Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder and constitutes a significant threat to global public health. Increasing evidence has shown the therapeutic potential of probiotics in the management of T2DM. This study established a T2DM mouse model through high-fat diet combined with streptozotocin injection (HFD/STZ) and investigated the preventive effects of two probiotic strains: Bifidobacterium animalis subsp. lactis BLa80 and Lactobacillus acidophilus LA85. The results indicated that both probiotic strains significantly improved glucose homeostasis by reducing fasting blood glucose (FBG) levels, enhancing insulin sensitivity, and increasing glucagon-like peptide-1 (GLP-1) levels. Moreover, probiotics decreased blood lipid and pro-inflammatory mediator levels, enhanced the production of anti-inflammatory cytokines, and mitigated pathological alterations in ileal, hepatic, pancreatic, and renal tissues. Subsequent 16S rRNA amplicon sequencing analysis revealed that BLa80 and LA85 interventions effectively modulated gut microbiota composition, particularly by increasing the relative abundance of short-chain fatty acids (SCFAs)-producing bacterial taxa. Notably, the mechanisms of action were strain-specific: BLa80 primarily impacted glycemic control and promoted the proliferation of Bifidobacterium and Limosilactobacillus, whereas LA85 exhibited superior efficacy in regulating lipid metabolism and promoted the growth of Lactobacillus and Alistipes populations. These findings indicate that BLa80 and LA85 can ameliorate symptoms related to T2DM despite their distinct regulatory pathways, suggesting their potential as therapeutic agents in diabetes management.

Cumulative studies have shown that the composition of the gut microbiome is strongly associated with the development of type 2 diabetes mellitus (T2DM). Electroacupuncture (EA) therapy has been reported to alleviate various diseases, including T2DM, by targeting specific acupuncture points and regulating metabolic homeostasis. A recent review published in the World Journal of Diabetes detailed the role of the gut microbiome in T2DM, discussing the role of therapeutic strategies developed to alleviate T2DM and its complications based on gut microbiome in ameliorating T2DM, as well as the effects of multiple diabetes medications on gut microbiome. However, the review did not elucidate the therapeutic role of EA therapy, a common non-pharmacological intervention for T2DM. This letter complemented the effect of EA therapy on glucose metabolism by adjusting the gut microbiome composition, which reveals the underlying mechanism of glucose lowering by EA therapy and provides a scientific basis for the application of EA therapy in clinical treatment.

Helicteres angustifolia L. (H. angustifolia), a well-known traditional Chinese medicine, has been demonstrated to have hypoglycemic activity. We found that the EtOAc extract of H. angustifolia (HAEF) showed stronger α-glucosidase inhibitory activity than that of positive control. Furthermore, the hypoglycemic activity of HAEF was evaluated in streptozotocin (STZ)-induced type 2 diabetes mellitus (T2DM) rats. The results demonstrated that HAEF reduced the drinking quantity, feeding quantity, and controlled weight loss in diabetic rats. Besides, the fasting blood glucose (FBG), viscera index, and the area under time-blood glucose curve (AUC) were significantly decreased, and the oral glucose tolerance was also improved after 5 weeks. Then, the high-performance liquid chromatography with quadrupole time of flight tandem mass spectrometry (HPLC-Q-TOF-MS/MS) method was performed for qualitative analysis of the chemical constituents in HAEF. Twenty-one compounds were identified from in HAEF. Four compounds were further isolated from HAEF and subjected to α-glucosidase inhibition experiments. At the end, molecular docking was empolyed simulate the interaction of three compounds with α-glucosidase. This is the first report on major hypoglycaemic components has been identified in the roots of H. angustifolia. These findings provide a material basis for the use of H. angustifolia in the treatment of diabetes.

A recent study reported that a deficiency of Col5a3 reduces dermal fat. However, the regulatory mechanism of the Col5a3 gene on adipose deposition remains unclear.

In this study, we assessed the effects of Col5a3 interference on the proliferation and differentiation of 3T3-L1 preadipocytes through CCK-8, EdU staining, cell cycle detection, RT-qPCR, Western blot, a triglyceride assay, and Oil Red O staining. RNA-seq was then performed on differentiated adipocytes to identify key differentially expressed genes (DEGs) and signaling pathways.

Col5a3 interference significantly promoted the proliferation of 3T3-L1 cells but inhibited their differentiation. RNA-seq analysis identified 368 DEGs, with the most significant enrichment observed in the oxidative phosphorylation pathway.

This study demonstrates the regulatory role of Col5a3 in the proliferation and differentiation of preadipocytes, identifying various genes regulated by Col5a3 in adipogenesis. We speculate that Col5a3 may influence adipogenesis through the oxidative phosphorylation pathway in 3T3-L1 cells. The findings help gain a better understanding of the molecular mechanisms underlying fat deposition and obesity-related metabolic diseases.

Pterostilbene, a polyphenolic compound and an analog of resveratrol, exerts various biological activities and has higher bioavailability and metabolic stability than resveratrol. However, the effectiveness of pterostilbene intake in humans, particularly its effect on blood microRNA (miRNA) expression levels, has not been evaluated. Accordingly, this pilot study aimed to investigate the effects of pterostilbene on blood biochemistry and blood miRNA expression levels and the safety of continuous intake at doses of 10 or 100 mg/d over 12 wk. A double-blind, placebo-controlled parallel-arm comparison trial was conducted with 30 healthy men. In the analysis of blood miRNA expression levels, miR-34a and miR-193b showed very high increases at week 4 and after week 4 of intake, respectively, suggesting that the responders might be present among participants in the pterostilbene intake group. No adverse events were reported during the trial in any participant, and no abnormalities were observed upon examination by the responsible physician. Thus, pterostilbene intake would regulate blood miRNA expression levels, and the results can be utilized in human studies investigating miRNA expression levels with functional food ingredients.

As natural polymers, Lactiplantibacillus plantarum exopolysaccharides (EPS) possess a wide range of bioactivities but suffer from low yields and unclear relationships between functional activity and structure. To this end, the chemical structure and bioactive properties of EPS from Lactiplantibacillus plantarum MY04 were investigated. As a result, three polysaccharide fractions (EPS-1, EPS-2, EPS-3) were separated and purified, of which EPS-2 had better antioxidant activity and α-glucosidase inhibitory ability. More importantly, EPS-2 can significantly enhance insulin sensitivity in HepG2 cells by upregulating enzyme activities in the glycolytic pathway and mitigating oxidative stress-induced damage. In addition, the structural characterization of EPS-2 was also comprehensively elucidated. It was found that EPS-2 was mainly composed of mannose with a molecular weight of 2.3 × 106 Da, and its main chain structure is →3)-Manp-(1 → 2)-Manp-(1 → 2,6)-Manp-(1 → 2,6)-Manp-(1→, providing a theoretical basis for understanding the relationship between structure and function of polysaccharides.

Pterostilbene is a phenolic compound commonly found in blueberries, peanuts, grapes, and other plants. It is a dimethoxy derivative of resveratrol. In recent years, it has gained significant attention due to its remarkable anti-inflammatory and antioxidant effects. In addition, its high bioavailability and low toxicity in many species has contributed to its promising research prospects. Cardiovascular disease is closely related to pathological processes such as inflammation and oxidative stress, which aligns well with the treatment applications of pterostilbene. As a result, numerous studies have investigated the effects of pterostilbene on cardiovascular health and disease. This paper summarizes the current research on pterostilbene, with a specific focus on its potential therapeutic role in treating cardiovascular disease.

Polycystic ovary syndrome (PCOS) is an intricate endocrine disorder that targets millions of women globally. Recent research has drawn attention to its association with cognitive impairment and Alzheimer's disease (AD) risk, yet the exact mechanism remains elusive. This study aimed to explore the potential role of PCOS-associated insulin resistance (IR) and inflammation in linking PCOS to AD pathogenesis. It additionally investigated the therapeutic merits of pterostilbene (PTS) in ameliorating PCOS and associated cognitive deficits in comparison to metformin (MET). Rats were divided into five groups; vehicle group, PTS group [30 mg/kg, per os (p.o.) for 13 days], and the remaining three groups received letrozole (1 mg/kg, p.o. for 21 days) to represent the PCOS, PCOS + MET (300 mg/kg, p.o. for 13 days), and PCOS + PTS groups, respectively. Behavioral tests were conducted, along with a histopathological investigation of brains and ovaries. Assessment of serum hormonal profile and hippocampal IRS-1/PI3K/AKT/GSK-3β insulin signaling pathway components were performed. PTS rats exhibited improved insulin sensitivity and hormonal profile, besides enhanced neurobehavioral tests performance and histopathological findings. These effects may be attributed to modulation of the IRS-1/PI3K/AKT/GSK-3β pathway, reducing GSK-3β activity, and mitigating Tau hyperphosphorylation and Aβ accumulation in the brain. Likewise, PTS attenuated nuclear factor kappa B-mediated inflammation and reversed AChE elevation, suggesting multifaceted neuroprotective effects. Comparatively, PTS showed outcomes similar to those of MET in most parameters. The obtained findings validated that dysregulated insulin signaling in PCOS rats detrimentally affects cognitive function, which is halted by PTS, unveiling the potential of PTS as a novel therapy for PCOS and related cognitive deficits.

Type 2 diabetes mellitus (T2DM) is an immensely debilitating chronic disease that progressively undermines the well-being of various bodily organs and, indeed, most patients succumb to the disease due to post-T2DM complications. Although there is evidence supporting the activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway by insulin, which is essential in regulating glucose metabolism and insulin resistance, the significance of this pathway in T2DM has only been explored in a few studies. The current review aims to unravel the mechanisms by which different classes of PI3Ks control the metabolism of glucose; and also to discuss the original data obtained from international research laboratories on this topic. We also summarized the role of the PI3K/Akt signaling axis in target tissues spanning from the skeletal muscle to the adipose tissue and liver. Furthermore, inquiries regarding the impact of disrupting this axis on insulin function and the development of insulin resistance have been addressed. We also provide a general overview of the association of impaired PI3K/Akt signaling pathways in the pathogenesis of the most prevalent diabetes-related complications. The last section provides a special focus on the therapeutic potential of this axis by outlining the latest advances in active compounds that alleviate diabetes via modulation of the PI3K/Akt pathway. Finally, we comment on the future research aspects in which the field of T2DM therapies using PI3K modulators might be developed.

Serum/glucocorticoid-inducible kinase 1 (SGK1) gene encodes a serine/threonine protein kinase that plays an essential role in cellular stress response and regulation of multiple metabolic processes. However, its role in bovine adipogenesis remains unknown. In this study, we aimed to clarify the role of SGK1 in bovine lipid accumulation and improvement of meat quality.

Preadipocytes were induced to differentiation to detect the temporal expression pattern of SGK1. Heart, liver, lung, spleen, kidney, muscle and fat tissues were collected to detect its tissue expression profile. Recombinant adenovirus and the lentivirus were packaged for overexpression and knockdown. Oil Red O staining, quantitative real-time PCR, Western blot analysis, Yeast two-hybrid assay, luciferase assay and RNA-seq were performed to study the regulatory mechanism of SGK1.

SGK1 showed significantly higher expression in adipose and significantly induced expression in differentiated adipocytes. Furthermore, overexpression of SGK1 greatly promoted adipogenesis and inhibited proliferation, which could be shown by the remarkable increasement of lipid droplet, and the expression levels of adipogenic marker genes and cell cycle-related genes. Inversely, its knockdown inhibited adipogenesis and facilitated proliferation. Mechanistically, SGK1 regulates the phosphorylation and expression of two critical proteins of FoxO family, FOXO1/FOXO3. Importantly, SGK1 attenuates the transcriptional repression role of FOXO1 for PPARγ via phosphorylating the site S256, then promoting the bovine fat deposition.

SGK1 is a required epigenetic regulatory factor for bovine preadipocyte proliferation and differentiation, which contributes to a better understanding of fat deposition and meat quality improvement in cattle.

Pterostilbene is the dimethylated analogue of Resveratrol, a compound with well-known biological activities, such as antioxidant, chemopreventive, anti-diabetic, anti-obesity, and cardioprotective. Despite many studies on the general effect of such polyphenolic molecules and their derivatives, a deep comprehension of their action and systematic structure-activity relationship studies are still rare. Herein, three different analogues of functionalizable Pterostilbene were efficiently synthesized and derivatized with a selected library of antioxidant amino acids, allowing for a highly diversified exploration of the chemical space. The library was analyzed towards cancer cells. Collectively, our data demonstrated the enhanced anti-proliferative activity of Tryptophan-conjugated compounds. In breast cancer cells, the treatment with Tryptophan-conjugated analogues induced the activation of cellular stress pathways, including autophagy signaling.

Acupuncture, an important green and side effect-free therapy in traditional Chinese medicine, is widely use both domestically and internationally. Acupuncture can interact with the gut microbiota and influence various diseases, including metabolic diseases, gastrointestinal diseases, mental disorders, nervous system diseases, and other diseases. This review presents a thorough analysis of these interactions and their impacts and examines the alterations in the gut microbiota and the potential clinical outcomes following acupuncture intervention to establish a basis for the future utilization of acupuncture in clinical treatments.

Whole-grain foods are rich in bound polyphenols (BPs) whose health benefits were largely underestimated compared with free polyphenols. We first found that DFBP (dietary fiber with BPs from oat bran) exhibited stronger colonic antioxidant activities than DF. 16S rRNA sequencing showed that DFBP selectively changed gut microbial composition, which reciprocally released BPs from DFBP. Released polyphenols from DFBP reduced excessive colonic ROS and exhibited colonic antioxidant activities via the ROS/Akt/Nrf2 pathway revealed by transcriptome and western blot analysis. Colonic antioxidant activities of DFBP mediated by gut microbiota were next proven by treating mice with broad-spectrum antibiotics. Next, Clostridium butyricum, as a distinguished bacterium after DFBP intervention, improved colonic antioxidant capacities synergistically with DFBP in HFD-fed mice. This was explained by the upregulated mRNA expression of esterase, and cellulase of Clostridium butyricum participated in releasing BPs. Our results would provide a solid basis for explaining the health benefits of whole grains.

The intensification of microplastics (MPs) pollution has emerged as a formidable environmental challenge, with profound global implications. The pervasive presence of MPs across a multitude of environmental mediums, such as the atmosphere, soil, and oceans, extends to commonplace items, culminating in widespread human ingestion and accumulation via channels like food, water, and air. In the domestic realm, kitchens have become significant epicenters for MPs pollution. A plethora of kitchen utensils, encompassing coated non-stick pans, plastic cutting boards, and disposable utensils, are known to release substantial quantities of MPs particles in everyday use, which can then be ingested alongside food. This paper conducts a thorough examination of contemporary research addressing the release of MPs from kitchen utensils during usage and focuses on the health risks associated with MPs ingestion, as well as the myriad factors influencing the release of MPs in kitchen utensils. Leveraging the insights derived from this analysis, this paper proposes a series of strategic recommendations and measures targeted at mitigating the production of MPs in kitchen settings. These initiatives are designed not solely to diminish the release of MPs but also to enhance public awareness regarding this pressing environmental concern. By adopting more informed practices in kitchens, we can significantly contribute to the reduction of the environmental burden of MPs pollution, thus safeguarding both human health and the ecological system.

Type 2 diabetes mellitus is a chronic metabolic disease characterized by insulin resistance, with high morbidity and mortality worldwide. Due to the tightly intertwined connection between the insulin resistance pathway and the PI3K/AKT signaling pathway, regulating the PI3K/AKT pathway and its associated targets is essential for hypoglycemia and the prevention of type 2 diabetes mellitus. In recent years, metabolites isolated from traditional Chinese medicine has received more attention and acceptance for its superior bioactivity, high safety, and fewer side effects. Meanwhile, numerous in vivo and in vitro studies have revealed that the metabolites present in traditional Chinese medicine possess better bioactivities in regulating the balance of glucose metabolism, ameliorating insulin resistance, and preventing type 2 diabetes mellitus via the PI3K/AKT signaling pathway. In this article, we reviewed the literature related to the metabolites of traditional Chinese medicine improving IR and possessing therapeutic potential for type 2 diabetes mellitus by targeting the PI3K/AKT signaling pathway, focusing on the hypoglycemic mechanism of the metabolites of traditional Chinese medicine in type 2 diabetes mellitus and elaborating on the significant role of the PI3K/AKT signaling pathway in type 2 diabetes mellitus. In order to provide reference for clinical prevention and treatment of type 2 diabetes mellitus.

Cafeteria diet (CD) model for in-vivo studies mimics the western diet having imbalanced nutritional value, high caloric-density and palatability. Uncontrolled eating leads to the development of childhood obesity, poor self-esteem and depression due to its effects on brain development. Herbal supplements are novel inclusion in the management of obesity and mental well-being. Pterostilbene (PTE) found in blueberries and Pterocarpus marsupium heartwood, is known to prevent obesity in invivo models. Adolescent Swiss albino male mice were fed on CD for 70 days and the development of obesity was assessed by gain in body weight, abdominal circumference. Forced swim and tail suspension test confirmed depression in CD fed mice. Obesity induced depressed (OID) mice were treated with PTE (10, 20, 40 mg/kg), standard antiobesity drug cetilistat (10 mg/kg), antidepressant fluoxetine (10 mg/kg) for 28 days. Post treatment, PTE-treated mice showed reduction in BW and depression-like behavior analysed using paradigms such as sucrose preference, open field, marble burying, and resident intruder test in comparison to the CD group. Insulin resistance, lipid profile, antioxidant enzyme, inflammatory cytokines (NF-κB, IL-6, TNF α) and cortisol levels were mitigated by PTE. It also restored normal cellular architecture of the brain and adipose tissue and increased the Silent mating type information regulation 2 homolog1 (SIRT1), leptin and ghrelin receptors gene expression in the brain. Thus, it can be concluded that PTE might have inhibited OID like behavior in mice via inhibition of IR, modulating neuroinflammation and hypothalamic-pituitary-adrenal axis dysfunction and upregulating SIRT1 mediated leptin-ghrelin signaling.

Fibrosis is a prevailing pathology in chronic diseases and accounts for 45% of deaths in developed countries. This condition is primarily identified by the transformation of fibroblasts into myofibroblasts and the overproduction of extracellular matrix (ECM) by myofibroblasts. Pterostilbene (PTS) is a natural analogue of resveratrol and is most commonly found in blueberries. Research has shown that PTS exerts a wide range of pharmacological effects, such as antioxidant, anti-inflammatory, and anticancer effects. As a result, PTS has the potential to prevent and cure numerous diseases. Emerging evidence has indicated that PTS can alleviate myocardial fibrosis, renal fibrosis, pulmonary fibrosis, hepatic fibrosis, and colon fibrosis via the inhibition of inflammation, oxidative stress, and fibrogenesis effects in vivo and in vitro, and the potential mechanisms are linked to various pathways, including transforming growth factor-β1 (TGF-β1)/small mother against decapentaplegic proteins (Smads) signalling, the reactive oxygen species (ROS)-driven Pitx2c/mir-15b pathway, nuclear factor kappa B (NF-κB) signalling, Kelch-like epichlorohydrin-associated protein-1 (Keap-1)/NF-E2-related factor-2 (Nrf2) cascade, the NLR family pyridine structure domain 3 (NLRP3) pathway, the Janus kinase-2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway, and the Src/STAT3 pathway. In this review, we comprehensively summarize the antifibrotic effects of PTS both in vivo and in vitro and the pharmacological mechanisms, pharmacokinetics, and toxicology of PTS and provide insights into and strategies for exploring promising agents for the treatment of fibrosis.

Hyperglycemia has become a global health problem due to changes in diet and lifestyle. Most importantly, persistent hyperglycemia can eventually develop into type II diabetes. While the usage of current drugs is limited by their side effects, stilbenes derived from fruits and herbal/dietary plants are considered as important phytochemicals with potential hypoglycemic properties. Herein, the most common stilbenoids in consumed foods, i.e. resveratrol, pterostilbene, piceatannol, oxyresveratrol, and 2,3,5,4'-tetrahydroxystilbene-2-O-β-glucopyranoside (THSG), are reviewed in this paper. These stilbenes are found to regulate glucose homeostasis via (a) modulation of feeding behaviour and nutrition absorption; (b) restoration of insulin signalling by enhancing insulin production/insulin sensitivity; (c) improvement of gut permeability, gut microbial profile and resulting metabolomes; and (d) amelioration of circadian rhythm disruption. In this review, we have summarized the underlying mechanisms for the hypoglycemic effects of the five most common dietary stilbenoids listed above, providing a comprehensive framework for future study and applications.

In this study, amorphous solid dispersions (ASDs) of pterostilbene (PTR) with polyvinylpyrrolidone polymers (PVP K30 and VA64) were prepared through milling, affirming the amorphous dispersion of PTR via X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). Subsequent analysis of DSC thermograms, augmented using mathematical equations such as the Gordon-Taylor and Couchman-Karasz equations, facilitated the determination of predicted values for glass transition (Tg), PTR's miscibility with PVP, and the strength of PTR's interaction with the polymers. Fourier-transform infrared (FTIR) analysis validated interactions maintaining PTR's amorphous state and identified involved functional groups, namely, the 4'-OH and/or -CH groups of PTR and the C=O group of PVP. The study culminated in evaluating the impact of amorphization on water solubility, the release profile in pH 6.8, and in vitro permeability (PAMPA-GIT and BBB methods). In addition, it was determined how improving water solubility affects the increase in antioxidant (ABTS, DPPH, CUPRAC, and FRAP assays) and neuroprotective (inhibition of cholinesterases: AChE and BChE) properties. The apparent solubility of the pure PTR was ~4.0 µg·mL-1 and showed no activity in the considered assays. For obtained ASDs (PTR-PVP30/PTR-PVPVA64, respectively) improvements in apparent solubility (410.8 and 383.2 µg·mL-1), release profile, permeability, antioxidant properties (ABTS: IC50 = 52.37/52.99 μg·mL-1, DPPH: IC50 = 163.43/173.96 μg·mL-1, CUPRAC: IC0.5 = 122.27/129.59 μg·mL-1, FRAP: IC0.5 = 95.69/98.57 μg·mL-1), and neuroprotective effects (AChE: 39.1%/36.2%, BChE: 76.9%/73.2%) were confirmed.

Obesity can be associated with significant metabolic disorders. Our previous study found that medium-chain triglycerides (MCTs) improved lipid metabolism in obese rats. However, scant attention has been given to exploring the impact of MCTs on glucose metabolism in obese rats. This study is designed to examine the effects and mechanisms of three distinct MCTs on glucose metabolism in obese rats. To induce obesity, Sprague-Dawley (SD) rats were fed a high-fat diet, followed by a 12-week treatment with caprylic triglyceride (CYT), capric triglyceride (CT), and lauric triglyceride (LT). The results showed that three types of MCT intervention reduced the levels of lipids (TC, TG, LDL-c, and HDL-c), hyperglycemia, insulin resistance (insulin, OGTT, HOMA-IR, and ISI), and inflammatory markers (IL-4, IL-1β, and TNF-α) in obese rats (p < 0.01), The above parameters have been minimally improved in the high-fat restoring group (HR) group. MCTs can modulate the PI3K/AKT signaling pathways to alleviate insulin resistance and improve glucose metabolism in obese rats. Furthermore, MCTs can activate peroxisome proliferator-activated receptor (PPAR) γ and reduce the phosphorylation of PPARγser237 mediated by CDK5, which can improve insulin sensitivity without lipid deposition in obese rats. Among the MCT group, CT administration performed the best in the above pathways, with the lowest blood glucose level and insulin resistance. These findings contribute to a deeper understanding of the connection between health benefits and the specific type of MCT employed.

Pterostilbene (PTS), a naturally occurring analog of resveratrol (RSV), has garnered significant attention due to its potential therapeutic effects in treating inflammatory and oncological diseases. This comprehensive review elucidates the pharmacological properties, mechanisms of action, and therapeutic potential of PTS. Various studies indicate that PTS exhibits anti-inflammatory, antioxidant, and antitumour properties, potentially making it a promising candidate for clinical applications. Its influence on regulatory pathways like NF-κB and PI3K/Akt underscores its diverse strategies in addressing diseases. Additionally, PTS showcases a favorable pharmacokinetic profile with better oral bioavailability compared to other stilbenoids, thus enhancing its therapeutic potential. Given these findings, there is an increased interest in incorporating PTS into treatment regimens for inflammatory and cancer-related conditions. However, more extensive clinical trials are imperative to establish its safety and efficacy in diverse patient populations.

MicroRNAs (miRNA) are small noncoding RNAs that play a significant role in the regulation of gene expression. The literature has explored the key involvement of miRNAs in the diagnosis, prognosis, and treatment of various neurodegenerative diseases (NDD), such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). The miRNA regulates various signalling pathways; its dysregulation is involved in the pathogenesis of NDD.

The present review is focused on the involvement of miRNAs in the pathogenesis of NDD and their role in the treatment or management of NDD. The literature provides comprehensive and cutting-edge knowledge for students studying neurology, researchers, clinical psychologists, practitioners, pathologists, and drug development agencies to comprehend the role of miRNAs in the NDD's pathogenesis, regulation of various genes/signalling pathways, such as α-synuclein, P53, amyloid-β, high mobility group protein (HMGB1), and IL-1β, NMDA receptor signalling, cholinergic signalling, etc. Methods: The issues associated with using anti-miRNA therapy are also summarized in this review. The data for this literature were extracted and summarized using various search engines, such as Google Scholar, Pubmed, Scopus, and NCBI using different terms, such as NDD, PD, AD, HD, nanoformulations of mRNA, and role of miRNA in diagnosis and treatment.

The miRNAs control various biological actions, such as neuronal differentiation, synaptic plasticity, cytoprotection, neuroinflammation, oxidative stress, apoptosis and chaperone-mediated autophagy, and neurite growth in the central nervous system and diagnosis. Various miRNAs are involved in the regulation of protein aggregation in PD and modulating β-secretase activity in AD. In HD, mutation in the huntingtin (Htt) protein interferes with Ago1 and Ago2, thus affecting the miRNA biogenesis. Currently, many anti-sense technologies are in the research phase for either inhibiting or promoting the activity of miRNA.

This review provides new therapeutic approaches and novel biomarkers for the diagnosis and prognosis of NDDs by using miRNA.

The therapeutic potential of natural stilbenes, with a particular focus on pterostilbene (PTE), has emerged as a promising avenue of research targeting age-associated conditions encompassing cardiovascular diseases (CVD), diabetes mellitus (DM), and cognitive decline. This comprehensive investigation delves into the intricate mechanisms through which PTE, a polyphenolic compound abundant in grapes and blueberries, exerts its advantageous effects as an anti-aging agent. Central to its action is the modulation of hallmark aging processes, including oxidative damage, inflammatory responses, telomere attrition, and cellular senescence. PTE's ability to effectively penetrate the blood-brain barrier amplifies its potential for safeguarding neural health, thereby facilitating the regulation of neuronal signalling cascades, synaptic plasticity, and mitochondrial functionality. Through engagement with sirtuin proteins, it orchestrates cellular resilience, longevity, and metabolic equilibrium. Encouraging findings from preclinical studies portray PTE as a robust candidate for counteracting age-linked cognitive decline, augmenting memory consolidation, and potentially ameliorating neurodegenerative maladies such as Alzheimer's disease (AD). The synthesis of current scientific insights accentuates the promising translational prospects of PTE as a potent, naturally derived therapeutic agent against cognitive impairments associated with aging. Consequently, these collective findings lay a solid groundwork for forthcoming clinical inquiries and innovative therapeutic interventions in this realm.

Background: Yuquan Pill (YQW) is a modern concentrated pill preparation of six herbs, namely, Ge Gen (Pueraria lobata Ohwi), Di huang (Rehmannia glutinosa Libosch.), Tian Huafen (Trichosanthes kirilowii Maxim.), Mai Dong (Ophiopogon japonicus (L. f.) Ker Gawl.), Wu Weizi (Schisandra chinensis (Turcz.) Baill.) and Gan Cao (Glycyrrhiza uralensis Fisch.). It is extensively used to treat type 2 diabetes-related glucose and lipid metabolism disorders. But what's the pharmacodynamic substance and how it works in the treatment of Type 2 diabetes mellitus (T2DM) are still unclear. Purpose: The purpose of this study is to determine the likely pharmacological components and molecular mechanism of YQW's intervention on T2DM by combining serum pharmacochemistry, network analysis and transcriptomics. Methods: The efficacy and prototypical components of blood entry were determined after oral administration of YQW aqueous solution to T2DM rats induced by high-fat feed and low-dose streptozotocin (STZ), and the key targets and pathways for these compounds to intervene in T2DM rats were predicted and integrated using network analysis and transcriptomics techniques. Results: In diabetic rats, YQW can lower TG, CHO, NO, and MDA levels (p < 0.05) while increasing HDL-C levels (p < 0.01), and protecting the liver and kidney. 22 prototype components (including puerarin, daidzein, 3'-methoxypuerarin, and liquiritigenin, among others) were found in the serum of rats after oral administration of YQW for 90 min, which might be used as a possible important ingredient for YQW to intervene in T2DM rats. 538 YQW pharmacodynamic components-related targets and 1,667 disease-related targets were projected through the PharmMapper database, with 217 common targets between the two, all of which were engaged in regulating PI3K-Akt, MAPK, Ras and FoxO signal pathway. Finally, the mRNA expression profiles of liver tissues from rats in the control, model, and YQW groups were investigated using high-throughput mRNA sequencing technology. YQW can regulate the abnormal expression of 89 differential genes in a disease state, including 28 genes with abnormally high expression and 61 genes with abnormally low expression. Five common genes (Kit, Ppard, Ppara, Fabp4, and Tymp) and two extensively used regulatory pathways (PI3K-Akt and MAPK signaling pathways) were revealed by the integrated transcriptomics and network analysis study. Conclusion: The mechanism of YQW's intervention in T2DM rats could be linked to 22 important components like puerarin, daidzein, and glycyrrhetinic acid further activating PI3K-Akt and MAPK signaling pathways by regulating key targets Kit, Ppard, Ppara, Fabp4, and Tymp, and thus improving lipid metabolism disorder, oxidative stress, and inflammation levels in T2DM rats. On the topic, more research into the pharmacological ingredient foundation and mechanism of YQW intervention in T2DM rats can be done.

Diabetic wounds are severe complications of diabetes mellitus (DM), which have difficulty in healing. Although diverse treatments have been used, the prognosis of diabetic wounds is not satisfactory; therefore, an effective therapy to accelerate diabetic wound healing is urgently needed. In our review, we summarized that resveratrol can promote diabetic wound healing by protecting against hyperglycemia, inflammation, oxidative stress, vascular pathology, infection, and peripheral neuropathy. To clarify it clearly, we highlighted its underlying mechanisms of protective effects of resveratrol against diabetic wounds, and high-quality studies are needed to firmly establish its clinical efficacy. Otherwise, with the development of material sciences, resveratrol can exert its therapeutic effectiveness efficiently; however, more high-quality studies are needed to confirm the clinical efficacy of resveratrol on diabetic wounds.

One of the most serious mental health comorbidities associated with diabetes mellitus is depression. The occurrence is almost double in type 2 diabetes mellitus (T2DM) compared with the general population. Pterostilbene (PTE), a dimethylated analog of resveratrol, has been reported for significant neuroprotective, anti-inflammatory, hypolipidemic, hypoglycaemic and antioxidant effects. However, its effect on diabetes-induced depression-like behavior (DID) has not been studied. The current study aimed at studying the effects of PTE on depressive-like behavior in male Wistar rats with T2DM. It was induced by single dose administration of nicotinamide (NA) and streptozotocin (STZ). On day 21, forced swim test (FST) was conducted for the confirmation of DID. Rats demonstrating depressive-like behavior were treated with PTE (10, 20 and 40 mg/kg), metformin (MET; 500 mg/kg) and fluoxetine (FLX; 10 mg/kg) for 28 days, orally. At the end of the treatment, behavioral assessment for depression, blood glucose (BG) and lipid profile, oxidative stress markers, gene expression of Sirtuin 1 (SIRT1) and histopathological parameters were investigated. PTE significantly reduced weight loss and mitigated depressive-like behavior paradigms such as sucrose preference test (SPT), resident intruder test (RIT) and open field test (OFT). It significantly restored BG, lipid and liver profile, creatinine and antioxidant level. It Improved glucose tolerance, insulin resistance (IR) and reduced cortisol level as well as inflammatory markers. It showed improved morphology of the pancreas, brain, liver and kidney. Gene expression studies revealed that, PTE significantly increased SIRT1 expression. PTE by its virtue to maintain BG, reduced IR, amelioration of the HPA axis, anti-inflammatory, antioxidant activity and improvement of SIRT1 gene expression proved to be effective in the treatment of DID-like behavior in rats.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by hyperglycemia and insulin resistance. Mung bean sprouts are traditionally considered a "folk" hypoglycemic food and their pharmacological effects and underlying mechanisms warrant further investigation.

This study aimed to investigate the anti-diabetic effects of the exosomes-like nanoparticles in mung bean sprouts (MELNs) and explore the related molecular mechanisms.

MELNs were isolated using a differential centrifugation-polyethylene glycol (PEG) method, and the identification of MELNs were confirmed by PAGE gel electrophoresis, agarose gel electrophoresis, thin-layer chromatography (TLC), and transmission electron microscopy (TEM). In the high-fat diet/streptozotocin (HFD/STZ) mouse model, MELNs ameliorated the progression of T2DM by increasing oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) results, decreasing the fasting blood glucose level, and reducing the serum triglycerides (TG) and total cholesterol (TC). Histopathological examinations indicated MELNs diminished inflammatory infiltration of hepatocytes and amplified the area of islet B cells. In addition, MELNs decreased the oxidative stress levels in liver tissue and had good biocompatibility. In vitro experiments verified that MELNs improved the viability of glucosamine (GlcN) induced insulin-resistant hepatocytes. Furthermore, this study also revealed that MELNs upregulated GLUT4 & Nrf2 and down-regulated GSK-3β via activating the PI3K/Akt signaling pathway, promoting the production of antioxidant enzymes, such as HO-1 and SOD, to reduce oxidative stress.

MELNs mitigated the progression of type 2 diabetes in HFD/STZ mouse model. The underlying molecular mechanism is related to PI3K/Akt/GLUT4/GSK-3β signaling pathway.

Pterostilbene, an important analogue of the star molecule resveratrol and a novel compound naturally occurring in blueberries and grapes, exerts a significant neuroprotective effect on cerebral ischemia/reperfusion (I/R), but its mechanism is still unclear. This study aimed to follow the molecular mechanisms behind the potential protective effect of pterostilbene against I/R induced injury. For fulfilment of our aim, we investigated the protective effects of pterostilbene on I/R injury caused by middle cerebral artery occlusion (MCAO) in vivo and oxygen-glucose deprivation (OGD) in vitro. Machine learning models and molecular docking were used for target exploration and validated by western blotting. Pterostilbene significantly reduced the cerebral infarction volume, improved neurological deficits, increased cerebral microcirculation and improved blood-brain barrier (BBB) leakage. Machine learning models confirmed that the stroke target MMP-9 bound to pterostilbene, and molecular docking demonstrated the strong binding activity. We further found that pterostilbene could depolymerize stress fibers and maintain the cytoskeleton by effectively increasing the expression of the non-phosphorylated actin depolymerizing factor (ADF) in the early stage of I/R. In the late stage of I/R, pterostilbene could activate the Wnt pathway and inhibit the expression of MMP-9 to decrease the degradation of the extracellular basement membrane (BM) and increase the expression of junction proteins. In this study, we explored the protective mechanisms of pterostilbene in terms of both endothelial cytoskeleton and extracellular matrix. The early and late protective effects jointly maintain BBB stability and attenuate I/R injury, showing its potential to be a promising drug candidate for the treatment of ischemic stroke.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a potent modulator of cholesterol metabolism and plays a crucial role in the normal functioning of pancreatic islets and the progression of diabetes. Islet autocrine PCSK9 deficiency can lead to the enrichment of low-density lipoprotein (LDL) receptor (LDLR) and excessive LDL cholesterol (LDL-C) uptake, subsequently impairing the insulin secretion in β-cells. Circulatory PCSK9 levels are primarily attributed to hepatocyte secretion. Notably, anti-PCSK9 strategies proposed for individuals with hypercholesterolemia chiefly target liver-derived PCSK9; however, these anti-PCSK9 strategies have been associated with the risk of new-onset diabetes mellitus (NODM). In the current review, we highlight a new direction in PCSK9 inhibition therapy strategies: screening candidates for anti-PCSK9 from the drugs used in type 2 diabetes mellitus (T2DM) treatment. We explored the association between circulating, local pancreatic PCSK9 and T2DM, as well as the relationship between PCSK9 monoclonal antibodies and NODM. We discussed the emergence of artificial and natural drugs in recent years, exhibiting dual benefits of antidiabetic activity and PCSK9 reduction, confirming that the diverse effects of these drugs may potentially impact the progression of diabetes and associated disorders, thereby introducing novel avenues and methodologies to enhance disease prognosis.

Gluconeogenesis is closely related to the occurrence and development of type 2 diabetes mellitus (T2DM). Gentiopicroside (GPS) is the main active secoiridoid glycoside in Gentiana manshurica Kitagawa, which can improve chronic complications associated with diabetes and regulate glucose metabolism. However, the effects and potential mechanisms by which GPS affects T2DM understudied and poorly understood. In this study, we systematically explored the pharmacological effects of GPS on T2DM induced by a high-fat diet (HFD) and streptozotocin (STZ) as well as explored its related mechanisms. The results showed that GPS supplementation discernibly decreased blood glucose levels, food intake and water consumption, ameliorated glucose intolerance, abnormal pyruvate tolerance, insulin resistance and dyslipidemia. Furthermore, GPS discernibly ameliorated pathological morphological abnormalities of the liver and pancreas, reduced hepatic steatosis and maintain the balance between α-cells and β-cells in pancreas. Moreover, GPS significantly inhibited gluconeogenesis, as evidenced by the suppressed protein expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) in the liver. Additionally, the results of Western blot analysis revealed that GPS increased p-PI3K, p-AKT, and p-FOXO1 expression levels, and decreased FOXO1 expression at protein level in the liver. Furthermore, the results of the immunostaining and Western blot analysis demonstrated that GPS supplementation increased the expression of zonula occludens-1 (ZO-1) and occludin in the ileum. Collectively, these results indicate that GPS may inhibit hepatic gluconeogenesis by regulating the PI3K/AKT/FOXO1 signaling pathway and maintain intestinal barrier integrity, and ultimately improve T2DM. Together, these findings indicate that GPS is a potential candidate drug for the prevention and treatment of T2DM, and the results of our study will provide experimental basis for further exploration of the possibility of GPS as a therapeutic agent for T2DM.

Nephropathy is the most prevalent microvascular disorder in diabetes mellitus. Oxidative stress and inflammatory cascade provoked by the persistent hyperglycemic milieu play integral roles in the aggravation of renal injury and fibrosis. We explored the impact of biochanin A (BCA), an isoflavonoid, on the inflammatory response, nod-like receptor protein 3 (NLRP3) inflammasome activation, oxidative stress, and fibrosis in diabetic kidneys. A high-fat-diet/streptozotocin (HFD/STZ)-induced experimental model of diabetic nephropathy (DN) was established in Sprague Dawley rats, and in vitro studies were performed in high-glucose-induced renal tubular epithelial (NRK-52E) cells. Persistent hyperglycemia in diabetic rats was manifested by perturbation of renal function, marked histological alterations, and oxidative and inflammatory renal damage. Therapeutic intervention of BCA mitigated histological changes, improved renal function and antioxidant capacity, and suppressed phosphorylation of nuclear factor-kappa B (NF-κB) and nuclear factor-kappa B inhibitor alpha (IκBα) proteins. Our in vitro data reveal excessive superoxide generation, apoptosis, and altered mitochondrial membrane potential in NRK-52E cells that were cultured in a high-glucose (HG) environment were subsided by BCA intervention. Meanwhile, the upregulated expressions of NLRP3 and its associated proteins, the pyroptosis-indicative protein gasdermin-D (GSDMD) in the kidneys, and HG-stimulated NRK-52E cells were significantly ameliorated by BCA treatment. Additionally, BCA blunted transforming growth factor (TGF)-β/Smad signaling and production of collagen I, collagen III, fibronectin, and alfa-smooth muscle actin (α-SMA) in diabetic kidneys. Our results indicate the plausible role of BCA in attenuating DN, presumably through modulation of the apoptotic cascade in renal tubular epithelial cells and the NF-κB/NLRP3 axis.

Obesity is a disorder with an increasing prevalence, which impairs the life quality of patients and intensifies societal health care costs. The development of safe and innovative prevention strategies and therapeutic approaches is thus of great importance. The complex pathophysiology of obesity involves multiple signaling pathways that influence energy metabolism in different tissues. The phosphatidylinositol 3-kinases (PI3K)/protein kinase B (AKT) pathway is critical for the metabolic homeostasis and its function in insulin-sensitive tissues is described in the context of health, obesity and obesity-related complications. The PI3K family participates in the regulation of diverse physiological processes including but not limited to cell growth, survival, differentiation, autophagy, chemotaxis, and metabolism depending on the cellular context. AKT is downstream of PI3K in the insulin signaling pathway, and promotes multiple cellular processes by targeting a plethora of regulatory proteins that control glucose and lipid metabolism. Natural products are essential for prevention and treatment of many human diseases, including obesity. Anti-obesity natural compounds effect multiple pathophysiological mechanisms involved in obesity development. Numerous recent preclinical studies reveal the advances in using plant secondary metabolites to target the PI3K/AKT signaling pathway for obesity management. In this paper the druggability of PI3K as a target for compounds with anti-obesity potential is evaluated. Perspectives on the strategies and limitations for clinical implementation of obesity management using natural compounds modulating the PI3K/AKT pathway are suggested.

Nanoplastics have become ubiquitous in the global environment and have attracted increasing attention. However, whether there is an influence between exposure to nanoplastics and diabetes is unclear. To determine the effects of exposure to Polystyrene nanoplastics (PS-NPs) and evaluate the underlying mechanisms, mice were orally exposed to PS-NPs at dosages of 1, 10, 30 mg/kg/day for 8 weeks, alone or combined with a high fat diet and streptozocin (STZ) injection. Our data showed that exposure to 30 mg/kg/day PS-NPs alone induced a significant increase in blood glucose, glucose intolerance and insulin resistance. Combined with a high fat diet and STZ injection, PS-NPs exposure markedly aggravated oxidative stress, glucose intolerance, insulin tolerance and insulin resistance, and induced lesions in the liver and pancreas. PS-NPs exposure could decrease the phosphorylation of AKT and GSK3β, and treatment with SC79, a selective AKT activator, could increase the level of AKT and GSK3β phosphorylation, effectively alleviating the increase in ROS levels in the liver or pancreas, and slightly attenuating the increase in fasting blood glucose levels and insulin resistance induced by PS-NPs exposure. This showed that exposure to PS-NPs aggravated type 2 diabetes and the underlying mechanism partly involved in the inhibition of AKT/GSK3β phosphorylation.

Type 2 diabetes mellitus leads to metabolic impairment caused by insulin resistance and hyperglycemia, giving rise to chronic diabetic complications and poor disease prognosis. The heartwood of Pterocarpus marsupium has been used in Ayurveda for a long time, and we sought to find the actual mechanism(s) driving its antidiabetic potential. Methanol was used to prepare the extract using a Soxhlet extraction, and the identification of metabolites was performed by thin-layer chromatography (TLC) and ultraperformance-liquid chromatography and mass spectroscopy (UP-LCMS). The antioxidant potential of methanolic heartwood extract of Pterocarpus marsupium MHPM was determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and a reducing power assay. The α-amylase and α-glucosidase enzyme inhibitory potential of MHPM were investigated for their antidiabetic activity against acarbose. TLC-MS-bioautography was performed to identify the compounds responsible for possible antioxidant and antidiabetic activities. Moreover, targeting protein tyrosine phosphatase 1B (PTP1B), a key regulator of insulin resistance, by identified metabolites from MHPM through molecular docking and all-atom molecular dynamics (MD) simulations was also undertaken, suggesting its potential as an antidiabetic herb. The IC₅₀ of free-radical scavenging activity of MHPM against DPPH was 156.342 ± 10.70 μg/mL. Further, the IC₅₀ values of MHPM in α-amylase and α-glucosidase enzymatic inhibitions were 158.663 ± 10.986 μg/mL and 180.21 ± 11.35 μg/mL, respectively. TLC-MS-bioautography identified four free radical scavenging metabolites, and vanillic acid identified by MS analysis showed both free radical scavenging activity and α-amylase inhibitory activity. Among the identified metabolites from MHPM, epicatechin showed significant PTP1B docking interactions, and its MD simulations revealed that PTP1B forms a stable protein-ligand complex with epicatechin throughout the progression, which indicates that epicatechin may be used as a promising scaffold in the development of the antidiabetic drug after isolation from Pterocarpus marsupium. Overall, these findings imply that Pterocarpus marsupium is a source of valuable metabolites that are accountable for its antioxidant and antidiabetic properties.

Pterostilbene is a stilbene flavonoid that occurs naturally in various plants as well as produced by genetic engineering. It exhibits anti-inflammatory, analgesic, anti-oxidant and neuroprotective activities. This research was aimed to determine the potential of pterostilbene against arthritis and peripheral neuropathy in Complete Freund's Adjuvant (CFA) induced arthritis. Rat hind paw was injected with 0.1 ml CFA to induce arthritis. Standard control animals received oral methotrexate (3 mg/kg/week). Pterostilbene at 12.5, 25 and 50 mg/kg was given orally to different groups of arthritic rats from day 7-28 for 21 days. Pterostilbene significantly reduced paw diameter and retarded the decrease in body weight of arthritic rats. It profoundly (p < 0.05-0.0001) reduced lipid peroxidation and nitrites, while increased superoxide dismutase (SOD) in the liver tissue. Pterostilbene treatment significantly (p < 0.0001) reduced TNF-α and IL-6 levels. Pterostilbene markedly improved (p < 0.05-0.001) motor activity and showed analgesic effect in arthritic rats at 25 and 50 mg/kg as compared to disease control rats. Furthermore, it notably (p < 0.05-0.0001) increased SOD activity, nitrites, noradrenaline and serotonin levels in the sciatic nerve of arthritic rats. Treatment with pterostilbene also ameliorated the CFA-induced pannus formation, cartilage damage and synovial hyperplasia in the arthritic rat paws. It is determined from the current study that pterostilbene was effective in reducing CFA-induced arthritis in rats through amelioration of oxidative stress and inflammatory mediators. It was also effective to treat peripheral neuropathy through modulation of oxidative stress and neurotransmitters in sciatic nerves.

The development of diabetes is closely related to the gut microbiota in recent studies, which can be influenced by intestinal motility. A few studies report that electroacupuncture (EA) can lower blood glucose. EA can promote colonic motility and influence gut microbes. In this study, we explored the effect of the EA on blood glucose level in mice with type 2 diabetes (T2D) and its mechanism.

The T2D mice model, fecal microbiota transplantation mice model, and Kit^W/Wv mice model （Point mutation of mouse W locus encoding kit gene）were used to investigate the effect of EA on blood glucose as well as the mechanism; The blood glucose and insulin resistance level and the intestinal flora were evaluated. The level of intestinal junction protein, inflammatory cytokines in the serum, interstitial cells of Cajal content, and colonic motility were detected. Lastly, the IKKβ/NF-κB-JNK-IRS-1-AKT pathway was explored.

EA lowered the blood glucose level, altered the gut microbiota, and promoted colonic motility in T2D mice. EA-altered microbiota decreased the blood glucose level and insulin resistance in the antibiotics-treated diabetic mice. EA increased tight junction protein, lowered inflammatory factors, and regulated the IKKβ/NF-κB-JNK-IRS-1-AKT pathway in the liver and muscles. EA could not reduce the blood glucose and regulated gut microbiota in the Kit^W/Wv mice model.

EA promoted intestinal motility to regulate the intestinal flora, thereby reducing the level of systemic inflammation, and ultimately lowering the blood glucose by the IKKβ/NF-κB-JNK-IRS-1-AKT signal pathway.

Impaired wound healing is one of a variety of severe diabetic complications and involves many factors, including consistent oxidative stress, prolonged inflammation, impaired angiogenesis, and delayed re-epithelialization. Despite the severe negative impacts that impaired wound healing has on patients' lives, detailed mechanisms and effective therapies are still not fully developed. In this study, we aim to investigate the potential effects and mechanisms of topical administration of pterostilbene and resveratrol on burn wound healing in diabetes. Our in vitro experiments in human umbilical vein endothelial cells showed that long term exposure of hyperglycemia induces oxidative stress and suppression of hypoxia inducible factor1α (HIF1α) signaling pathway, and pterostilbene treatment completely, while resveratrol treatment partly, reversed this effect. Further in vivo experiments in diabetic rats showed that topical administration of pterostilbene exhibited stronger efficacy than resveratrol in normalizing oxidative stress, HIF1α activity, and accelerating burn wound healing in diabetes. We conclude that topical administration of pterostilbene accelerates burn wound healing in diabetes through activation of the HIF1α signaling pathway; thus, pterostilbene may be a potential candidate for clinical treatment of burn wound healing in diabetes.

American ginseng (Panax quinquefolius L.) is popularly consumed as traditional herbal medicine and health food for the treatment of type 2 diabetes mellitus (T2DM). Malonyl ginsenosides (MGR) are the main natural ginsenosides in American ginseng. However, whether the malonyl ginsenosides in P. quinquefolius (PQ-MGR) possess antidiabetic effects has not been explored yet. In this study, the antidiabetic effects and the underlying mechanism of PQ-MGR in high-fat diet/streptozotocin (HFD/STZ)-induced T2DM mice were investigated. The chemical composition was analyzed by high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). Our results showed that 14 malonyl ginsenosides were identified in the PQ-MGR. Among them, the content of m-Rb₁ represented about 77.4% of the total malonyl ginsenosides. After a 5-week experiment, the PQ-MGR significantly reduced the fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), nonesterified fatty acid (NEFA), alanine transaminase (ALT), and aspartate transaminase (AST) levels and improved glucose tolerance and insulin resistance. Furthermore, Western blot analysis demonstrated that the protein expressions of p-PI3K, p-AKT, p-AMPK, p-ACC, PPAR_γ, and GLUT4 in the liver and skeletal muscle were significantly upregulated after PQ-MGR treatment. In contrast, the protein expressions of p-IRS1 and p-JNK were significantly downregulated. Our results revealed that PQ-MGR could ameliorate glucose and lipid metabolism and insulin resistance in T2DM via regulation of the insulin receptor substrate-1/phosphoinositide3-kinase/protein-kinase B (IRS1/PI3K/Akt) and AMP-activated protein kinase/acetyl-CoA carboxylase (AMPK/ACC) pathways. These findings suggest that PQ-MGR may be used as an antidiabetic candidate drug for T2DM treatment.

Impaired wound healing is a major complication of diabetes and involves sustained inflammation and oxidative stress at the wound site. Here, we investigated the potential involvement of ferroptosis, a newly discovered form of cell death characterized by iron-dependent accumulation of lipid peroxides in the pathogenesis of diabetic wound healing. Fibroblasts and vascular endothelial cells exposed to high glucose concentrations in vitro contained elevated levels of reactive oxygen species (ROS), lipid peroxidation products, and ferroptosis-associated proteins and displayed reduced survival and migration. These effects of high glucose were all significantly reduced by treatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1). Similarly, in a rat model of diabetes, direct application of Fer-1 to the wound site reduced the expression of oxidative stress and inflammation markers and accelerated wound healing via activation of the anti-inflammatory phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. Our results implicate ferroptosis in wound healing and identify a potential new therapeutic target for difficult-to-treat diabetic wounds.NEW & NOTEWORTHY Ferroptosis-related characteristic changes were found in diabetic wound models. Inhibition of ferroptosis improved inflammatory infiltration of diabetic wounds. PI3K/AKT signal pathway was rescued by restraining of ferroptosis. Mitigation of ferroptosis in diabetic wound promoted the wound healing.

Biological targeting or molecular targeting is the main strategy in drug development and disease prevention. However, the problem of "off-targets" cannot be neglected. Naturally derived drugs are preferred over synthetic compounds in pharmaceutical markets, and the main goals are high effectiveness, lower cost, and fewer side effects. Single-target drug binding may be the major cause of failure, as the pathogenesis of diseases is predominantly multifactorial. Naturally derived drugs are advantageous because they are expected to have multitarget effects, but not off-targets, in disease prevention or therapeutic actions. The capability of phytochemicals to modulate molecular signals in numerous diseases has been widely discussed. Among them, stilbenoids, especially resveratrol, have been well-studied, along with their potential molecular targets, including AMPK, Sirt1, NF-κB, PKC, Nrf2, and PPARs. The analogues of resveratrol, pterostilbene, and hydroxylated-pterostilbene may have similar, if not more, potential biological targeting effects compared with their original counterpart. Furthermore, new targets that have been discussed in recent studies are reviewed in this paper.

In this study, we aimed to explore the antidiabetic effects of Lactobacillus rhamnosus LRa05 on glucose metabolism and gut microbiota in type 2 diabetes mellitus (T2DM) mice. Our data indicated that the fasting blood glucose levels were reduced by 53.5% after treatment with LRa05 at a dose of 10⁹ CFU·day^-1. Meanwhile, LRa05 attenuated insulin resistance, relieved hepatic oxidative stress, and alleviated metabolic lipopolysaccharide-related inflammation in T2DM mice. LRa05 promoted the expression of glucose transporter 2, while it inhibited the expression of glucagon receptor, glucose-6-phosphatase, cellular adenosine-3'-5'-cyclic monophosphate-dependent protein kinase, and phosphoenolpyruvate carboxykinase in diabetic mice. Meanwhile, LRa05 reshaped gut microbiota, resulting in increased short-chain fatty acid bacteria (Alloprevotella and Bacteroides) and decreased proinflammatory bacteria (Odoribacter and Mucispirillum). Thus, LRa05 may be used as a functional food supplement for modulating the disorder glucose metabolism and gut microbiota in T2DM.