The endoplasmic reticulum (ER) plays a fundamental role in maintaining cellular homeostasis by ensuring proper protein folding, lipid metabolism, and calcium regulation. However, disruptions to ER function, known as ER stress, activate the unfolded protein response (UPR) to restore balance. Chronic or unresolved ER stress contributes to metabolic dysfunctions, including insulin resistance, non-alcoholic fatty liver disease (NAFLD), and neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Recent studies have also highlighted the importance of mitochondria-ER contact sites (MERCs) and ER-associated inflammation in disease progression. This review explores the current pharmacological landscape targeting ER stress, focusing on therapeutic strategies for rare metabolic and neurodegenerative diseases. It examines small molecules such as tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA), repurposed drugs like 17-AAG (17-N-allylamino-17demethoxygeldanamycin (tanespimycin)) and berberine, and phytochemicals such as resveratrol and hesperidin. Additionally, it discusses emerging therapeutic areas, including soluble epoxide hydrolase (sEH) inhibitors for metabolic disorders and MERCs modulation for neurological diseases. The review emphasizes challenges in translating these therapies to clinical applications, such as toxicity, off-target effects, limited bioavailability, and the lack of large-scale randomized controlled trials (RCTs). It also highlights the potential of personalized medicine approaches and pharmacogenomics in optimizing ER stress-targeting therapies.

Oxidative stress, which results from the overproduction of reactive oxygen species (ROS) that induce protein, lipid, and DNA oxidation, has emerged as a key factor in the pathogenesis of various diseases, including type 2 diabetes (T2D). Recently, the relationship between oxidative stress and T2D has gained considerable attention. Widely utilized as probiotics in fermented foods and beverages, lactic acid bacteria (LAB) exhibit potent antioxidant properties. However, the precise mechanisms enabling LAB to behave as antioxidants remain elusive. LAB play a pivotal role in promoting and maintaining host health while mitigating the development and progression of various disorders, including T2D. Against the backdrop of a large number of studies highlighting the beneficial role of LAB in mitigating oxidative stress-related diseases, this review explores potential biomarkers for the prevention of oxidative stress and examines the potential contribution of LAB to the fight against T2D.

Glucagon-like peptide-1 receptor agonists (GLP-1RA) are antihyperglycemic agents used to control type 2 diabetes mellitus (T2DM). Recently, there has been increased recognition of the potential pulmonary protective effects of GLP-1RA. Given the bidirectional association between T2DM and obstructive lung disease (OLD) incidence and progression, our systematic review aimed to determine if GLP-1RA therapy for comorbid T2DM was associated with a decreased risk of asthma and COPD exacerbations, relative to other T2DM treatments.

We systematically searched for English-language articles published in Ovid Medline, Embase, Scopus, CENTRAL and CINAHL databases from inception to June 25, 2024. Random effects meta-analysis was used to aggregate data where feasible.

Of 23 full-text manuscripts considered for inclusion, six retrospective observational studies were selected (total N = 62,678). The pooled incidence rate ratios (IRR) of asthma or COPD exacerbations demonstrated a statistically significant lower risk of exacerbations associated with GLP-1RA compared to sulfonylureas (IRR, 95 %CI: 0.52, 0.42-0.64) or dipeptidyl peptidase-4 inhibitors (DPP-4I) (IRR 0.63, 0.47-0.86), but not sodium glucose cotransporter-2 inhibitors (SGLT2I) (IRR 0.66, 0.21-2.05). The risk of exacerbations rate was also lower in GLP-1RA users relative to insulin in a single study (IRR 0.39, 0.26-0.58) and higher compared to metformin in a single Japanese cohort (IRR 1.24, 1.08-1.43).

Our systematic review and meta-analysis provides evidence for a reduced risk for asthma and COPD exacerbations associated with GLP-1RA use in adults with OLD and T2DM, relative to sulfonylureas or DPP-4I medications. Future research should focus on confirming our observed relationships in prospective trials.

As some of the most promising candidates available, fullerene-derived bioactive agents have been explored as new drugs with high efficacy and safety for biomedical applications. In this study, a fullerene-lysine derivative (C60-Lys) was synthesized successfully and proved to be good at treating type 2 diabetes mellitus (T2DM). C60-Lys could alleviate oxidative stress both in streptozotocin (STZ)-induced MIN6 cells and in STZ-induced T2DM mice subjected to a high-fat diet, and it significantly normalized glucose uptake and reduced blood glucose. In addition, C60-Lys can alleviate insulin resistance, hyperinsulinemia and lipid levels in T2DM mice. It was further confirmed that C60-Lys could alleviate oxidative stress by increasing the activities of antioxidant enzymes and stabilizing the mitochondrial membrane potential (MMP) of pancreatic β-cells to reduce the overproduction of ROS. The results provide compelling evidence that C60-Lys possesses promising applications for T2DM treatment.

An 8-week feeding experiment was carries out to explore the impacts of dietary tauroursodeoxycholic acid (TUDCA) on growth and gut integrity in spotted seabass (Lateolabrax maculatus) under heat stress (33 °C). Three hundred fish (2 ± 0.02 g) were allocated to triplicate groups and fed five diets containing graded levels of TUDCA at 0, 10, 20, 30, or 40 mg/kg (designated as Con, T10, T20, T30 and T40 diets). Growth performance was significantly (P < 0.05) enhanced in fish receiving ≥30 mg/kg TUDCA compared to the control group. Progressive increases in intestinal total antioxidant capacity and superoxide dismutase activity, accompanied by decreased malondialdehyde concentration, were observed as TUDCA dose increased. TUDCA application modulated the expression of intestinal antioxidant-related genes, downregulating keap1 and upregulating nrf2. Notably, supplementation with 40 mg/kg TUDCA improved intestinal morphology, as evidenced by increased villus height and number. Furthermore, in the T40 group, a marked downregulation of pro-apoptotic genes (caspase3, caspase8, caspase9, and bax) and reduced immunofluorescence intensity were observed, while the expression of the anti-apoptotic gene bcl was significantly up-regulated. Additionally, the expression of pro-inflammatory genes (il-1β, il-8, and tnf-α) and immunofluorescence intensity were significantly reduced in the T40 group compared to control. In contrast, the expression of anti-inflammatory genes (il-4, il-10, and tgf-β) was markedly upregulated. Furthermore, dietary inclusion of 40 mg/kg TUDCA suppressed the expression of endoplasmic reticulum stress-related genes (grp78, chop, perk, atf6, and ire1) and activated the bile acid receptor gene tgr5 in the intestine. Concurrently, TUDCA treatment enhanced the PI3K-Akt signaling pathway, contributing to the inhibition of apoptosis. The data generated in this study demonstrated that dietary supplementation with 40 mg/kg TUDCA promotes growth, activates the Nrf2-Keap1 and PI3K-AKT signaling pathways, enhances intestinal antioxidant defenses, suppresses inflammation and apoptosis, alleviates endoplasmic reticulum stress, and mitigates the physiological impacts of heat stress in L. maculatus reared at elevated temperatures.

Diabetes mellitus, a complex metabolic disorder, is marked by chronic hyperglycemia that drives oxidative stress and inflammation, leading to complications such as neuropathy, retinopathy, and cardiovascular disease. The Nrf2 pathway, a key regulator of cellular antioxidant defenses, plays a vital role in mitigating oxidative damage and maintaining glucose homeostasis. Dysfunction of Nrf2 has been implicated in the progression of diabetes and its related complications. Polyphenols, a class of plant-derived bioactive compounds, have shown potential in modulating the Nrf2 pathway. Numerous compounds have been found to activate Nrf2 through mechanisms including Keap1 interaction, transcriptional regulation, and epigenetic modification. Preclinical studies indicate their ability to reduce reactive oxygen species (ROS), improve insulin sensitivity, and attenuate inflammation in diabetic models. Clinical trials with certain polyphenols, such as resveratrol, have demonstrated improvements in glycemic parameters, though results remain inconsistent. While polyphenols show promise as a component of non-pharmacological approaches to diabetes management, challenges such as bioavailability, individual variability in response, and limited clinical evidence highlight the need for further investigation. Continued research could enhance understanding of their mechanisms and improve their practical application in mitigating diabetes-related complications.

Inflammation is a crucial response to harmful stimuli, but its chronic activation contributes to various diseases, including inflammatory bowel disease, osteoarthritis, and neurological disorders. While nonsteroidal anti-inflammatory drugs are widely used as anti-inflammation drugs, their extended usage often results in severe side effects, emphasizing the need for safer alternatives. Therefore, it is of the greatest importance to identify and discover new anti-inflammatory agents that exhibit a reduced incidence of adverse side effects. This study investigates the anti-inflammatory potential of methanol extracts from eight native Vietnamese plant species. These extracts were screened for their ability to inhibit nitric oxide production and pro-inflammatory cytokine expression in lipopolysaccharides-stimulated RAW264.7 macrophages. Among the tested extracts, those derived from Huberantha luensis (Pierre) Chaowasku and Ancistrocladus tectorius (Lour.) Merr. demonstrated notable reductions in NO, TNF-α, interleukin (IL)-1β, and IL-6 levels. Further analysis revealed that these extracts are abundant in polyphenols and flavonoids, compounds recognized for their anti-inflammatory effects. Furthermore, these extracts exerted their effects by inhibiting the kappa-light-chain-enhancer of activated B cells and mitogen-activated protein kinase signaling pathways, as evidenced by reduced phosphorylation of the proteins. These results suggest that the methanol extracts obtained from H. luensis and A. tectorius possess considerable potential in paving the way towards the innovative development of new therapeutic approaches aimed at alleviating chronic inflammation.

This study aimed to investigate the impact of hydrogen peroxide-induced oxidative stress on the protein expression profiles of submandibular and parotid acinar cells using a proteomic approach. We sought to evaluate how oxidative stress might contribute to salivary gland dysfunction and whether the two glands respond differently.

Immortalized rat parotid gland (PG) and submandibular gland (SMG) acinar epithelial cell lines were exposed to 50 µM and 150 µM hydrogen peroxide for 24 hr, followed by protein identification and quantification via liquid chromatography-mass spectrometry. Immunofluorescence microscopy and western blot analysis validated selected protein expressions, and cell viability was assessed using trypan blue exclusion assays.

Compared to controls, histone H4 expression increased in both cell types after hydrogen peroxide exposure, whereas voltage-dependent anion-selective channel 1, keratin 7, and keratin 8 increased only in parotid gland cells. Conversely, mitochondrial aldehyde dehydrogenase and kidney isoform glutaminase were downregulated in parotid gland cells. Basal expression of mitochondrial aldehyde dehydrogenase and catalase was higher in submandibular gland cells. At higher hydrogen peroxide concentrations, antioxidant proteins expression and cell viability were greater in submandibular gland cells compared to parotid gland cells.

Our results suggest that submandibular gland acinar cells exhibit greater resistance to oxidative stress compared to parotid gland cells, potentially due to distinct antioxidant and metabolic coping strategies. Understanding these gland-specific responses may contribute to future approaches to protect salivary glands from oxidative damage under pathological conditions.

Oxidative stress, driven by excess ROS, damages lipids, proteins, and DNA, leading to neuronal apoptosis and inflammation, a key factor in neurodegenerative diseases. This study explored stigmasterol, a bioactive phytosterol, with neuroprotective potential, revealing strong docking interactions, especially with Keap1 (binding energy of -11.62 Kcal/mol). Stigmasterol formed two hydrogen bonds with Ile258 and Val305 in Keap1, suggesting it could disrupt Keap1-Nrf2 interactions, potentially activating antioxidant responses by promoting Nrf2 translocation to the nucleus. In the Bcl2-stigmasterol complex, which exhibited a binding energy of -8.41 Kcal/mol, hydrophobic interactions with residues Ser50, Gln52, and Leu185 stabilized the complex, indicating stigmasterol's role in inhibiting apoptosis by strengthening of Bcl2 mediated inhibition of pro-apoptotic factors like Bax. Furthermore, the IKKβ-stigmasterol complex displayed a hydrogen bond between Asp385 residue and stigmasterol (2.83 Å), with a binding energy of -8.33 Kcal/mol, suggested that stigmasterol may regulate inflammation by stabilizing IKKβ, thereby preventing NF-κB translocation and reducing inflammation. Molecular dynamics simulations confirmed the stability of stigmasterol's interactions, especially with Keap1, which showed low RMSD values and consistent hydrogen bonding. RMSF and Rg analyses indicated that stigmasterol had stabilizing effects on Bcl2 and IKKβ. These results underscore stigmasterol's potential for neuroprotection through antioxidant and anti-inflammatory actions.

Clerodendrum glandulosum is utilized as a soup or vegetable in Northeast India and has been reported to exhibit a range of medicinal and pharmacological properties. Its use in traditional cuisine and medicine highlights its potential importance in both dietary and therapeutic applications. This study focuses on the bioactive potential of the ethyl acetate fraction (EAF) derived from the hydro-alcoholic extract of C. glandulosum leaves against palmitate-induced oxidative stress and mitochondrial dysfunction. The EAF exhibited significant radical scavenging activities, with IC50 values of 29.56 µg/mL (ABTS inhibition) and 36.61 µg/mL (DPPH inhibition). Additionally, EAF demonstrated strong anti-glycation properties, effectively reducing fructosamine levels and protein carbonylation while increasing total thiol content. Phytochemical analysis revealed the presence of several bioactive compounds--namely verbascoside, isoverbascoside, and ferulic acid--associated with potential biological activities. Chromatographic analysis showed that verbascoside is the primary compound, with a concentration of 240.41 ± 8.62 µg/mg. Furthermore, EAF pretreatment significantly lowered the levels of reactive oxygen species, DNA damage, and lactate dehydrogenase release in palmitate-induced cells. During extracellular flux analysis for mitochondrial and glycolysis stress tests, EAF treatment demonstrated effective recovery of mitochondrial respiration and ATP production in palmitate-induced cells. EAF also upregulated essential mitochondrial markers, including peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and mitochondrial transcription factor A (TFAM), which enhanced mitochondrial biogenesis and function. Overall, our study underscores the potential of the EAF from Clerodendrum glandulosum as a therapeutic agent to mitigate oxidative stress and mitochondrial dysfunction. This study suggests the efficacy of the active compounds for further development of phytopharmaceutical interventions for metabolic syndrome and related disorders.

The growing prevalence of diabetes highlights the urgent need to study diabetic cardiovascular complications, specifically diabetic cardiomyopathy, which is a diabetes-induced myocardial dysfunction independent of hypertension or coronary artery disease. This review examines the role of mitochondrial dysfunction in promoting diabetic cardiac dysfunction and highlights metabolic mechanisms such as hyperglycaemia-induced oxidative stress. Chronic hyperglycaemia and insulin resistance can activate harmful pathways, including advanced glycation end-products (AGEs), protein kinase C (PKC) and hexosamine signalling, uncontrolled reactive oxygen species (ROS) production and mishandling of Ca2+ transient. These processes lead to cardiomyocyte apoptosis, fibrosis and contractile dysfunction. Moreover, endoplasmic reticulum (ER) stress and dysregulated RNA-binding proteins (RBPs) and extracellular vesicles (EVs) contribute to tissue damage, which drives cardiac function towards heart failure (HF). Advanced patient-derived induced pluripotent stem cell (iPSC) cardiac organoids (iPS-COs) are transformative tools for modelling diabetic cardiomyopathy and capturing human disease's genetic, epigenetic and metabolic hallmarks. iPS-COs may facilitate the precise examination of molecular pathways and therapeutic interventions. Future research directions encourage the integration of advanced models with mechanistic techniques to promote novel therapeutic strategies.

Chronic liver diseases (CLDs) in dogs are progressive conditions that often lead to liver failure. Metabolic dysfunctions such as cholestasis, obesity, hyperlipidemia, and endocrine disorders play a key role in human liver diseases like MASLD (Metabolic Dysfunction Associated Steatotic Liver Disease) and MASH (Metabolic Dysfunction Associated Steatohepatitis), but their significance in canine CLDs is poorly understood. This study aims to evaluate the association between hepatic lipid accumulation and inflammation or fibrosis in canine CLDs and its potential association with metabolic dysfunctions. Sixteen client-owned dogs with CLDs were assessed for clinical data, histological features, and liver immunohistochemistry (IHC). Histological and IHC markers of inflammation (Iba-1, iNOS, NF-κB), fibrosis (CD206, α-SMA, Sirius Red), and lipid accumulation (adipophilin) were assessed to identify correlations with clinical conditions. The applied markers showed effectiveness in their use on canine liver tissue. Adipophilin-marked lipid accumulation correlated positively with inflammatory markers, indicating a link between steatosis and inflammation. Metabolic dysfunctions were linked to hepatic lipid accumulation and inflammation. These findings show a potential alignment of canine CLDs with human MASLD/MASH, where lipid-induced inflammation drives disease progression. IHC markers could effectively assess these processes, suggesting potential for guiding diagnostics and therapies, though further research is needed to clarify clinical associations.

Alzheimer's disease (AD) is a neurodegenerative disease caused by the progressive deposition of extracellular amyloid beta (Aβ) and intracellular neurofibrillary tangles (NFTs). Of note, metabolic disorders such as insulin resistance (IR) and type 2 diabetes (T2D) are associated with the development of brain IR and associated neurodegeneration. In addition, AD neuropathology and linked cognitive impairment accelerate the development of peripheral IR and the progression of T2D. Therefore, there is a bidirectional relationship between T2D and AD. It has been demonstrated that AD and T2D induce dysregulation of peroxisome proliferator-activated receptor alpha (PPAR-α) leading to the central and peripheral metabolic disturbances. Hence, dysregulated PPAR-α could be a shared mechanism in both AD and T2D, and restoration of PPAR-α signalling by PPAR-α agonist fenofibrate (FN) may alleviate T2D and AD. Therefore, this review aims to shed light on the potential involvement of PPAR-α in T2D and AD, and how FN could be effective in the management of AD. FN seems to be effective in both AD and T2D by dual neuroprotective and antidiabetic effects that can mitigate AD neuropathology and T2D-related complications by modulating various cellular processes and inflammatory signalling pathways. In conclusion, FN could be a possible candidate in the management of AD and T2D by modulating different signalling pathways involved in the pathogenesis of these conditions.

The aim of this study was to determine the anti-inflammatory and anti-endoplasmic reticulum (ER) stress effects of Aruncus dioicus var. kamtschaticus (ADK) extract on ARPE-19 cells. Pretreatment with ADK effectively mitigated thapsigargin (Tg)-induced increases in vascular endothelial growth factor protein secretion and intracellular calcium levels. Furthermore, pretreatment with ADK suppressed ocular ER stress-related protein expression in a dose-dependent manner, inhibited the loss of tight junctions, and suppressed interleukin-6 gene expression. Moreover, ADK pretreatment significantly prevented lipopolysaccharide-inducible proinflammatory cytokine gene expression at the transcription level and the phosphorylation of proteins involved in the mitogen-activated protein kinase-nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) axis at the posttranslational level. Additionally, ADK extract enhanced antioxidant activity, as evidenced by increased heme oxygenase-1 protein expression and increased 2,2-diphenyl-1-picrylhydrazyl radical scavenging and ferric-reducing antioxidant power. In conclusion, ADK extract effectively protected ARPE-19 cells from ocular ER stress, inflammation, and oxidative stress, demonstrating its potential as a nutraceutical intervention for ocular diseases.

People with type 2 diabetes (T2D) have a 2-3-time higher risk of developing sarcopenia, a musculoskeletal disease marked by a progressive loss of skeletal muscle mass and strength, compared to people without T2D. This narrative review examines the effectiveness of lifestyle interventions in enhancing muscle mass and strength in people with T2D, emphasizing their growing importance with advancements in obesity treatments. PubMed and Google Scholar were utilized to identify the most relevant published studies based on the authors' knowledge. The maintenance of skeletal muscle strength and mass in people with T2D is becoming more prominent due to the advent of weight loss therapies such as low-energy diets, bariatric surgery and pharmacotherapies. Although the weight loss is to be commended, a large proportion (20-50%) of the weight loss comes from lean mass, indicative of a loss in muscle mass. There are currently no pharmacotherapies to increase, or mitigate the loss of, lean mass, with lifestyle strategies prominent in this arena. Resistance exercise is the most effective method to increase muscle mass and strength in people with T2D, but there is some evidence of an anabolic resistance. Aerobic exercise and increased dietary protein intake may result in small increases in muscle mass and strength, with no evidence of an anabolic resistance to these stimuli. Exercise and protein supplementation can increase, or aid in the retention of, muscle strength and mass in individuals with T2D, but further research is needed to explore their benefits in patients undergoing concomitant pharmaceutical and surgical treatments.

Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterized by insulin resistance and beta cell dysfunction, resulting in hyperglycemia. Olive oil, a cornerstone of the Mediterranean diet, has attracted considerable attention due to its potential health benefits, including reducing the risk of developing T2DM. This literature review aims to critically examine and synthesize existing research regarding the impact of olive oil on the expression of genes relevant to T2DM. This paper also seeks to provide an immunological and genetic perspective on the signaling pathways of the main components of extra virgin olive oil. Key bioactive components of olive oil, such as oleic acid and phenolic compounds, were identified as modulators of insulin signaling. These compounds enhanced the insulin signaling pathway, improved lipid metabolism, and reduced oxidative stress by decreasing reactive oxygen species (ROS) production. Additionally, they were shown to alleviate inflammation by inhibiting the NF-κB pathway and downregulating pro-inflammatory cytokines and enzymes. Furthermore, these bioactive compounds were observed to mitigate endoplasmic reticulum (ER) stress by downregulating stress markers, thereby protecting beta cells from apoptosis and preserving their function. In summary, olive oil, particularly its bioactive constituents, has been demonstrated to enhance insulin sensitivity, protect beta cell function, and reduce inflammation and oxidative stress by modulating key genes involved in these processes. These findings underscore olive oil's therapeutic potential in managing T2DM. However, further research, including well-designed human clinical trials, is required to fully elucidate the role of olive oil in personalized nutrition strategies for the prevention and treatment of T2DM.

Globally, diabetes mellitus (DM) and its complications are considered among the most significant public health problems. According to numerous scientific studies, Plants and their bioactive compounds may reduce inflammation and oxidative stress (OS), leading to a reduction in the progression of DM. Moringa oleifera (MO), widely used in Ayurvedic and Unani medicine for centuries because of its health-promoting characteristics, particularly its ability to control DM and its related complications. MO is a multi-purpose plant that has an impressive range of nutritional components including proteins, amino acids (Essential and non-essential amino acids), carbs, fats, fiber, vitamins, and phenolic compounds. In the modern era, scientists have paid close attention to the anti-diabetic, anti-oxidative and anti-inflammatory attributes and other medicinal properties, of MO leaves and seeds. MO leaves and seeds have modulatory effects on DM that are likely influenced by multiple mechanisms. Some of these mechanisms include direct effects, but other mechanisms involve inhibition the production of inflammatory markers, modulation of the gut microbiome, reduction of OS, enhancement of glucose metabolism through hexokinase and glucose 6-phosphate dehydrogenase, improve insulin sensitivity and glucose uptake in the liver and muscles. Overall, these findings suggest that MO may play a role in lowering the risk of DM and its related outcomes. The purpose of this review is to provide a comprehensive overview of the nutritional and bioactive profiles of MO leaves and seeds, as well as to investigate their possible anti-diabetic effects by modulating oxidative stress and inflammation. Our results indicate that MO may be a beneficial natural resource for management of DM and related issues by lowering oxidative stress and inflammation. Furthermore, studies on MO has yielded promising findings in diabetic animal models, indicating antioxidant and anti-inflammatory properties. However, human trials have shown less solid results, most likely due to a lack of studies, different techniques, and dosages. More clinical research is needed to fully understand MO's anti-diabetic potential, notably in lowering oxidative stress and inflammation, both of which are critical in controlling diabetes complications.

A wide range of factors contribute to the overlap of hyperglycemia-acute or chronic-and sarcopenia, as well as their associated adverse consequences, which can lead to impaired physical function, reduced quality of life, and increased mortality risk. These factors include malnutrition (both overnutrition and undernutrition) and low levels of physical activity. Hyperglycemia and sarcopenia are interconnected through a vicious cycle of events that mutually reinforce and worsen each other. To explore this association, our review compiles evidence on: (i) the impact of hyperglycemia on motor and muscle function, with a focus on the mechanisms underlying biochemical changes in the muscles of individuals with or at risk of diabetes and sarcopenia; (ii) the importance of the clinical assessment and control of sarcopenia under hyperglycemic conditions; and (iii) the potential benefits of medical nutrition therapy and increased physical activity as muscle-targeted treatments for this population. Based on the reviewed evidence, we conclude that a regular intake of key functional nutrients, together with structured and supervised resistance and/or aerobic physical activity, can help maintain euglycemia and improve muscle status in all patients with hyperglycemia and sarcopenia.

Free radicals, characterized by the presence of unpaired electrons, are highly reactive species that play a significant role in human health. These molecules can be generated through various endogenous processes, such as mitochondrial respiration and immune cell activation, as well as exogenous sources, including radiation, pollution, and smoking. While free radicals are essential for certain physiological processes, such as cell signaling and immune defense, their overproduction can disrupt the delicate balance between oxidants and antioxidants, leading to oxidative stress. Oxidative stress results in the damage of critical biomolecules like DNA, proteins, and lipids, contributing to the pathogenesis of various diseases. Chronic conditions such as cancer, cardiovascular diseases, neurodegenerative disorders, and inflammatory diseases have been strongly associated with the harmful effects of free radicals. This review provides a comprehensive overview of the characteristics and types of free radicals, their mechanisms of formation, and biological impacts. Additionally, we explore natural compounds and extracts studied for their antioxidant properties, offering potential therapeutic avenues for managing free radical-induced damage. Future research directions are also discussed to advance our understanding and treatment of free radical-associated diseases.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder that significantly increases the risk of cardiovascular disease, which is the leading cause of morbidity and mortality among diabetic patients. A central pathophysiological mechanism linking T2DM to cardiovascular complications is oxidative stress, defined as an imbalance between reactive oxygen species (ROS) production and the body's antioxidant defenses. Hyperglycemia in T2DM promotes oxidative stress through various pathways, including the formation of advanced glycation end products, the activation of protein kinase C, mitochondrial dysfunction, and the polyol pathway. These processes enhance ROS generation, leading to endothelial dysfunction, vascular inflammation, and the exacerbation of cardiovascular damage. Additionally, oxidative stress disrupts nitric oxide signaling, impairing vasodilation and promoting vasoconstriction, which contributes to vascular complications. This review explores the molecular mechanisms by which oxidative stress contributes to the pathogenesis of cardiovascular disease in T2DM. It also examines the potential of lifestyle modifications, such as dietary changes and physical activity, in reducing oxidative stress and mitigating cardiovascular risks in this high-risk population. Understanding these mechanisms is critical for developing targeted therapeutic strategies to improve cardiovascular outcomes in diabetic patients.

Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder characterized by chronic hyperglycemia, which often co-exists with other metabolic impairments. This condition can damage various tissues and organs, resulting in the development of severe complications, both microvascular, such as retinopathy, nephropathy, and neuropathy, and macrovascular, responsible for an increased risk of cardiovascular diseases. Curcumin is the main bioactive molecule found in the rhizomes of turmeric. Many studies have reported curcumin to exhibit antioxidant, anti-inflammatory, anti-infectious, and anti-cancer properties; thus, there is an increasing interest in exploiting these properties in order to prevent the rise or the progression of T2DM, as well as its possible associated conditions. In this review, we have presented the current state-ofart regarding the clinical trials that have involved curcumin administration and analyzed the possible mechanisms by which curcumin might exert the beneficial effects observed in literature.

Diabetic neuropathy, also known as diabetic peripheral sensorimotor neuropathy (DPN), is a consequential complexity of diabetes, alongside diabetic nephropathy, diabetic cardiomyopathy, and diabetic retinopathy. It is characterized by signs and symptoms of peripheral nerve damage in diabetes patients after ruling out other causes. Approximately 20% of people with diabetes are affected by this painful and severe condition. The development of diabetic neuropathy is influenced by factors such as impaired blood flow to the peripheral nerves and metabolic issues, including increased polyol pathway activation, myo-inositol loss, and nonenzymatic glycation. The present review article provides a brief overview of the pathological changes in diabetic neuropathy and the mechanisms and types of DPN. Various diagnostic tests and biomarkers are available to assess nerve damage and its severity. Pharmacotherapy for neuropathic pain in diabetic neuropathy is complex. This review will explore current treatment options and potential future developments to improve the quality of life for patients suffering from diabetic neuropathy.

Emerging evidence suggests that the JAK/STAT/SOCS signaling pathway is crucial for maintaining homeostasis, and its dysregulation contributes to diabetes development. This study aimed to evaluate the roles of SOCS-1 and SOCS-3 in the pancreas, liver, and kidney and to explore the involvement of the JAK/STAT pathway in the molecular mechanisms underlying their effects on inflammation and apoptosis, as well as organ injury in a diabetes mellitus (DM) model. Additionally, we sought to elucidate the role of the JAK/STAT/SOCS pathway in mediating the effects of lycopene (LYC).

Forty Sprague-Dawley rats were divided into control, DM, LYC, and LYC+DM groups. Diabetes was induced in the DM groups using streptozotocin. LYC was administered to the LYC and LYC+DM groups for 30 days. After the study, pancreas, liver, and kidney tissues were analyzed using histopathological, immunohistochemical, and PCR methods.

Significant vacuolization and degenerative changes were observed in the DM group's pancreatic islet cells. Kidney and liver tissues showed hyperemia, hemorrhage, and degenerative changes. Immunohistochemical analysis revealed increased expression of Cas-3, TNF-α, IFN-α, and IL-6, while IL-10 was significantly reduced in the DM group. PCR analysis showed elevated levels of TNF-α and Cas-3, with decreased SOCS-1 and SOCS-3 expression in the DM group.

This study highlights the therapeutic potential of targeting the JAK/STAT/SOCS pathway with lycopene, demonstrating its promise in mitigating diabetes and related complications.

Fine particulate matter (PM2.5) has become an important risk factor threatening human health. Epidemiological and toxicological investigations have revealed that PM2.5 not only leads to cardiovascular dysfunction, but it also gives rise to various adverse health effects on the human body, such as cardiovascular and cerebrovascular diseases, cancers, neurodevelopmental disorders, depression and autism. PM2.5 is able to penetrate both respiratory and placental barriers, thereby resulting in negative effects on fetal development. A large body of epidemiological evidences has suggested that gestational exposure to PM2.5 increases the incidence of congenital diseases in offspring, including congenital heart defects. In addition, animal model studies have revealed that gestational exposure to PM2.5 can disrupt normal heart development in offspring, although the potential molecular mechanisms have yet to be fully elucidated. The aim of the present review was to provide a brief overview of what is currently known regarding the molecular mechanisms underlying cardiac developmental toxicity in offspring induced by gestational exposure to PM2.5.

Endoplasmic reticulum stress, oxidative stress, and mitochondrial dysfunction are interconnected processes involved in the pathogenesis of diabetes mellitus (DM). In the present study, we demonstrate a distinct unfolded protein response (UPR) signaling pathways in two mammalian models of DM: β-TC-6 cell line and streptozotocin-induced type 1 diabetes model in rats. However, a feature common to both systems was the upregulation of the GRP78 protein. Moreover, in vivo studies showed the disruption of the antioxidant system and an escalation of mitophagy against the background of a depletion of the level of ATP in pancreatic cells. In conclusion, we suggest that glucotoxic conditions induced GRP78 upregulation, and next cause depletion of the antioxidant pool and disruption of the functioning of antioxidant defense enzymes and in consequence promote mitophagy in pancreatic cells. Therefore, GRP78 may be considered as a potential therapeutic factor in patients with diabetes.

Type 2 diabetes mellitus (T2DM) is significantly associated with oxidative stress, resulting from the imbalance between reactive oxygen species (ROS) production and antioxidant defenses. This imbalance contributes to insulin resistance, β-cell dysfunction, and complications in organs like the vasculature and nervous system. Glutathione (GSH), a major antioxidant, is crucial for neutralizing ROS, but GSH levels are notably low in T2DM, exacerbating oxidative stress and inflammation. Elevated interleukin-6 (IL-6) levels further intensify inflammation and oxidative stress, disrupting insulin signaling and worsening complications such as nephropathy, retinopathy, and neuropathy. While lifestyle modifications and antioxidant supplementation are current approaches for managing oxidative stress, their effectiveness in preventing complications remains under study. Recent investigations suggest that GSH and Vitamin D3 supplementation may offer dual-action benefits, as Vitamin D3 not only has anti-inflammatory properties but also promotes GSH synthesis. This dual action helps mitigate both oxidative stress and inflammation, addressing key pathological features of T2DM. This review highlights the complex interactions between oxidative stress, GSH insufficiency, and IL-6, and emphasizes the potential of targeted therapies to improve the management and outcomes of T2DM.

Cognitive decline, an important comorbidity of type 2 diabetes (T2D), is attributed to oxidative stress and impaired cholinergic signaling in the brain. The α7 nicotinic acetylcholine receptor (α7nAChR) is densely distributed in the hippocampus and cortex, and exerts neuroprotective and procognitive actions. Ethyl gallate (EG), a natural phenolic antioxidant compound, showed high in-silico binding affinity towards α7nAChR and brain penetrability. Therefore, the present study aimed to evaluate the involvement of α7nAChR in the potential of EG to ameliorate T2D-induced Alzheimer's disease-like condition. T2D was induced by intraperitoneal (i.p.) injection of streptozotocin (35 mg/kg) in rats on high-fat diet. Diabetic animals were treated with EG (10 and 20 mg/kg, i.p.) for four weeks, and their learning and memory performance was evaluated by the Morris water maze (MWM). Further, the brains were subjected to biochemical analysis of antioxidants like glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT), and oxidative stress marker malonaldehyde (MDA). While diabetic rats showed a significant decline in cognitive performance in the MWM, a substantial improvement was noticed following EG treatment. Further, the diabetes-associated reductions in GSH, SOD, and CAT levels, along with increased MDA contents in the brain, were effectively restored by EG. Interestingly, pre-treatment with α7nAChR antagonist methyllycaconitine (1 mg/kg, i.p.) attenuated the effects of EG on behavioral and biochemical parameters. The results suggest that EG may augment cholinergic signaling in the brain via α7nAChR to mitigate oxidative stress, consequently alleviating T2D-associated dementia. Therefore, EG could be a potential candidate for addressing cognitive impairment comorbid with T2D.

The formation and characterization of new diamagnetic ruthenium uracil mono-imine compounds: [(η6-p-cymene)RuII(L)Cl][BF4] (L=H2urpda=5-((pyridin-2-yl)methyleneamino)-6-aminouracil) for 1, urdpy=6-amino-1,3-dimethyl-5-((pyridin-2-ylmethylene)amino)uracil) for 2 or urqda=5-((quinolin-2-yl)methyleneamino)-6-aminouracil) for 3); cis-[Ru(bipy)2(urpy)](BF4)2 (4) (urpy=5-((pyridin-2-yl)methyleneamino)uracil) and cis-[Ru(bipy)2(dapd)] (5) (H2dadp=5,6-diaminouracil) are described. A ruthenium(IV) uracil Schiff base compound, trans-[Ru(urpda)(PPh3)Cl2] (6) was also formed. Various physicochemical techniques were utilized to characterize the novel ruthenium compounds. Similarly, the stabilities of 1-3 and 6 monitored in chloro-containing and the non-coordinating solvent, dichloromethane show that they are kinetically inert, whereas, in a high nucleophilic environment, the chloride co-ligands of these ruthenium complexes were rapidly substituted by DMSO. In contrast, the substitution of the labile co-ligands for these ruthenium complexes by DMSO molecules in a high chloride content was suppressed. Solution chemical reactivities of the different ruthenium complexes were rationalized by density functional theory computations. Furthermore, the binding affinities and strengths between BSA and the respective ruthenium complexes were monitored using fluorescence spectroscopy. In addition, the in vitro anti-diabetic activities of the novel metal complexes were assessed in selected skeletal muscle and liver cell lines.

Diabetic bone disease, a form of secondary osteoporosis, is characterized by weakened bones and an increased risk of fractures, especially in patients with type 2 diabetes (T2D). This review explores the key mechanisms driving this condition, including hyperglycemia, insulin resistance, advanced glycation end products (AGEs), and proinflammatory cytokines, all of which disturb normal bone turnover by disrupting the functions of osteoblasts and osteoclasts. We examine the roles of bone turnover and mineralization, as well as how microvascular complications affect bone microarchitecture. Additionally, the influence of gut hormones, such as GLP-1 and GIP, and gut microbiota, particularly species like Akkermansia muciniphila, on the gut-bone axis is discussed, as these factors play a role in regulating bone density and structure. While T2D patients may show normal or even elevated bone mineral density (BMD), the underlying quality of bone is often compromised, leading to increased fragility. This review integrates current knowledge on the molecular, hormonal, and microbial interactions contributing to diabetic bone disease. By highlighting these pathways, we aim to offer insights into potential therapeutic strategies and inform future research aimed at improving the diagnosis, treatment, and overall management of this condition.

Hyperglycemia, a hallmark of diabetes mellitus, significantly contributes to skeletal muscle atrophy, characterized by progressive muscle mass and strength loss. This review summarizes the mechanisms of hyperglycemia-induced muscle atrophy, examines clinical evidence, and discusses preventive and therapeutic strategies. A systematic search of electronic databases, including PubMed, Scopus, and Web of Science, was conducted to identify relevant papers on hyperglycemic skeletal muscle atrophy. Key mechanisms include insulin resistance, chronic inflammation, oxidative stress, and mitochondrial dysfunction. Crucial molecular pathways involved are Phosphoinositide 3-kinase/Protein kinase B signaling, Forkhead box O transcription factors, the ubiquitin-proteasome system, and myostatin-mediated degradation. Hyperglycemia disrupts normal glucose and lipid metabolism, exacerbating muscle protein degradation and impairing synthesis. Clinical studies support the association between hyperglycemia and muscle atrophy, emphasizing the need for early diagnosis and intervention. Biomarkers, imaging techniques, and functional tests are vital for detecting and monitoring muscle atrophy in hyperglycemic patients. Management strategies focus on glycemic control, pharmacological interventions targeting specific molecular pathways, nutritional support, and tailored exercise regimens. Despite these advances, research gaps remain in understanding the long-term impact of hyperglycemia on muscle health and identifying novel therapeutic targets. The review aims to provide a comprehensive understanding of the mechanisms, clinical implications, and potential therapeutic strategies for addressing hyperglycemia-induced skeletal muscle atrophy.

Metabolic syndrome, as a complex pathological condition, is caused by a series of pathogenic factors and has become a global public health challenge. Anthocyanins, a natural water-soluble flavonoid pigment, have attracted much attention due to their antioxidant, anti-inflammatory, and anticancer biological activities. After ingestion, a majority of anthocyanins is not directly absorbed but rather reaches the colon. Hence, the exertion of their biological benefits is closely intertwined with the role played by gut microbiota. In this review, we introduce the pathogenesis and intervention methods of metabolic syndrome, as well as the interaction between anthocyanins and gut microbiota. We also discuss the therapeutic potential of anthocyanins through gut microbiota in addressing a range of metabolic syndrome conditions, including obesity, type 2 diabetes mellitus, cardiovascular diseases, non-alcoholic fatty liver disease, inflammatory bowel disease, polycystic ovary syndrome, osteoporosis, and cancer.

p66Shc is an adaptor protein and one of the cellular fate regulators since it modulates mitogenic signaling pathways, mitochondrial function, and reactive oxygen species (ROS) production. p66Shc is localized mostly in the cytosol and endoplasmic reticulum (ER); however, under oxidative stress, p66Shc is post-translationally modified and relocates to mitochondria. p66Shc was found in the intermembrane space, where it interacts with cytochrome c, contributing to the hydrogen peroxide generation by the mitochondrial respiratory chain. Our previous studies suggested that p66Shc is localized also in mitochondria-associated membranes (MAM). MAM fraction consists of mitochondria and mostly ER membranes. Contact sites between ER and mitochondria host proteins involved in multiple processes including calcium homeostasis, apoptosis, and autophagy regulation. Thus, p66Shc in MAM could participate in processes related to cell fate determination. Due to reports on various and conditional p66Shc intracellular localization, in the present paper, we describe the allocation of p66Shc pools in different subcellular compartments in mouse liver tissue and HepG2 cell culture. We provide additional evidence for p66Shc localization in MAM. In the present study, we use precisely purified subcellular fraction isolated by differential centrifugation-based protocol from control mouse liver tissue and HepG2 cells and from cells treated with hydrogen peroxide to promote mitochondrial p66Shc translocation. We performed controlled digestion of crude mitochondrial fraction, in which the degradation patterns of p66Shc and MAM fraction marker proteins were comparable. Moreover, we assessed the distribution of the individual ShcA isoforms (p46Shc, p52Shc, and p66Shc) in the subcellular fractions and their contribution to the total ShcA in control mice livers and HepG2 cells. In conclusion, we showed that a substantial pool of p66Shc protein resides in MAM in control conditions and after oxidative stress induction.

Diabetic cognitive dysfunction (DCD) has attracted increased attention, but its precise mechanism remains to be explored. Oligodendrocytes form myelin sheaths that wrap around axons. Granzyme B (GZMB) can cause axonal degeneration of the central nervous system. However, the role of GZMB in diabetic cognitive dysfunction (DCD) has not been reported. This study aimed to investigate whether GZMB promotes demyelination and participates in DCD by regulating the endoplasmic reticulum stress function of oligodendrocytes.

Streptozotocin was injected intraperitoneally to establish a diabetic model in C57BL/6 mice. The mice were randomly divided into four groups: control group, diabetic group, diabetic + SerpinA3N group, and diabetic + saline treatment group. We performed the Morris water maze test to assess the learning and memory abilities of the mice. An immunofluorescence assay was performed to detect the expression sites of GZMB and OLIG2 in the hippocampal CA1 region. Luxol Fast Blue staining and electron microscopy were performed to detect the myelin number and myelin plate densities. Immunohistochemistry was used to detect the expression levels of MBP and CNPase. Protein blotting was used to assess the expression levels of GZMB, PERK, p-PERK, eIF2α, p-eIF2α, NLRP3, Caspase-1, GSDMD-N, IL-1β, and IL-18 as well as MBP and CNPase.

The GZMB inhibitor SerpinA3N reduces escape latency and increases the traversing platforms and residence time in the target area, improving DCD in mice. It also reduces endoplasmic reticulum stress in hippocampal oligodendrocytes and focal prolapse, further promoting MBP and CNPase expression and reducing demyelination.

Our findings suggest that inhibition of GZMB activity modulates oligodendrocyte endoplasmic reticulum stress and pyroptosis, reduces demyelination, and ameliorates diabetes-related cognitive impairment.

Acute kidney injury (AKI) is a severe medical condition that can lead to illness and death. A disintegrin and metalloprotease (ADAM) protein family is a potential treatment target for AKI due to its involvement in inflammation, growth, and differentiation. While ADAM10 and ADAM17 have been identified as significant contributors to inflammation, it is unclear whether they play a critical role in AKI. In this study, we induced AKI in male and female mice using lipopolysaccharide, a bacterial endotoxin that causes inflammation and oxidative stress. The role of kaempferol, which is found in many natural products and known to have antioxidant and anti-inflammatory activity in many pre-clinical studies, was investigated through ADAM10/17 enzymes in AKI. We also investigated the efficacy of a selective synthetic inhibitor named GW280264X for ADAM10/17 inhibition in AKI. Blood urea nitrogen and creatinine levels were measured in serum, while tumor necrosis factor-α, vascular adhesion molecule, interleukin (IL)-1β, glucose regulatory protein-78, IL-10, nuclear factor κ-B, thiobarbituric acid reactive substances, total thiol, ADAM10, and ADAM17 levels were measured in kidney tissue. We also evaluated kidney tissue histologically using hematoxylin and eosin, periodic acid-schiff, and caspase-3 staining. This research demonstrates that GW280264X and kaempferol reduces inflammation and oxidative stress, as evidenced by biochemical and histopathological results in AKI through ADAM10/17 inhibition. These findings suggest that inhibiting ADAM10/17 may be a promising therapeutic approach for treating acute kidney injury.

The liver plays an important role in glucose regulation, and their dysfunction is closely associated with the development of type 2 diabetes mellitus (T2DM), and insulin resistance (IR) in hepatocyte mediate the pathogenesis of diabetes mellitus. In T2DM rats and their correlated control, we investigated various genes expression at transcriptional and translational level by utilizing transcriptomic using RNA sequencing (RNA-seq) and proteomics using isobaric tags for relative and absolute quantification (iTRAQ) to disclose potential candidates for Type 2 diabetes diagnosis and therapy. We found the lecithin retinol acyltransferase (Lrat) gene regulate hepatocyte IR in T2DM. Furthermore, BRL-3A cells, rat liver cells, worked as the IR model in vitro study. Hence, Lrat gene was overexpressed in BRL-3A cells to explore the role of Lrat gene in IR by measuring the cellular glucose consumption, TCHO, and LDL-C levels. Finally, we found that Lrat gene can improve the level of glycolipid metabolism in BRL-3A cells and reduce the degree of IR in BRL-3A cells. Therefore, further exploration of Lrat gene related molecular mechanism is meaningful.

To explore the potential protective effect of resveratrol (RES) on cold-exposed broilers, 360 21-day-old broilers were equally divided into 5 groups with 6 replicates. A control (CON) group was reared at the normal feeding temperature and received a basal diet, and 4 cold exposure (8 ± 1°C for 10 h/d from d 29 to 42) groups were fed the basal diet with 0 (CE), 250 (CE + RES250), 500 (CE + RES500), and 750 (CE + RES750) mg/kg RES from d 22 to 42. Broilers were slaughtered on d 42 and heart tissues were collected to measure the relevant indexes. The results showed that heart tissues of all CE-broilers had inflammatory cell infiltrations, and dietary RES supplementation reduced this phenomenon. Compared to CON group, the concentrations of MDA and H2O2 were increased and activities of SOD and CAT were decreased in all CE-broilers (P < 0.05). mRNA expression of genes related to endoplasmic reticulum (ER) stress (GRP78, IRE1, PERK, EIF-2α, ATF4, ATF6, and CHOP), pyroptosis (NLRP3, ASC, Caspase1, GSDME, IL-18, and IL-1β), and proinflammation (TNF-α, IFN-γ, IL-2, and IL-6) was upregulated and that of ant-inflammatory cytokines (IL-4 and IL-10) was downregulated in CE and all CE + RES groups compared to CON group (P < 0.05). Compared to CE group, the activities of SOD and CAT and mRNA expression of anti-inflammatory genes were increased (P < 0.05), and concentrations of MDA and H2O2 and mRNA expression of ER stress, pyroptosis and proinflammatory genes were reduced (P < 0.05) in 3 CE + RES groups. Additionally, protein levels of PERK, ATF4, CHOP, NLRP3, Caspase1, GSDMD, IL-18, IL-1β, TNF-α, and IL-10 were similar in their mRNA expression. Overall, cold exposure caused oxidative stress and ER stress, and induced pyroptosis and inflammatory response, resulting in heart injury in broilers, and dietary RES addition reduced heart damage by enhancing antioxidant defense function. This study indicates that RES can be a feed additive to alleviate cold exposure-induced heart injury in broilers, and a 500 mg RES/kg diet is the optimal supplemental level.

Despite the fact that environmental pollution has been implicated in the global rise of diabetes, the research on the impact of emerging pollutants such as novel flame retardants remains limited. In line with the shift towards the use of non-animal approaches in toxicological testing, this study aimed to investigate the effects of two novel flame retardants tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and triphenyl phosphate (TPhP) in rat (INS1E) and human (NES2Y) pancreatic beta-cell lines. One-week exposure to 1 μM and 10 μM TDCIPP and TPhP altered intracellular insulin and proinsulin levels, but not the levels of secreted insulin (despite the presence of a statistically insignificant trend). The exposures also altered the protein expression of several factors involved in beta-cell metabolic pathways and signaling, including ATP citrate lyase, isocitrate dehydrogenase 1, perilipins, glucose transporters, ER stress-related factors, and antioxidant enzymes. This study has brought new and valuable insights into the toxicity of TDCIPP and TPhP on beta-cell function and revealed alterations that might impact insulin secretion after more extended exposure. It also adds to the scarce studies using in vitro pancreatic beta-cells models in toxicological testing, thereby promoting the development of non-animal testing strategy for identifying pro-diabetic effects of chemical pollutants.

Dysregulated inflammation after trauma or infection could result in the further disease and delayed tissue reconstruction. The conventional anti-inflammatory drug treatment suffers to the poor bioavailability and side effects. Herein, we developed an amphiphilic multifunctional poly (citrate-polyglycol-curcumin) (PCGC) nano oligomer with the robust anti-inflammatory activity for treating acute lung injury (ALI) and Methicillin-resistant staphylococcus aureus (MRSA) infected wound. PCGC demonstrated the sustained curcumin release, inherent photoluminescence, good cellular compatibility, hemocompatibility, robust antioxidant activity and enhanced cellular uptake. PCGC could efficiently scavenge nitrogen-based free radicals, oxygen-based free radicals, and intracellular oxygen species, enhance the endothelial cell migration and reduce the expression of pro-inflammatory factors through the NF-κB signal pathway. Combined the anti-inflammation and antioxidant properties, PCGC can shortened the inflammatory process. In animal model of ALI, PCGC was able to reduce the pulmonary edema, bronchial cell infiltration, and lung inflammation, while exhibiting rapid metabolic behavior in vivo. The MRSA-infection wound model showed that PCGC significantly reduced the expression of pro-inflammatory factors, promoted the angiogenesis and accelerated the wound healing. The transcriptome sequencing and molecular mechanism studies further demonstrated that PCGC could inhibit multiple inflammatory related pathways including TNFAIP3, IL-15RA, NF-κB. This work demonstrates that PCGC is efficient in resolving inflammation and promotes the prospect of application in inflammatory diseases as the drug-loaded therapeutic system.

The substance P (SP) and neurokinin-1 receptor (NK-1R) axis is crucial in numerous pathological processes, including inflammation, stress responses, pain perception, and vomiting. Consequently, aprepitant, an NK-1R blocker, is used as an antiemetic in chemotherapy, including the use of doxorubicin (DOX), but whether aprepitant can also assuage DOX-mediated chemobrain remains to be unveiled. Here, we scrutinized the potential neuroprotective effect and underlying mechanisms of aprepitant using DOX-induced chemobrain model, where rats were allocated into 4 groups (control, aprepitant, DOX, and DOX+ aprepitant). Cognitive deficits were assessed through behavioral tests and hippocampal structural alterations were determined by H&E and toluidine blue staining. Biochemical measurements were performed using ELISA, real-time quantitative PCR, western blotting, and immunohistochemical methods. Aprepitant improved cognitive responses, and hippocampal morphology, enhancing the presence of intact neurons. At the molecular tier, aprepitant significantly reduced hippocampal contents of SP and the inflammatory markers NF-κB and IL-1β. Additionally, it signified its antioxidant and antiapoptotic capacities by downregulating cleaved caspase-3 protein expression and curbing the content of malondialdehyde but boosted those of glutathione and Bcl-2. Aprepitant also downregulated the expression of miR-146a and turned off the endoplasmic reticulum (ER) stress cascade PERK/eIF-2α/ATF-4/CHOP. To recapitulate, aprepitant demonstrates a neuroprotective effect against DOX-mediated chemobrain by alleviating inflammatory, oxidative, and apoptotic responses, partly by reducing SP, ER stress, and miR-146a. These findings not only underscore the potential of aprepitant as a neuroprotective agent but also offer new understanding of the mechanisms behind chemobrain, leading to better therapeutic strategies for cancer patients.

Diabetes mellitus (DM), a chronic metabolic disease, poses a significant global health challenge, with current treatments often fail to prevent the long-term disease complications. Mesenchymal stem/stromal cells (MSCs) are, adult progenitors, able to repair injured tissues, exhibiting regenerative effects and immunoregulatory and anti-inflammatory responses, so they have been emerged as a promising therapeutic approach in many immune-related and inflammatory diseases. This review summarizes the therapeutic mechanisms and outcomes of MSCs, derived from different human tissue sources (hMSCs), in the context of DM type 1 and type 2. Animal model studies and clinical trials indicate that hMSCs can facilitate pleiotropic actions in the diabetic milieu for improved metabolic indices. In addition to modulating abnormally active immune system, hMSCs can ameliorate peripheral insulin resistance, halt beta-cell destruction, preserve residual beta-cell mass, promote beta-cell regeneration and insulin production, support islet grafts, and correct lipid metabolism. Moreover, hMSC-free derivatives, importantly extracellular vesicles, have shown potent experimental anti-diabetic efficacy. Moreover, the review discusses the diverse priming strategies that are introduced to enhance the preclinical anti-diabetic actions of hMSCs. Such strategies are recommended to restore the characteristics and functions of MSCs isolated from patients with DM for autologous implications. Finally, limitations and merits for the wide spread clinical applications of MSCs in DM such as the challenge of autologous versus allogeneic MSCs, the optimal MSC tissue source and administration route, the necessity of larger clinical trials for longer evaluation duration to assess safety concerns, are briefly presented.

Antihyperglycemic effects of a novel polyherbal formula (HF344), comprising fifteen Thai herbal extracts, were elucidated for pharmacological mechanisms and potential for managing type 2 diabetes mellitus, by employing in vitro, ex vivo, and in vivo approaches. LC/MS analysis of HF344 extract revealed several phytoconstituents, with piperine identified as the major active compound. HF344 extract significantly enhanced insulin secretion in RINm5F cells in vitro and inhibited glucose uptake into the everted sacs of the mouse small intestine ex vivo in a concentration-dependent manner compared to the control (p < 0.05). It exhibited potent α-glucosidase inhibition in vitro, with an IC50 of 96.74 μg/mL. Moreover, HF344 extract upregulated mRNA levels of GLUT1 in L6 skeletal myoblasts, suggesting increased glucose uptake into skeletal muscle. In addition, in vivo antihyperglycemic effects were assessed in streptozotocin (STZ)-nicotinamide (NA)-induced diabetic mice. Acute oral toxicity testing confirmed the HF344 extract's safety, with an LD50 exceeding 2000 mg/kg. Oral administration of HF344 extract (500 and 1000 mg/kg) in STZ-NA-induced diabetic mice significantly reduced the area under the fasting blood glucose (FBG)-time curve (AUC) in the oral glucose tolerance test (OGTT) model and treatment for 28-day reduced the FBG levels as compared with control (p < 0.05). This was accompanied by increased serum insulin levels and improved insulin resistance. HF344 extract also demonstrated a concentration-dependent inhibitory effect on malondialdehyde (MDA) production in vitro, with an IC50 of 7.24 μg/mL. Oral treatment with HF344 extract decreased MDA production in the homogenized muscle ex vivo collected from STZ-NA-induced mice. Furthermore, pretreatment with HF344 extract effectively restored the survival of RINm5F cells from STZ-induced damage. These findings suggest that HF344 is a promising polyherbal formula for managing blood glucose levels, enhancing insulin production, and providing antioxidant benefits in T2DM. Further research is required to evaluate the clinical efficacy and safety profiles of HF344.