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Background: Isorhamnetin is a flavonoid that is found in medical plants. Several studies showed that isorhamnetin has anti-inflammatory and anti-obesity effects. This study aims to investigate the anti-diabetic effects of isorhamnetin in a high-fat diet and Streptozotocin-(HFD/STZ)-induced mice model of type 2 diabetes. Materials and Methods: Mice were fed with HFD followed by two consecutive low doses of STZ (40 mg/kg). HFD/STZ diabetic mice were treated orally with isorhamnetin (10 mg/kg) or (200 mg/kg) metformin for 10 days before sacrificing the mice and collecting plasma and soleus muscle for further analysis. Results: Isorhamnetin reduced the elevated levels of serum glucose compared to the vehicle control group (p < 0.001). Isorhamnetin abrogated the increase in serum insulin in the treated diabetic group compared to the vehicle control mice (p < 0.001). The homeostasis model assessment of insulin resistance (HOMA-IR) was decreased in diabetic mice treated with isorhamnetin compared to the vehicle controls. Fasting glucose level was significantly lower in diabetic mice treated with isorhamnetin during the intraperitoneal glucose tolerance test (IPGTT) (p < 0.001). The skeletal muscle protein contents of GLUT4 and p-AMPK-α were upregulated following treatment with isorhamnetin (p > 0.01). LDL, triglyceride, and cholesterol were reduced in diabetic mice treated with isorhamnetin compared to vehicle control (p < 0.001). Isorhamnetin reduced MDA, and IL-6 levels (p < 0.001), increased GSH levels (p < 0.001), and reduced GSSG levels (p < 0.05) in diabetic mice compared to vehicle control. Conclusions: Isorhamnetin ameliorates insulin resistance, oxidative stress, and inflammation. Isorhamnetin could represent a promising therapeutic agent to treat T2D.

The perturbation in plasma free amino acid metabolome has been observed previously in diabetes mellitus, and is associated with insulin resistance as well as the onset of cardiovascular disease in this population. In this study, we investigated, for the first time, changes in the amino acid profile in a group of people with and without type 2 diabetes (T2D) with normal BMI, from Jordan, who were only managed on metformin. Twenty one amino acids were evaluated in plasma samples from 124 people with T2D and 67 healthy controls, matched for age, gender and BMI, using amino acids analyser. Total amino acids, essential amino acids, non-essential amino acids and semi-essential amino acids were similar in T2D compared to healthy controls. Plasma concentrations of four essential amino acids were increased in the presence of T2D (Leucine, p < 0.01, Lysine, p < 0.001, Phenylalanine, p < 0.01, Tryptophan, p < 0.05). On the other hand, in relation to non-essential amino acids, Alanine and Serine were reduced in T2D ( p < 0.01, p < 0.001, respectively), whereas Aspartate and Glutamate were increased in T2D compared to healthy controls ( p < 0.001, p < 0.01, respectively). A semi-essential amino acid, Cystine, was also increased in T2D compared to healthy controls ( p < 0.01). Citrulline, a metabolic indicator amino acid, demonstrated lower plasma concentration in T2D compared to healthy controls ( p < 0.01). These amino acids were also correlated with fasting blood glucose and HbA1c ( p < 0.05). Glutamate, glycine and arginine were correlated with the duration of metformin treatment ( p < 0.05). No amino acid was correlated with lipid profiles. Disturbances in the metabolism of these amino acids are closely implicated in the pathogenesis of T2D and associated cardiovascular disease. Therefore, these perturbed amino acids could be explored as therapeutic targets to improve T2D management and prevent associated cardiovascular complications.

Insulin resistance in skeletal muscle is a feature associated with exposure to an excess of saturated fatty acids such as palmitate. Oleic acid has been shown to blunt palmitate-induced insulin resistance in muscle cells. However, there is no literature available regarding the effect of oleic acid on palmitate-induced insulin resistance in intact muscle. Therefore, this study investigated the effect of oleic acid on palmitate-induced insulin resistance in rat soleus muscle and its underlying mechanisms. For these purposes, oleic acid (1 mM) was administered for 12 h in the absence or presence of palmitate (2 mM). At the end of the experiment, plasmalemmal GLUT4, the phosphorylation of AS160 and Akt-2, and the total expression of these signaling proteins were examined. We found that treatment with palmitate for 12 h reduced insulin-stimulated GLUT4 translocation and the phosphorylation of AS160 and Akt-2. However, the administration of oleic acid fully restored insulin-stimulated GLUT4 translocation ( P  < 0.05), as well as AS160 and Akt-2 phosphorylation ( P  < 0.05) despite the continuous presence of palmitate. Wortmannin, an inhibitor of PI3-K, only slightly prevented the oleic acid-induced improvements in insulin-stimulated GLUT4 translocation, and AS160 phosphorylation. However, this treatment completely inhibited the oleic acid-induced improvement in insulin-stimulated Akt-2 phosphorylation. In contrast, the oleic acid-induced improvement in insulin signaling was not affected by compound C, an AMPK specific inhibitor. In conclusion, the results clearly indicate that oleic acid administration alleviates palmitate-induced insulin resistance by promoting GLUT4 translocation in muscle, at least in part, by activating the PI3K pathway.

This research evaluated the analgesic properties of Arvelexin through different models of nociception. Different concentrations of Arvelexin (50, 100, 150, and 200 µg/kg body weight) were administered to male mice, and their responses to pain were assessed using various evaluation techniques. The results were compared with those from mice receiving treatments of acetylsalicylic acid or morphine, with and without the addition of naloxone. Furthermore, to explore the impact of Arvelexin on pain modulation systems, additional tests using capsaicin and glutamate focused on its influence on vanilloid and glutamatergic pathways. The research illustrated a significant, dose-related reduction in pain during the acetic acid-induced writhing assay, with a peak decrease of 75.1% observed at 200 µg/kg body weight. Similarly, Arvelexin increased the delay before pain response in the hot plate test by 69.5% at the same dosage. In tests of formalin-induced paw licking, Arvelexin notably reduced pain in both the neurogenic and inflammatory phases, effects which were negated by naloxone, suggesting opioid system engagement. Furthermore, the compound effectively inhibited neurogenic pain triggered by capsaicin and glutamate. ELISA results showed that Arvelexin markedly reduced levels of pro-inflammatory cytokines (IL-1β, TNF-α, and IFN-γ) in the serum of mice at 100 and 200 µg/kg. The results demonstrate that Arvelexin has analgesic effects mediated by both central and peripheral pathways, involving interactions with vanilloid receptors, opioid receptors, and elements of the glutamatergic system. While findings suggest significant pain relief, the exclusion of female mice may limit the applicability of results across sexes.

2′,3,3,5′-Tetramethyl-4′-nitro-2′H-1,3′-bipyrazole (TMNB) is a novel bipyrazole compound with unknown therapeutic potential in diabetes mellitus. This study aims to investigate the anti-diabetic effects of TMNB in a high-fat diet and streptozotocin-(HFD/STZ)-induced rat model of type 2 diabetes mellitus (T2D). Rats were fed HFD, followed by a single low dose of STZ (40 mg/kg). HFD/STZ diabetic rats were treated orally with TMNB (10 mg/kg) or (200 mg/kg) metformin for 10 days before terminating the experiment and collecting plasma, soleus muscle, adipose tissue, and liver for further downstream analysis. TMNB reduced the elevated levels of serum glucose in diabetic rats compared to the vehicle control group (p < 0.001). TMNB abrogated the increase in serum insulin in the treated diabetic group compared to the vehicle control rats (p < 0.001). The homeostasis model assessment of insulin resistance (HOMA-IR) was decreased in the diabetic rats treated with TMNB compared to the vehicle controls. The skeletal muscle and adipose tissue protein contents of GLUT4 and AMPK were upregulated following treatment with TMNB (p < 0.001, < 0.01, respectively). TMNB was able to upregulate GLUT2 and AMPK protein expression in liver (p < 0.001, < 0.001, respectively). LDL, triglyceride, and cholesterol were reduced in diabetic rats treated with TMNB compared to the vehicle controls (p < 0.001, 0.01, respectively). TMNB reduced MDA and IL-6 levels (p < 0.001), and increased GSH level (p < 0.05) in diabetic rats compared to the vehicle controls. Conclusion: TMNB ameliorates insulin resistance, oxidative stress, and inflammation in a T2D model. TMNB could represent a promising therapeutic agent to treat T2D.

This study investigated the therapeutic impact of dual immune checkpoint inhibition targeting TIGIT and VISTA in non-small cell lung cancer (NSCLC). Current monotherapies have failed to produce consistent and durable responses owing to tumor heterogeneity and immune evasion. By evaluating the biological and immunomodulatory roles of TIGIT and VISTA, this study provides a rationale for their simultaneous blockade. Preclinical models have shown that this dual strategy not only revitalizes T-cell function but also alters the suppressive tumor microenvironment, leading to improved antitumor immunity in mice. Preliminary clinical data suggest potential survival benefits; however, the long-term outcomes and resistance dynamics remain uncertain. These findings suggest a paradigm shift toward precision-designed, multi-target immunotherapies. Future studies should integrate molecular profiling, adaptive clinical trial designs, and follow-up models to optimize patient selection and sustain therapeutic benefits. See also the graphical abstract(Fig. 1).

Background and objectives: Community pharmacists play an important role in ensuring the patient’s adherence to medications, thus achieving therapeutic outcomes. The present study had two aims: to measure the extent of knowledge that community pharmacists had about psychotropic medications and to determine the factors associated with higher knowledge scores. Methods: A cross-sectional design was employed, using a structured online questionnaire. The study instrument assessed demographics, general practice characteristics related to psychotropics and a battery of factual questions that assessed the knowledge of pharmacists about psychotropic medications using closed-ended responses. A total knowledge score consisting of the sum of correct responses was calculated; the passing score was 75%. A total of 676 pharmacists completed the survey. Results: Only 20% passed the threshold score (75%) for the factual knowledge questions, and only (11.0%) were very comfortable with their knowledge of psychotropic agents. A total of 49.0% of the respondents felt that they had been adequately trained to counsel patients on psychotropic agents. According to the regression model, pharmacists who reported higher knowledge were more experienced (0.63, (0.26–1.0), p < 0.001), reported studying the topic in the pharmacy school (0.77 (0.27–1.26), p = 0.002) holding a Doctor of Pharmacy (Pharm D) degree (0.24 (0.05–0.43), p = 0.01), and reported a higher perceived knowledge (0.29 (0.01–0.38), p = 0.038). Conclusion: Community pharmacists reported poor knowledge of psychotropic medications, and continuous medical and professional education programs are mandatory.

Background: Sodium/glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral anti-diabetic drugs which improve glycaemic control in type 2 diabetes mellitus (T2DM) by preventing the kidney from reabsorbing glucose back to blood. Community pharmacists have long-term relationships with most of their chronic patients, so they play a key role in care for people with diabetes. Therefore, the objective of this study was to assess pharmacists' knowledge and practice towards SGLT2 inhibitors. Thus, improving pharmacists' knowledge about this group of medications could improve the treatment outcome of people with diabetes. Methods: A cross-sectional study was conducted to meet the study objectives. A convenience sample of 348 community pharmacists in Jordan was recruited. knowledge and practice were assessed using a self-administered questionnaire created for the purpose of this study. Results: A total of 400 community pharmacists were reached, of whom 348 answered the survey (response rate 87%). The results indicated that SGLT2 inhibitors knowledge score among community pharmacists in Jordan was 6.61 (out of 12). Factors like age, gender, location of the pharmacy, years of pharmacists' experience had no effect on knowledge score; however, pharmacists who attended training courses on diabetes had higher knowledge scores. Additionally, pharmacists' dispensing practice toward SGLT2 inhibitors had insufficient knowledge, such as lack of knowledge about the superiority of SGLT2 inhibitors over other anti-diabetics and inability to give the best advice to patients. Conclusions: Our findings reflect a moderate knowledge among community pharmacists about SGLT2 inhibitors which may negatively affect the patients' outcome; thus, continuous education for the pharmacists is essential.

Background: Sodium/glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral anti-diabetic drugs which improve glycaemic control in type 2 diabetes mellitus (T2DM) by preventing the kidney from reabsorbing glucose back to blood. Community pharmacists have long-term relationships with most of their chronic patients, so they play a key role in care for people with diabetes. Therefore, the objective of this study was to assess pharmacists' knowledge and practice towards SGLT2 inhibitors. Methods: A cross-sectional study was conducted to meet the study objectives. A convenience sample of 348 community pharmacists in Jordan was recruited. knowledge and practice were assessed using a self-administered questionnaire created for the purpose of this study. Results: A total of 400 community pharmacists were reached, of whom 348 answered the survey (response rate 87%). The results indicated that SGLT2 inhibitors knowledge score among community pharmacists in Jordan was 6.61 (out of 12). Factors like age, gender, location of the pharmacy, years of pharmacists' experience had no effect on knowledge score; however, pharmacists who attended training courses on diabetes had higher knowledge scores. Additionally, pharmacists' dispensing practice toward SGLT2 inhibitors had insufficient knowledge, such as lack of knowledge about the superiority of SGLT2 inhibitors over other anti-diabetics and inability to give the best advice to patients. Conclusions: Our findings reflect a moderate knowledge among community pharmacists about SGLT2 inhibitors which may negatively affect the patients' outcome; thus, continuous education for the pharmacists is essential.

Immunophilins are a family of proteins encompassing FK506-binding proteins (FKBPs) and cyclophilins (Cyps). FKBPs and Cyps exert peptidyl-prolyl cis-trans isomerase (PPIase) activity, which facilitates diverse protein folding assembly, or disassembly. In addition, they bind to immunosuppressant medications where FKBPs bind to tacrolimus (FK506) and rapamycin, whereas cyclophilins bind to cyclosporin. Some large immunophilins have domains other than PPIase referred to as tetratricopeptide (TPR) domain, which is involved in heat shock protein 90 (Hsp90) and heat shock protein 70 (Hsp 70) chaperone interaction. The TPR domain confers immunophilins’ pleotropic actions to mediate various physiological and biochemical processes. So far, immunophilins have been implicated to play an important role in pathophysiology of inflammation, cancer and neurodegenerative disorders. However, their importance in the development of fibrosis has not yet been elucidated. In this review we focus on the pivotal functional and mechanistic roles of different immunophilins in fibrosis establishment affecting various organs. The vast majority of the studies reported that cyclophilin A, FKBP12 and FKBP10 likely induce organ fibrosis through the calcineurin or TGF-β pathways. FKBP51 demonstrated a role in myelofibrosis development through calcineurin-dependant pathway, STAT5 or NF-κB pathways. Inhibition of these specific immunophilins has been shown to decrease the extent of fibrosis suggesting that immunophilins could be a novel promising therapeutic target to prevent or reverse fibrosis.