey S., S. Wierzbicki A.

The sodium-glucose co-transporter 2 (SGLT2), located in the plasma membrane of cells lining the proximal tubule, facilitates the reabsorbtion of glucose in the kidney. Inhibition of SGLT2 has the potential to reduce blood glucose and represents an opportune target for managing blood glucose. By promoting the excretion of glucose, SGLT2 inhibitors are the first anti-diabetic treatment to target the removal rather than the metabolic redirection of glucose. Their mechanism of action is independent of that of endogenous insulin status and thus provides a means of managing plasma glucose irrespective of a patient's glycaemic status or treatments being used in combination. Several candidate SGLT2 inhibitors based on the core glucoside structure of phlorizin are currently being developed, of which, the metabolically more stable aromatic and heteroaromatic C-glucosides have demonstrated the most promising preclinical and clinical data. The inhibition of SGLT2 by messenger antisense technology is also being investigated. Current indications suggest that short-term benefits, in terms of HbA1(c) reductions, are modest and it remains to be seen whether encouraging exogenous glucose disposal will result in long term patient benefits in terms of returning metabolic balance or even weight loss. Indications are that clinical efficacy will be greater with molecules based on an O-glucoside structure. Concerns have been raised over the safety of these agents, particularly a possible predisposition to urinary tract infections, but these concerns have yet to be confirmed in clinical studies. Clinical development programs will need to establish those patients most likely to benefit from inhibition of SGLT2.

Gupta D., Kono T., Evans-Molina C.

Barr A.J.

Several ‘classical’ protein tyrosine phosphatases are attractive therapeutic targets, including PTP1B for obesity and Type II diabetes; SHP2 for cancer and Lyp for rheumatoid arthritis. Progress has been made in identifying a broad range of chemically distinct inhibitors; however, developing selective and cell-permeable clinically useful compounds has proved challenging. Here the ongoing challenges and recent significant advances in the field are reviewed. Key novel compounds are highlighted and a perspective on the future of phosphatase inhibitor development is presented.

Thomas S.E., Dalton L.E., Daly M., Malzer E., Marciniak S.J.

Kumar M., Rawat P., Khan M.F., Tamarkar A.K., Srivastava A.K., Arya K.R., Maurya R.

Phytochemical investigation of Dodecadenia grandiflora leaves led to the isolation and identification of three phenolic glycosides, designated 1-[(4'-O-(E)-p-coumaroyl)-beta-D-glucopyranosyl]-oxy-2-phenol (1), 1-[(6'-O-(E)-p-coumaroyl)-beta-D-glucopyranosyl]-oxy-2-phenol (2) and 1-[O-beta-D-glucopyranosyl(1-->2)-beta-D-glucopyranosyl]-oxy-2-phenol (3), along with nine known compounds. Compounds 1, 2, 5 and 9 exhibited significant glucose-6-phosphatase inhibitory activity (63.7, 66.9, 82.9 and 85.4%) with IC(50) values of 88.5, 81.0, 51 and 50 microM respectively. On the basis of biological results, a structure-activity relationship has been discussed.

Poirier D.

Aragão D.M., Guarize L., Lanini J., da Costa J.C., Garcia R.M., Scio E.

Leaves of Cecropia pachystachya are described in the folk medicine as possessing antitusive, expectorant, antiasthmatic and hypoglycemic effects.To investigate the hypoglycemic and antioxidant effects of methanolic extract from the leaves of Cecropia pachystachya. The total amount of phenolic and flavonoids compounds was determined and the qualitative composition of the extract was analyzed.The hypoglycemic effect of the extract was tested in normal, glucose loading and alloxan-induced diabetic rats. The antioxidant activity was assessed by DPPH free radical scavenging and reduction power assays. The total amount of phenolic and flavonoids compounds was determined by Folin-Denis and AlCl(3) reagent method, respectively. The qualitative composition of the extract was analyzed using a HPLC-DAD system.The glucose tolerance test showed that in diabetic rats, the extract caused a significant hypoglycemic effect with a blood glucose reduction of 68% after 12h. The administration of the extract in alloxan-induced diabetic rats also produced a significant reduction in the blood glucose levels at all points being more pronounced at 90min (reduction of 60%). After 120min, no significant difference was observed between the blood levels of the rats treated with the extract and those treated with the standard drugs (metformin and glibenclamide). The extract also presented relevant antioxidant activity with IC50=3.1microg/ml (DPPH assay) and EC50=10.8microg/ml (reduction power). Results were compared with the reference antioxidants quercetin, rutin, and ascorbic acid. The content of flavonoids was 83mg/g plant and that of phenolics was 326mg/g plant. Chlorogenic acid and the C-glycosylated flavones, orientin and isoorientin, were identified in the extract.In conclusion, the findings showed that the folk medicinal plant Cecropia pachystachya possesses hypoglycemic and antioxidant effects which confirmed the traditional use of the plant in the treatment of diabetes. Chlorogenic acid and the C-glycosylated flavonoids may explain these activities.

Fatima S.S., Rajasekhar M.D., Kumar K.V., Kumar M.T., Babu K.R., Rao C.A.

Ethanolic extract prepared from the seeds of Vernonia anthelmintica was evaluated for its antihyperglycemic activity in STZ (Streptozotocin) induced diabetic rats. Administration of ethanolic extract at a dosage of 0.50 g/kg bw produced the maximum fall (82%) in the blood glucose levels in diabetic rats after 6 h of treatment. Bioassay-directed fractionation using silica gel column chromatography was performed. Among the five fractions (A1, B1, C1, A2 and B2) obtained, of an initial chromatographic separation of the ethanolic extract, fraction A2 (100 mg/kg bw) showed the maximum antihyperglycemic activity which is significantly higher than that of the reference drug glibenclamide (20 mg/kg bw). Administration of the active fraction (100 mg/kg bw) for 45 days resulted in significant reduction in plasma glucose, HbA1(C), cholesterol, triglycerides, LDL, VLDL, free fatty acids, phospholipids and HMG-CoA reductase in STZ diabetic rats. In addition to that, significant decrease in plasma insulin, protein, HDL and hepatic glycogen observed in STZ diabetic rats, was normalized after 45 days of treatment with the active fraction of V. anthelmintica seeds. From the present study, it is evident that, the seeds of V. anthelmintica possess significant antidiabetic and antihyperlipidemic property without evident toxic effects.

Benhaddou-Andaloussi A., Martineau L.C., Vallerand D., Haddad Y., Afshar A., Settaf A., Haddad P.S.

Nigella sativa (N. sativa) is a plant widely used in traditional medicine of North African countries. During the last decade, several studies have shown that extracts from the seeds of N. sativa have antidiabetic effects.Our group has recently demonstrated that N. sativa seed ethanol extract (NSE) induces an important insulin-like stimulation of glucose uptake in C2C12 skeletal muscle cells and 3T3-L1 adipocytes following an 18 h treatment. The purpose of the present study was to elucidate the pathways mediating this insulin-like effect and the mechanisms through which these pathways are activated.Results from western immunoblot experiments indicate that in C2C12 cells as well as in H4IIE hepatocytes, but not in 3T3-L1 cells, NSE increases activity of Akt, a key mediator of the effects of insulin, and activity of AMP-activated protein kinase (AMPK), a master metabolic regulating enzyme. To test whether the activation of AMPK resulted from a disruption of mitochondrial function, the effects of NSE on oxygen consumption were assessed in isolated liver mitochondria. NSE was found to exhibit potent uncoupling activity.Finally, to provide an explanation for the effects of NSE in adipocytes, PPARgamma stimulating activity was tested using a reporter gene assay. Results indicate that NSE behaves as an agonist of PPARgamma. The data supports the ethnobotanical use of N. sativa seed oil as a treatment for diabetes, and suggests potential uses of this product, or compounds derived thereof, against obesity and the metabolic syndrome.

Eid H.M., Martineau L.C., Saleem A., Muhammad A., Vallerand D., Benhaddou-Andaloussi A., Nistor L., Afshar A., Arnason J.T., Haddad P.S.

Several medicinal plants that stimulate glucose uptake in skeletal muscle cells were identified from among species used by the Cree of Eeyou Istchee of northern Quebec to treat symptoms of diabetes. This study aimed to elucidate the mechanism of action of one of these products, the berries of Vaccinium vitis idaea, as well as to isolate and identify its active constituents using a classical bioassay-guided fractionation approach. Western immunoblot analysis in C2C12 muscle cells revealed that the ethanol extract of the berries stimulated the insulin-independent AMP-activated protein kinase (AMPK) pathway. The extract mildly inhibited ADP-stimulated oxygen consumption in isolated mitochondria, an effect consistent with metabolic stress and the ensuing stimulation of AMPK. This mechanism is highly analogous to that of Metformin. Fractionation guided by glucose uptake activity resulted in the isolation of ten compounds. The two most active, quercetin-3-O-glycosides, enhanced glucose uptake by 38-59% (50 muM; 18 h treatment) in the absence of insulin. Quercetin aglycone, a minor constituent, stimulated uptake by 37%. The quercetin glycosides and the aglycone stimulated the AMPK pathway at concentrations of 25-100 muM, but only the aglycone inhibited ATP synthase in isolated mitochondria (by 34 and 79% at 25 and 100 muM, respectively). This discrepancy suggests that the activity of the glycosides may require hydrolysis to the aglycone form. These findings indicate that quercetin and quercetin 3-O-glycosides are responsible for the antidiabetic activity of V. vitis crude berry extract mediated by AMPK. These common plant products may thus have potential applications for the prevention and treatment of insulin resistance and other metabolic diseases.

Bavarva J.H., Narasimhacharya A.V.

Leucas cephalotes (Roth.) Spreng. (Laminaceae) is an ayurvedic traditional medicinal plant used in India, Nepal and Pakistan to treat several ailments including diabetes.The aim of the present study is to investigate the antidiabetic, antihyperlipaemic and antioxidant activities of Leucas cephalotes for its purported use in diabetes.The ethanol extract of leaves of Leucas cephalotes was administered (150, 300 and 450 mg kg(-1)bw) to diabetes induced (IDDM and NIDDM) rats and carbohydrate, lipid, antioxidant, urea and creatinine profiles were assessed.All the three doses of extract decreased plasma glucose and lipid profiles and, improved the antioxidant status of both types of diabetic rats. The extract administration improved hepatic glycogen content and hexokinase activity, decreased glucose-6-phosphatase activity, blood urea, creatinine contents and decreased lipid peroxidation in diabetic rats. Of the three doses used, 450 mg kg(-1)bw dose was found to be more potent in its effects comparable to those of glibenclamide and metformin.Leucas cephalotes regulates both carbohydrate and lipid metabolism and, improves body antioxidant defense systems in both types of diabetes.

Zhang M., Chen M., Zhang H., Sun S., Xia B., Wu F.

Moracin M (1), Steppogenin-4'-O-beta-D-glucosiade (2), Mullberroside A (3) were isolated from the root bark of Morus alba L. and identified by spectral evidence. Compounds 1, 2 and 3 were studied in hypoglycemic effects on alloxan-diabetic mice. The results showed that compounds 1, 2 and 3 all produced hypoglycemic effects. The compound 2 in a dose of 50 mg/kg exerted significant effect (p

Pareek H., Sharma S., Khajja B.S., Jain K., Jain G.

Diabetes is a metabolic disorder affecting carbohydrate, fat and protein metabolism. Tridax procumbens Linn. (Family-Asteraceae; common name-Dhaman grass) is common herb found in India. Traditionally, the tribal inhabitants of Udaipur district in Rajasthan (India) uses the leaf powder (along with other herb) orally to treat diabetes. There is a need to evaluate extracts of this plant in order to provide scientific proof for it's application in traditional medicine system. Extraction of whole plant of T. procumbens using 50%methanol. The extract was tested for acute and sub-chronic anti-hyperglycemic activity in alloxan induced diabetic rats and for acute toxicity test among normal rats. Observations on body weight as well as on the oral glucose tolerance levels were also recorded. Oral administration of acute and sub chronic doses (250 and 500 mg/kg b.wt.) of T. procumbens extract showed a significant (p < 0.05) reduction in fasting blood glucose levels in diabetic rats, however the decline in blood sugar levels in normal rats was not observed. In acute study the maximum percent blood glucose reduction (68.26% at 250 mg/kg and 71.03% at 500 mg/kg body weight) in diabetic rats was observed at 6 h. The anti-hyperglycemic effects were not dependent of dose and the OGTT and Body weight supported the antihyperglycemic action of the drug. The results of anti-diabetic effect of T. procumbens were compared with the reference standard drug Glibenclamide (10 mg/kg b.wt.). These test results support traditional medicinal use of, T. procumbens for the treatment of diabetes mellitus with corrections in body weight and oral glucose tolerance and no visible signs or symptoms of toxicity in normal rats indicating a high margin of safety. These results warrant follow-up through bioassay-directed isolation of the active principles.

Sachdeva M.M., Claiborn K.C., Khoo C., Yang J., Groff D.N., Mirmira R.G., Stoffers D.A.

Type 2 diabetes mellitus (T2DM) results from pancreatic β cell failure in the setting of insulin resistance. Heterozygous mutations in the gene encoding the β cell transcription factor pancreatic duodenal homeobox 1 (Pdx1) are associated with both T2DM and maturity onset diabetes of the young (MODY4), and low levels of Pdx1 accompany β cell dysfunction in experimental models of glucotoxicity and diabetes. Here, we find that Pdx1 is required for compensatory β cell mass expansion in response to diet-induced insulin resistance through its roles in promoting β cell survival and compensatory hypertrophy. Pdx1-deficient β cells show evidence of endoplasmic reticulum (ER) stress both in the complex metabolic milieu of high-fat feeding as well as in the setting of acutely reduced Pdx1 expression in the Min6 mouse insulinoma cell line. Further, Pdx1 deficiency enhances β cell susceptibility to ER stress-associated apoptosis. The results of high throughput expression microarray and chromatin occupancy analyses reveal that Pdx1 regulates a broad array of genes involved in diverse functions of the ER, including proper disulfide bond formation, protein folding, and the unfolded protein response. These findings suggest that Pdx1 deficiency leads to a failure of β cell compensation for insulin resistance at least in part by impairing critical functions of the ER.

Paşayeva L., Yetimoğlu S., Fatullayev H., İnce U., Bozkurt N.M., Karaboğa Arslan A.K.

Yazici N., Engin S., Barut E.N., Kuran F.K., Hasbal-Celikok G., Yilmaz-Ozden T., Miski M.

Decoctions of Ferula orientalis L. (Apiaceae), have been traditionally used to lower blood glucose levels (BGLs). After in vitro enzyme inhibition tests on the dichloromethane extracts of the roots (FOD) and the methanol extract of the roots (FOM), isolation studies were carried out on the FOD extract. The anti-hyperglycemic effects of the FOD extract and the pure compounds were studied in mice using the Oral Glucose Tolerance Test (OGTT) and streptozotocin (STZ)-induced diabetes mellitus (DM) models. Molecular docking studies were performed on potent compounds in the binding pockets of enzymes α-glucosidase and α-amylase. The isolations of 11 compounds were isolated from the FOD extract, which comprised teferidine (1), ferutinin (FT) (2), teferin (3), epoxy-jaeschkeanadiol-p-hydroxybenzoate (4), epoxy-jaeschkeanadiol-6-vanillate (5), tovarol-8-angelate (6), leucoferin (7), tovarol-8-p-hydroxybenzoate (8), tovarol-8-vanillate (9), 6-β-p-hydroxybenzoyloxy-germacra-1(10),4-diene (10), and chimgin (11). Compounds 2 and 8-11 exhibited a higher inhibitory activity on α-glucosidase. In the OGTT, pretreatment with the FOD extract or compound 2 did not alter the BGLs after administration of the glucose solution compared to the control. In the STZ-induced diabetic mice model, no significant difference in the BGLs was observed with the FOD extract (200 mg/kg) or compound 2 (100 mg/kg)-treated diabetic mice compared to the diabetic control mice. The experimental studies all showed that the F. orientalis extract had significant effects on the enzyme systems involved in DM, and it would be appropriate to plan further studies on possible problems of bioavailability of the compound FT and the FOD extract, inadequate dose, and duration of administration.

Li X., Ju J.

Natural products (NPs), especially antibiotics, exhibit diverse bioactivities and often play critically important roles in dictating and/or driving medical, health, agricultural, animal husbandry, and cosmetic industry initiatives. An important realization in the field of NP applications is that both targeted pathogens and the antibiotic-producing hosts themselves have usually evolved a host of resistance strategies by which to protect themselves. Although the former class of microbes (pathogens) has come to be associated with the global antibiotic resistance crisis, mechanisms by which producing organisms become resistant or tolerant to the ill effects of their bioactive metabolites have begun to attract a great deal of attention. Studies aimed at understanding antibiotic resistance have shown that producer-bourne mechanisms of self-resistance are possible prototypes by which to understand corresponding resistance elements in antibiotic-resistant bacteria. Historically speaking, the most efficient and potent chemistries employed by pathogens to evade harm from antimicrobial NPs have evoked enzymatically-driven transformations. We summarize herein the primary chemical modifications known to impart upon bioactive NP-producing microbes a means of self-defense against their own antimicrobial secondary metabolites; in understanding these chemistries we expect to gain new insights into how antibiotic resistance mechanisms in targeted pathogens might be circumvented or prevented. Such a translation of knowledge has a high likelihood of advancing humanity's ability to counter drug-resistant pathogens.

El-Nashar H.A., Al-Qaaneh A.M., Bhuia M.S., Chowdhury R., Abdel-Maksoud M.A., Ebaid H., Malik A., Torequl Islam M., Aufy M., Elhawary E.A.

IntroductionThe genus Cedrela is one of the phytochemically rich genera of the family Meliaceae. In this study, two Cedrela species, namely, Cedrela odorata and Toona ciliata M. Roem (formerly Cedrela toona), were selected for in-depth phytochemical profiling with the aid of UPLC-ESI/MSn analysis followed by evaluation of their anti-diabetic potential through assessment of in vitro α-amylase and α-glucosidase inhibitory effects, alongside the molecular docking studies on these target enzymes.Materials and methodsUPLC-ESI/MSn technique was applied to tentatively identify the extracts. The anti-diabetic properties were assessed using BioVision α-amylase and α-glucosidase inhibitor screening kits. Further, the molecular docking studies utilized PyRx® and Discovery Studio software.Results and discussionThe UPLC-ESI/MSn analysis led to the identification and quantification of 55 metabolites with their fragmentation patterns for the first time for these two species. Flavonoids represented the main identified class, followed by phenylpropanoids, terpenes, tannins, and others. The two species showed potent enzyme inhibition, where C. odorata and C. toona significantly inhibited α-amylase (IC50 = 4.83 ± 0.01 and 3.50 ± 0.03 μg/mL) compared to pioglitazone (IC50 = 2.17 ± 0.23 μg/mL), while their α-glycosidase inhibitory properties were also potent with (IC50 = 7.17 ± 0.01 and 6.50 ± 0.69 μg/mL), respectively, compared to acarbose (IC50 = 4.83 ± 1.02 μg/mL). The enzyme inhibitory activities were further confirmed by in silico molecular docking of the main identified components with the respective binding sockets in both α-amylase and α-glycosidase enzymes.ConclusionThese promising results could pave the way for a novel discovery of natural phytoconstituents with potent anti-diabetic activity.

Gupta S., Bose A.

AbstractDiabetes mellitus is a complex and widespread disease affecting over 100 million people globally. It increases the risk of severe complications such as heart attack, neuropathy, and retinopathy. While various therapies aim to manage the disease, one effective approach involves reducing the activity of starch-degrading enzymes, such as α-amylase, to limit the amount of free glucose in the body. Another target is lactate dehydrogenase-A (LDH-A), an enzyme involved in gluconeogenesis through its role in generating pyruvate.In recent years, flavonoids have gained significant attention for their potential to inhibit both α-amylase and LDH-A. This study investigates the flavonoids present in green and black tea for their ability to inhibit porcine pancreatic amylase (PPA) and LDH-A, comparing their efficacy to established anti-diabetic drugs such as Acarbose and Metformin using computational methods.In vitro experiments demonstrated that Quercetin shows potent anti-LDHA-A activity with an IC50of 4.161 µM. Quercetin inhibits PPA with an IC50value of 20 µM, while eriodyctiol and myricetin exhibit IC50values of 22 µM and 24 µM, respectively. Additionally, quercetin was found to synergistically enhance the inhibitory effects of the commonly used α-amylase inhibitor, Acarbose.

Arvindekar A., Arvindekar S., Mali S.N., Mali S.

Breast cancer (BC) is a complex disease that manifests with a malignancy of the mammary gland. Globally, the year 2020 witnessed 2.3 million diagnosis cases and 685,000 deaths due to breast cancer. Therefore, there is a dire need for the development of new anticancer drugs for BC. Traditional herbal medicine offers a rich source in the prospect of new drug discovery. In this pursuit, this review covers the discovery of compounds against breast cancer with the possible mechanisms of action, which can assist the development of novel phytomedicines in the drug discovery process. Specifically, the bioactives against breast cancer developed from 1999 to 2023 were categorized based on their chemical class based on a systematic search on PubMed and Embase. Over 70 + natural products belonging to different chemical classes and their mechanisms of action for anticancer activity with commonly used drugs in clinical practice are summarized for a simple understanding of the experimental data. The review draws attention to the vital need to isolate novel bioactive constituents and to develop new drugs based on these isolated bioactives using novel drug delivery systems, so as to increase the target specificity and thereby reduce the adverse effects.Finally, we highlighted the natural bioactives undergoing preclinical and clinical trials to determine their potential for use in the treatment of BC, which could pave the way towards new target-specific drugs against breast cancer.

Vijh D., Gupta P.

Diabetes is a metabolic condition defined by abnormal blood sugar levels. Targeting starch-hydrolyzing enzymes and Dipeptidyl Peptidase 4 (DPP-4) expressed on the surface of numerous cells is one of the key strategies to lower the risk of Type-2 diabetes mellitus (T2DM). Dalbergia sissoo Roxb. bark (DSB) extracts have been reported to have anti-diabetic properties. This study intended to scientifically validate use of alcoholic and hydro-alcoholic extracts of DSB for T2DM by conducting preliminary phytochemical investigations, characterising potential phytochemicals using Fourier transform infrared (FT-IR) spectroscopy and Gas chromatography-mass spectrometry (GC–MS) analysis followed by comprehensive in-silico analysis. A qualitative phytochemical evaluation indicated the presence of alkaloids, phenolics, glycosides, conjugated acids and flavonoids. Ethanolic extracts showed highest total phenolic content (TPC) (127.072 ± 14.08031 μg GAE/g dry extract) and total flavonoid content (106.911 ± 5.84516 μg QE /g dry extract). Further FT-IR spectroscopy also revealed typical band values associated with phenol, alcohol, alkene, alkane and conjugated acid functional groups. The GC–MS analysis identified 139 compounds, 18 of which had anti-diabetic potential. In-silico ADMET analysis of potential compounds revealed 15 compounds that followed Lipinski’s rule and demonstrated drug-like properties, as well as good oral bioavailability. Molecular docking was utilised to analyse their potential to interact with three targets: α-amylase, α-glucosidase, and DPP-4, which are crucial in managing diabetes-related problems. Molecular Docking analysis and membrane permeability test utilising the PerMM platform revealed that compounds in the extracts, such as Soyasapogenol B and Corydine, had better interactions and permeability across the plasma membrane than standard drugs in use. Molecular dynamics simulations also showed that selected compounds remained stable upon interaction with α-amylase. Overall, using the in-silico approaches it was predicted that DSB extracts contain potential phytochemicals with diverse anti-diabetic properties. It further needs to be investigated for possible development as formulation or drug of choice for treating T2DM.

Mostafa M., El-Emam M.M., Mansour M.F., Behairy A., khamis T., Mahmoud S.M., Alsemeh A.E., El Sayed M.M., Mady F.M., Qelliny M.R.

Sundaram R., Muthu K., Prabhakaran J.

β-Sitosterol is a plant-derived compound that shares structural similarities with cholesterol and is used to treat coronary artery disease, prostate cancer, breast cancer, and hypercholesterolemia etc. Lupeol is a natural pentacyclic triterpene, found in a variety of fruits, vegetables, and traditional Chinese medicines like Astragalusmembranaceus and AtractylodesmacrocephalaKoidz. Numerous pharmacological activities of lupeol have been investigated; they include applications as antioxidant, antiviral, antihypertensive, anti-inflammatory and antitumor agents.The current study wasaimed to examine the potential benefits of β-sitosterol and lupeol in reducing pathophysiological complications caused by high fat diet and streptozotocin by regulating the enzymes involved in the metabolism of carbohydrates in diabetic rats as there was no study on this aspect. Male albino wistar rats were given a high-fat diet for two weeks in order to cause diabetes in them. Following a two-week period, the animals were administered a low dosage of streptozotocin and maintained on an overnight fast. Using commercial diagnostic kits, we assessed plasma glucose and glycated hemoglobin (HbA1C). Plasma insulin level was assayed with the help of an ELISA kit and other assays were made biochemically. The homeostatic model of insulin resistance, glucose 6-phosphatase, fructose 1,6-bisphosphatase, and blood glucose levels all significantly increased in the diabetic rats, while plasma insulin, hexokinase, glucose 6-phosphate dehydrogenase, and glycogen content significantly decreased.In addition, the hepatic (aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase) and renal (urea and creatinine) indicators in diabetic rats were raised, and their lipid profiles were disrupted. However, diabetic rats treated with lupeol and β-sitosterol significantly restored all these changed parameters to the levels close to normal. Furthermore, the treatment of lupeol and β sitosterol improved the liver, kidney and heart histology alteration to near normal and prevented the body weight loss. Because of its structural polymorphism, β-sitosterol appeared to be more effective than lupeol in all the parameters investigated and thus these results imply that β sitosterol is a more effective antidiabetic medication than lupeol.

El-Nashar H.A., Shabana E., Kamli H., Shaikh A., Adel M.

Geng H.

The genus Eupatorium belongs to the Asteraceae (Compositae) family and has multiple properties, such as invasiveness and toxicity, and is used in folk medicine. The last review on the chemical constituents of this genus and their biological activities was published in 2015. The present review provides an overview of 192 natural products discovered from 2015 to the present. These products include 63 sesquiterpenoids, 53 benzofuran derivatives, 39 thymol derivatives, 15 fatty acids, 7 diterpenoids, 5 monoterpenoids, 4 acetophenones, and 6 other compounds. We also characterized their respective chemical structures and cytotoxic, antifungal, insecticidal, antibacterial, anti-inflammatory, and antinociceptive activities.

Gawli K., Bojja K.S.

The review is a comprehensive overview of targets of antidiabetic interest and molecules that are reported to possess modulatory effects on glucose homeostasis. Drugs available in the market to treat diabetes restore blood glucose levels to normal but are associated with undesirable effects. This has compelled the investigators to search for a more benign candidate molecule that could counter the high levels of blood glucose, minimize, or diminish further complications and improve lifestyle. In light of this, literature survey was performed using the scientific databases viz., PubMed, Scopus, Google scholar and EMBASE. Twenty targets and 233 molecules, their source, structure, chemical formula, IC50 values and mechanism of action are described. The review has focused on the growing interest in discovering novel targets such as antagonists of glucagon and glucocorticoids receptor, inhibitors of aldose reductase, fructose-1,6-bisphosphatase, and glycogen phosphorylase that have led to effective clinical development. The enzyme inhibitors, antagonists, agonists, and blockers of receptors are reported to be plant-derived metabolites and therefore, can target cellular and molecular mechanisms leading to glucose homeostasis. Overall, the information provided here could serve as a guide for investigators and drug-based companies to explore the listed molecules for developing potential antidiabetic drug candidates with fewer or no side effects.

Jiang Q., Luo J., Zhao X.

Organocatalytic enantioselective cross-dehydrogenative coupling reaction provides a great opportunity for the synthesis of highly enantioenriched molecules. In this review, recent progress in this field is summarized.

Wang L., Xi W., Yuan X., Yang X.

Paul A., Sarkar A., Banerjee T., Maji A., Sarkar S., Paul S., Karmakar S., Ghosh N., Maity T.K.

Diabetes mellitus (DM), especially type 2 diabetes mellitus (T2DM), is the most disruptive metabolic disorder globally affecting human health. To effectively manage this medical condition, the quest for a new medication to treat T2DM continues. The emergence of medication resistance to the insulin and leptin receptors leads to significant concerns. The compounds which can tackle this resistance issue may be helpful in the therapeutic management of T2DM. Protein tyrosine phosphatase 1B (PTP1B) is a promising therapeutic target for treating T2DM. Diverse natural bioactive and synthetic molecules have offered great opportunities for developing lead molecules with significant inhibitory action in in vitro and in vivo against PTP1B. Numerous PTP1B inhibitors have recently been found from natural sources or synthesized by organic synthesis and shown effectiveness for treating T2DM. This review comprehensively updates the latest research findings in developing potent natural and synthetic PTP1B inhibitors over the past six years, including structural features of PTP1B, classification of inhibitors, biological effects, and protein-inhibitors interaction modalities. These studies will be highly helpful for the medicinal chemists working in this field to design and develop novel selective PTP1B inhibitors as anti-diabetic agents in the future.