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Aims Materials and Methods Results Conclusions Type 2 diabetes (T2D) patients with a clinical phenotype characterized by a high degree of insulin resistance are at increased risk of chronic kidney disease (CKD). We previously demonstrated that the endothelin receptor antagonist (ERA) atrasentan reduced insulin resistance in T2D. In this study, we compared the effect of atrasentan on insulin resistance across different phenotypic clusters of patients with T2D.We performed a post hoc analysis of the SONAR trial, a randomized, placebo‐controlled trial of the ERA atrasentan in patients with T2D and CKD. Patients were stratified into four previously identified phenotypic clusters: severe insulin‐deficient diabetes (SIDD), severe insulin‐resistant diabetes (SIRD), mild obesity‐related diabetes (MOD) and mild age‐related diabetes (MARD). Changes in insulin resistance, assessed by HOMA‐IR, were compared between the phenotypic clusters using a mixed effects model.In total, 931 patients were included in the analysis. In the overall population, atrasentan compared to placebo reduced HOMA‐IR by 12.9% [95%CI 3.5,21.4]. This effect of atrasentan was more pronounced in clusters characterized by insulin resistance or deficiency: (SIRD cluster 26.2% [95% CI 3.8,43.3] and SIDD cluster 18.5% [95%CI −3.8,35.9]), although the latter did not reach statistical significance. The effect of atrasentan compared to placebo was less pronounced in the other two clusters (MARD 12.2% [95% CI −1.7,24.12] and MOD −5.3% [95% CI −28.9,13.9]).Atrasentan significantly improved insulin sensitivity in patients with T2D and CKD, especially in those characterized by high insulin resistance (SIRD cluster). Further studies are warranted to investigate the long‐term clinical outcomes of atrasentan treatment in these distinct phenotypic clusters. [ABSTRACT FROM AUTHOR]

Aims Materials and Methods Results Conclusions This study aimed to explore the effect of discontinuation of long‐term spironolactone treatment on markers of kidney function in individuals with type 2 diabetes (T2D) at high risk of kidney disease enrolled in the Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria (PRIORITY) study.An observational study following the nested randomised part of the PRIORITY study was conducted. A total of 115 individuals with T2D and normoalbuminuria but high risk for progression based on urinary proteomics, randomised to daily spironolactone (n = 50) or placebo (n = 65) for a median of 2.5 years, were re‐examined approximately 6 weeks after the final visit in the PRIORITY study. Primary endpoint was relative change in geometric mean of urinary albumin‐creatinine ratio (UACR) between the final visit in PRIORITY (baseline) and follow‐up. Secondary endpoints were change in estimated glomerular filtration rate (eGFR), systolic blood pressure (SBP) and serum potassium.No change in UACR was observed in neither the spironolactone (geometric mean change: 17%; 95% CI −12, 55; p = 0.28) nor the placebo (5%; 95% CI −13, 26; p = 0.63) group at follow‐up. No difference in UACR between the groups was observed at follow‐up (relative difference in geometric mean: 11%, 95% CI −26, 67; p = 0.60). For eGFR and SBP, an increase after discontinuation of spironolactone was observed, as well as for SBP after placebo discontinuation. Potassium levels were lower after discontinuation of spironolactone, but higher after placebo discontinuation (all p < 0.05).UACR did not change after discontinuation of long‐term treatment with spironolactone. However, an increase in eGFR was observed supporting a haemodynamic effect of spironolactone in the kidneys. [ABSTRACT FROM AUTHOR]

Aims: To investigate the effects of the selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine at therapeutically relevant concentrations on beta‐cell mass and function. Methods: Viability was quantified in mouse insulinoma (MIN6) beta cells and mouse islets after 48‐h exposure to sertraline (1–10 μM) or paroxetine (0.01–1 μM) using the Trypan blue exclusion test. The effects of therapeutic concentrations of these SSRIs on insulin secretion were determined by static incubation and perifusion experiments, while islet apoptosis was investigated by Caspase‐Glo 3/7 assay, TUNEL staining and quantitative PCR analysis. Finally, proliferation of MIN6 and mouse islet beta cells was assessed by bromodeoxyuridine (BrdU) enzyme‐linked immunosorbent assay and immunofluorescence. Results: Sertraline (0.1–1 μM) and paroxetine (0.01–0.1 μM) were well tolerated by MIN6 beta cells and islets, whereas 10 μM sertraline and 1 μM paroxetine were cytotoxic. Exposure to 1 μM sertraline and 0.1 μM paroxetine significantly potentiated glucose‐stimulated insulin secretion from mouse and human islets. Moreover, they showed protective effects against cytokine‐ and palmitate‐induced apoptosis of islets, they downregulated cytokine‐induced Stat1 and Traf1 mRNA expression, and they significantly increased proliferation of mouse beta cells. Conclusions: Our data demonstrate that sertraline and paroxetine act directly on beta cells to enhance glucose‐stimulated insulin secretion and stimulate beta‐cell mass expansion by increasing proliferation and decreasing apoptosis. These drugs are therefore likely to be appropriate for treating depression in people with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Metformin is the first‐line medication for type 2 diabetes. It is effective and safe, provided some caution is taken in specific populations. In patients with chronic kidney disease, metformin may provide long‐term benefits, and it is a first‐line therapy for diabetes, but the estimated glomerular filtration rate (eGFR) must be assessed regularly, to minimize the risk for metformin accumulation. When eGFR is 30‐60 mL/min/1.73m2, the dose should be reconsidered, and sick‐days education provided. Metformin should be discontinued when eGFR falls below 30 mL/min/1.73m2. Metformin accumulation may increase the risk for lactic acidosis if concomitant risk factors for hyperlactataemia (liver or respiratory insufficiency, sepsis, acute heart failure) are present; in these conditions, metformin is contraindicated, even although the available evidence is reassuring. Patients on metformin often complain of gastrointestinal side effects (mainly diarrhoea and nausea) during therapy initiation, but they may sometimes occur after years of stable therapy. These usually resolve if the dose is carefully titrated, or by switching to the extended‐release formulation. Patients with obesity may benefit from the significant, although modest, metformin‐associated weight loss and appetite reduction. During pregnancy, metformin is associated with a reduction of pregnancy complications, especially in obese women, but some concern remains, because metformin crosses the placenta, and it is associated with a significantly lower mean birth weight than insulin. In the elderly, gastrointestinal tolerability and renal function must be reassessed more often. Vitamin B‐12 should be screened regularly in long‐time metformin users because metformin may induce clinical vitamin B‐12 deficiency. [ABSTRACT FROM AUTHOR]

Fibrosis is a common feature of more than 50 different diseases and the cause of more than 35% of deaths worldwide, of which liver, kidney, skin, heart and, recently, lungs are receiving the most attention. Tissue changes, resulting in loss of organ function, are both a cause and consequence of disease and outcome. Fibrosis is caused by an excess deposition of extracellular matrix proteins, which over time results in impaired organ function and organ failure, and the pathways leading to increased fibroblast activation are many. This narrative review investigated the common denominator of fibrosis, fibroblasts, and the activation of fibroblasts, in response to excess energy consumption in liver, kidney, heart, skin and lung fibrosis. Fibroblasts are the main drivers of organ function loss in lung, liver, skin, heart and kidney disease. Fibroblast activation in response to excess energy consumption results in the overproduction of a range of collagens, of which types I, III and VI seem to be the essential drivers of disease progression. Fibroblast activation may be quantified in serum, enabling profiling and selection of patients. Activation of fibroblasts results in the overproduction of collagens, which deteriorates organ function. Patient profiling of fibroblast activities in serum, quantified as collagen production, may identify an organ death trajectory, better enabling identification of the right treatment for use in different metabolic interventions. As metabolically activated patients have highly elevated risk of kidney, liver and heart failure, it is essential to identify which organ to treat first and monitor organ status to correct treatment regimes. In direct alignment with this, it is essential to identify the right patients with the right organ deterioration trajectory for enrolment in clinical studies. [ABSTRACT FROM AUTHOR]

Background: Metabolic syndrome (MetS), which can be induced or exacerbated by the current class of antipsychotic drugs, is highly prevalent in patients with schizophrenia and presents significant challenges to lifetime disease management. Supported by initial clinical results, trace amine‐associated receptor 1 (TAAR1) agonists have emerged as potential novel treatments for schizophrenia. Notably, non‐clinical studies have also shown weight‐lowering and glucoregulatory effects of TAAR1 agonists, including the investigational agent ulotaront. However, the translatability of these findings to humans has not been adequately assessed. Given that delayed gastric emptying (GE) was identified as a potential mechanism contributing to the metabolic benefits of TAAR1 agonists in rodents, the aim of this study was to evaluate the effect of ulotaront on GE in patients with schizophrenia and concurrent MetS with prediabetes. Methods: Patients with schizophrenia were randomized to receive a single oral dose of ulotaront (150 mg) and their previous antipsychotic (PA) in an open‐label, crossover, two‐sequence design (NCT05402111). Eligible participants fulfilled at least three of five MetS criteria and had prediabetes defined by elevated glycated haemoglobin (5.7‐6.4%) and/or fasting homeostatic model assessment of insulin resistance (i.e. ≥2.22). Following an overnight fast and 4 h post‐dose, participants ingested a 99mTc‐sulphur colloid radiolabelled egg meal (320 kcal, 30% fat). GE was measured by scintigraphy over 4 h. Endpoints included GE of solids half‐time (T1/2) and percentage gastric retention at 1, 2 and 4 h. Results: Thirty‐one adults were randomized and 27 completed the study. Ulotaront significantly delayed GE of solids [median GE T1/2 ulotaront at 139 min (119, 182) vs. the participant's PA of 124 min (109, 132), p =.006]. A significant increase in gastric retention was seen in the ulotaront versus the PA group at 1 h (80% vs. 75%, p =.015), 2 h (61% vs. 50%, p =.023) and 4 h (17% vs. 7%, p =.002) post‐meal. Conclusion: Ulotaront delayed the GE of solids in patients with schizophrenia and concurrent MetS with prediabetes. Additional studies are needed to assess whether treatment with TAAR1 agonists is associated with weight loss and glucoregulatory improvement. [ABSTRACT FROM AUTHOR]

Aim: Despite the increasing use of combination treatment with sodium‐glucose cotransporter 2 inhibitors and glucagon‐like peptide‐1 receptor agonists, data are limited on the effects of combination treatment on markers of cardiovascular disease. This study aimed to investigate the effect of empagliflozin, semaglutide, and their combination on vascular function. Materials and Methods: In total, 120 patients with type 2 diabetes were randomized into four groups (n = 30 in each) for 32 weeks: placebo, semaglutide, empagliflozin, and their combination. The study had two co‐primary outcomes: change in arterial stiffness and kidney oxygenation. This paper reports on arterial stiffness assessed as carotid‐femoral pulse wave velocity. Secondary outcomes included 24‐h blood pressure (BP), 24‐h central BP, urinary albumin to creatinine ratio and glycaemic control assessed by both continuous glucose monitoring and glycated haemoglobin. Results: The carotid‐femoral pulse wave velocity did not change significantly in any of the groups compared with placebo. Twenty‐four‐hour systolic BP was reduced by 10 mmHg (95% CI 6–14), p <.001 in the combination group, significantly superior to both placebo and monotherapy (p <.05). Combination treatment increased glycaemic time in range from 72% at baseline to 91% at week 32, p <.001, without increasing time below range. The urinary albumin to creatinine ratio decreased by 36% (95% CI 4–57), p =.03 in the combination group compared with placebo. Conclusions: Empagliflozin, semaglutide, or their combination did not reduce arterial stiffness. Combination treatment showed a substantial and clinically important reduction in 24‐h systolic BP compared with either treatment alone. Combination treatment increased glycaemic time in range without increasing the risk of hypoglycaemia. [ABSTRACT FROM AUTHOR]

Metformin is the initial medication recommended for the treatment of type 2 diabetes mellitus (T2DM). In addition to diabetes treatment, the function of metformin also can be anti-aging, antiviral, and anti-inflammatory. Nevertheless, further exploration is required to fully understand its mode of operation. Historically, the liver has been acknowledged as the main location where metformin reduces glucose levels, however, there is increasing evidence suggesting that the gastrointestinal tract also plays a significant role in its action. In the gastrointestinal tract, metformin effects glucose uptake and absorption, increases glucagon-like peptide-1 (GLP-1) secretion, alters the composition and structure of the gut microbiota, and modulates the immune response. However, the side effects of it cannot be ignored such as gastrointestinal distress in patients. This review outlines the impact of metformin on the digestive system and explores potential explanations for variations in metformin effectiveness and adverse effects like gastrointestinal discomfort. [ABSTRACT FROM AUTHOR]

Aim: Bile acid sequestrants are cholesterol‐lowering drugs, which also improve glycaemic control in people with type 2 diabetes. The mechanism behind the glucose‐lowering effect is unknown but has been proposed to be mediated by increased glucagon‐like peptide‐1 (GLP‐1) secretion. Here, we investigated the glucose‐lowering effects of sevelamer including any contribution from GLP‐1 in people with type 2 diabetes. Materials and Methods: In a randomized, double‐blind, placebo‐controlled, crossover study, 15 people with type 2 diabetes on metformin monotherapy underwent two 17‐day treatment periods with the bile acid sequestrant sevelamer and placebo, respectively, in a randomized order and with an interposed wash‐out period of minimum 6 weeks. On days 15 and 17 of each treatment period, participants underwent experimental days with 4‐h liquid meal tests and application of concomitant infusion of exendin(9‐39)NH2 or saline. Results: Compared with placebo, sevelamer improved insulin sensitivity (assessed by homeostatic model assessment of insulin resistance) and beta‐cell sensitivity to glucose and lowered fasting and postprandial plasma glucose concentrations. In both treatment periods, exendin(9‐39)NH2 increased postprandial glucose excursions compared with saline but without absolute or relative difference between the two treatment periods. In contrast, exendin(9‐39)NH2 abolished the sevelamer‐induced improvement in beta‐cell glucose sensitivity. Conclusions: The bile acid sequestrant sevelamer improved insulin sensitivity and beta‐cell sensitivity to glucose, but using the GLP‐1 receptor antagonist exendin(9‐39)NH2 we were not able to detect a GLP‐1‐mediated glucose‐lowering effect of sevelamer in individuals with type 2 diabetes. Nevertheless, the sevelamer‐induced improvement of beta‐cell sensitivity to glucose was shown to be GLP‐1‐dependent. [ABSTRACT FROM AUTHOR]

Platinum (Pt) compounds such as oxaliplatin are among the most commonly prescribed anti-cancer drugs. Despite their considerable clinical impact, the molecular basis of platinum cytotoxicity and cancer specificity remain unclear. Here we show that oxaliplatin, a backbone for the treatment of colorectal cancer, causes liquid-liquid demixing of nucleoli at clinically relevant concentrations. Our data suggest that this biophysical defect leads to cell-cycle arrest, shutdown of Pol I-mediated transcription, and ultimately cell death. We propose that instead of targeting a single molecule, oxaliplatin preferentially partitions into nucleoli, where it modifies nucleolar RNA and proteins. This mechanism provides a general approach for drugging the increasing number of cellular processes linked to biomolecular condensates.

Aim: To investigate the use of synthetic preimplantation factor (sPIF) as a potential therapeutic tool for improving glucose‐stimulated insulin secretion (GSIS), glucose tolerance and insulin sensitivity in the setting of diabetes. Materials and Methods: We used a preclinical murine model of type 2 diabetes (T2D) induced by high‐fat diet (HFD) feeding for 12 weeks. Saline or sPIF (1 mg/kg/day) was administered to mice by subcutaneously implanted osmotic mini‐pumps for 25 days. Glucose tolerance, circulating insulin and C‐peptide levels, and GSIS were assessed. In addition, β‐cells (Min‐6) were used to test the effects of sPIF on GSIS and insulin‐degrading enzyme (IDE) activity in vitro. The effect of sPIF on GSIS was also tested in human islets. Results: GSIS was enhanced 2‐fold by sPIF in human islets ex vivo. Furthermore, continuous administration of sPIF to HFD mice increased circulating levels of insulin and improved glucose tolerance, independently of hepatic insulin clearance. Of note, islets isolated from mice treated with sPIF exhibited restored β‐cell function. Finally, genetic (shRNA‐IDE) or pharmacological (6bK) inactivation of IDE in Min‐6 abolished sPIF‐mediated effects on GSIS, showing that both the protein and its protease activity are required for its action. Conclusions: We conclude that sPIF is a promising secretagogue for the treatment of T2D. [ABSTRACT FROM AUTHOR]

Aim: To identify the mediators between canagliflozin and renoprotection in patients with type 2 diabetes at a high risk of end‐stage kidney disease (ESKD). Methods: In this post hoc analysis of the CREDENCE trial, the effect of canagliflozin on potential mediators (42 biomarkers) at 52 weeks and the association between changes in mediators and renal outcomes were evaluated using mixed‐effects and Cox models, respectively. The renal outcome was a composite of ESKD, serum creatinine doubling or renal death. The percentage of the mediating effect of each significant mediator was calculated based on changes in the hazard ratios of canagliflozin after additional adjustment of the mediator. Results: Changes in haematocrit, haemoglobin, red blood cell (RBC) count and urinary albumin‐to‐creatinine ratio (UACR) at 52 weeks significantly mediated 47%, 41%, 40% and 29% risk reduction with canagliflozin, respectively. Further, 85% mediation was attributed to the combined effect of haematocrit and UACR. A large variation in mediating effects by haematocrit change existed among the subgroups, ranging from 17% in those patients with a UACR of more than 3000 mg/g to 63% in patients with a UACR of 3000 mg/g or less. In the subgroups with a UACR of more than 3000 mg/g, UACR change was the highest mediating factor (37%), driven by the strong association between UACR decline and renal risk reduction. Conclusions: The renoprotective effects of canagliflozin in patients at a high risk of ESKD can be significantly explained by changes in RBC variables and UACR. The complementary mediating effects of RBC variables and UACR may support the renoprotective effect of canagliflozin in different patient groups. [ABSTRACT FROM AUTHOR]

Aim: Evidence from mouse models suggests that brain serotonergic pathways control blood glucose. We hypothesized that sumatriptan (5HT1B‐receptor agonist) would alter glucose homeostasis in humans. Materials and Methods: We conducted a two‐visit random‐order double‐blinded placebo‐controlled cross‐over trial in 10 overweight adults that were otherwise healthy. Participants received sumatriptan (single dose, 100 mg) or placebo before undergoing a 60‐min intravenous glucose tolerance test, followed by a 120‐min hyperinsulinaemic euglycaemic clamp. Results: Glucose excursion was greater during intravenous glucose tolerance test with sumatriptan compared with placebo [iAUC0‐60 min 316 (268‐333) vs. 251 (197‐319) min/mmol/L p =.047]. This was probably explained by a combination of reduced circulating insulin levels [iAUC0‐10 min 1626 (1103‐2733) vs. 2336 (1702‐3269) min/pmol/L, p =.005], reduced insulin sensitivity [M/I‐value 2.11 (1.15, 4.05) vs. 3.03 (1.14, 4.90) mg/kg/min per pmol/L, p =.010] and glucose effectiveness [SG 0.17 (0.12, 0.21) vs. 0.22 (0.18, 0.65)/min, p =.027]. Conclusions: 5HT1B receptors have a glucoregulatory role in humans, probably acting on insulin secretion, insulin sensitivity and glucose effectiveness. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the molecular mechanisms underlying the therapeutic effects of dichloroacetic acid (DCA) in lung cancer by integrating multi-omics approaches, as the current understanding of DCA's role in cancer treatment remains insufficiently elucidated. Methods: We conducted a comprehensive analysis of publicly available RNA-seq and metabolomic datasets and established a subcutaneous xenograft model of lung cancer in BALB/c nude mice (n = 5 per group) treated with DCA (50 mg/kg, administered via intraperitoneal injection). Metabolomic profiling, gene expression analysis, and metabolite-gene interaction pathway analysis were employed to identify key pathways and molecular players involved in the response to DCA treatment. In vivo evaluation of DCA treatment on tumor growth and MIF gene expression was performed in the xenograft model. Results: Metabolomic profiling and gene expression analysis revealed significant alterations in metabolic pathways, including the Warburg effect and citric acid cycle, and identified the MIF gene as a potential therapeutic target in lung cancer. Our analysis indicated that DCA treatment led to a decrease in MIF gene expression and an increase in citric acid levels in the treatment group. Furthermore, we observed a potential interaction between citric acid and the MIF gene, suggesting a novel mechanism underlying the therapeutic effects of DCA in lung cancer. Conclusion: This study underscores the importance of integrated omics approaches in deciphering the complex molecular mechanisms of DCA treatment in lung cancer. The identification of key metabolic pathways and the novel finding of citric acid elevation, together with its interaction with the MIF gene, provide promising directions for the development of targeted therapeutic strategies and improving clinical outcomes for lung cancer patients. [ABSTRACT FROM AUTHOR]

Sodium‐glucose cotransporter 2 inhibitors (SGLT‐2is) were originally developed for the treatment of hyperglycaemia in type 2 diabetes. Because of regulatory requirements to show the safety of this new class of drugs, a large randomized cardiovascular (CV) outcomes trial was completed but this showed that instead of having a neutral effect on heart failure (HF) outcomes, that these drugs could reduce HF outcomes in this population. Subsequent trials with SGLT‐2is have shown that HF hospitalizations are reduced by 30% and CV death or HF hospitalization by 21% in patients with type 2 diabetes. These findings have extended to patients with HF with reduced and mildly reduced or preserved ejection fraction in whom further HF hospitalizations are reduced by 28% and CV death or HF hospitalizations reduced by 23%, and that it is becoming a central therapy for the treatment of HF. Moreover, the benefit in patients with HF is observed regardless of the presence or absence of type 2 diabetes. Similarly, in patients with chronic kidney disease and albuminuria, with and without type 2 diabetes, the benefit of SGLT‐2is is clearly seen with a 44% reduction in HF hospitalization and 25% reduction in CV death or HF hospitalization. These trials support the use of SGLT‐2is in improving HF outcomes in a broad range of patients, from those with type 2 diabetes, chronic kidney disease and those with pre‐existing HF regardless of ejection fraction. [ABSTRACT FROM AUTHOR]

Background: Drug repurposing provides an opportunity to redeploy drugs, which are already tested for safety or approved for use in humans, for the treatment of diseases distinct from their primary indication. For example, the repurposing of dexamethasone and baricitinib has played a crucial role in saving patient lives during the SARS-CoV-2 pandemic. There remains a need to expand therapeutic approaches to prevent life-threatening complications in vulnerable patients with COVID-19. Method: Using an in silico approach based on structural similarity to drugs already in clinical trials for COVID-19, potential drugs were predicted for repurposing. For a subset of identified drugs with different targets to their corresponding COVID-19 clinical trial drug, a mechanism of action analysis based on affected pathways in the context of the first 24 h of infection was applied to establish whether they might have a role in inhibiting the replication of SARS-CoV-2. Results: Twenty-nine structurally similar drugs with potential for repurposing against COVID-19 were predicted. Two of these with the potential to inhibit SARS-CoV-2 replication were identified using mechanism of action analysis. Triamcinolone is a corticosteroid that is structurally similar to dexamethasone; gallopamil is a calcium channel blocker that is structurally similar to verapamil. Conclusion: The identification of these drugs as potentially useful for patients with COVID-19 who are at a higher risk of developing severe disease supports the use of in silico approaches to facilitate quick and cost-effective identification of drugs for repurposing. Such drugs could expand the number of treatments available to the subset of patients who are not fully protected by vaccination.

BackgroundThe widespread availability of next generation genome sequencing technologies has enabled a wide range of variant detection applications, especially in cancer and inborn genetic disorders. For model systems and microorganisms, the same technology may be used to discover the causative mutations for any phenotype, including those generated in response to chemical perturbation. In the case of pathogenic organisms, these approaches have allowed the determination of drug targets by means of resistance selection followed by genome sequencing.ResultsMinorityReport is open source software written in python that facilitates the comparison of any two sets of genome alignments for the purpose of rapidly identifying the spectrum of nonsynonymous changes, insertions or deletions, and copy number variations in a presumed mutant relative to its parent. Specifically, MinorityReport relates mapped sequence reads in SAM format output from any alignment tool for both the mutant and parent genome, relative to a reference genome, and produces the set of variants that distinguishes the mutant from the parent, all presented in an intuitive, straightforward report format. MinorityReport features tunable parameters for evaluating evidence and a scoring system that prioritizes reported variants based on relative proportions of read counts supporting the variant in the mutant versus parent data sets. The utility of MinorityReport is demonstrated using previously published publicly available data sets to find the determinants of resistance for novel anti-malarial drugs.ConclusionsMinorityReport is readily available (github: JeremyHorst/MinorityReport) to identify the genetic mechanisms of drug resistance in Plasmodium, genotype-phenotype relationships in human diads, or genomic variations between any two related organisms.

Aims: Sacubitril/valsartan is a neprilysin‐inhibitor/angiotensin II receptor blocker used for the treatment of heart failure. Recently, a post‐hoc analysis of a 3‐year randomized controlled trial showed improved glycaemic control with sacubitril/valsartan in patients with heart failure and type 2 diabetes. We previously reported that sacubitril/valsartan combined with a dipeptidyl peptidase‐4 inhibitor increases active glucagon‐like peptide‐1 (GLP‐1) in healthy individuals. We now hypothesized that administration of sacubitril/valsartan with or without a dipeptidyl peptidase‐4 inhibitor would lower postprandial glucose concentrations (primary outcome) in patients with type 2 diabetes via increased active GLP‐1. Methods: We performed a crossover trial in 12 patients with obesity and type 2 diabetes. A mixed meal was ingested following five respective interventions: (a) a single dose of sacubitril/valsartan; (b) sitagliptin; (c) sacubitril/valsartan + sitagliptin; (d) control (no treatment); and (e) valsartan alone. Glucose, gut and pancreatic hormone responses were measured. Results: Postprandial plasma glucose increased by 57% (incremental area under the curve 0‐240 min) (p =.0003) and increased peak plasma glucose by 1.7 mM (95% CI: 0.6‐2.9) (p =.003) after sacubitril/valsartan compared with control, whereas postprandial glucose levels did not change significantly after sacubitril/valsartan + sitagliptin. Glucagon, GLP‐1 and C‐peptide concentrations increased after sacubitril/valsartan, but insulin and glucose‐dependent insulinotropic polypeptide did not change. Conclusions: The glucose‐lowering effects of long‐term sacubitril/valsartan treatment reported in patients with heart failure and type 2 diabetes may not depend on changes in entero‐pancreatic hormones. Neprilysin inhibition results in hyperglucagonaemia and this may explain the worsen glucose tolerance observed in this study. ClinicalTrials.gov (NCT03893526). [ABSTRACT FROM AUTHOR]

Background: Imipenem is a highly effective carbapenem antibiotic, which is widely used in the treatment of many serious bacterial infections. At the same time, it can also cause some adverse reactions, mental abnormalities are the most concerned central nervous system adverse reactions. Different patients respond differently to imipenem, and the effect of imipenem on psychiatric disorders is unclear. Therefore, meta-analysis summarizing the results of multiple previous studies can provide stronger evidence support for clinical guidelines to guide clinical rational use of imipenem to minimize risks., Aim: To systematically review the effects of imipenem on mental-health disorders., Methods: Method in Cochrane Library, Web of science, PubMed, ProQuest, and China's biomedical literature databases Wanfang, Weipu and China HowNet, the related literatures about the controlled trials of imipenem-induced mental disorders from the establishment of the database to May 2024 were searched; the included literatures were analyzed using RevMan 5.4 software; and the heterogeneity among the studies was also discussed., Results: After reviewing the literature published between 2003 and 2017, seven controlled trials with a total of 550 patients were included, with 273 and 277 patients in the control and experimental groups, respectively. The sample size of the study ranged from a minimum of 30 cases to a maximum of 61 cases. Patients in the experimental group were treated with imipenem while the control group was treated with conventional drugs. Meta-analysis showed that the incidence of mental disorders in the experimental group was higher than that in the control group (odds ratio = 3.66, 95% confidence interval: 1.11-12.11, P = 0.030); however, there was no significant difference in the incidence of adverse reactions between the two groups (odds ratio = 0.05, 95% confidence interval: 0.00 to 0.10, P = 0.060). Funnel diagrams showed that the scattered points of each study were symmetrical and distributed in an inverted funnel shape; therefore, there was no publication bias., Conclusion: Imipenem can cause mental disorders in patients. However, the low quality of the included literature may have affected the final results. Therefore, it is necessary to conduct a high-quality randomized controlled study with multiple samples to further confirm the mechanism of imipenem-induced mental disorders and provide effective guidance for clinical treatment., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Participants self-administered the oral glibenclamide suspension (0.3-6 mg/day, split dose twice daily), and fasting pre-dose blood samples were taken before each dose increase every 3-4 days (see Figure S1 for trial timeline). CONCLUSION In conclusion, low-dose glibenclamide safely reduced glucagon levels in a subpopulation of patients with T2D who had fasting hyperglucagonaemia, suggesting that inappropriately increased alpha-cell K SB ATP sb activity may be a key component in the metabolic dysregulation of diabetes. Reducing hyperglucagonaemia in type 2 diabetes using low-dose glibenclamide: Results of the LEGEND-A pilot study Keywords: antidiabetic drug; clinical trial; drug mechanism; experimental pharmacology; glucagon; type 2 diabetes EN antidiabetic drug clinical trial drug mechanism experimental pharmacology glucagon type 2 diabetes 1671 1675 5 07/11/22 20220801 NES 220801 INTRODUCTION Diabetes is a multi-hormonal disorder characterized by insufficient insulin secretion and aberrant glucagon secretion, with fasting hyperglucagonaemia leading to increased hepatic glucose production,1,2 further exacerbating hyperglycaemia. [Extracted from the article]

• We developed a computational drug repurposing platform to identify new therapies for patients infected with coronaviruses. • The platform only requires virus–host interactions and proteins that are differential expressed 24 h after infection to be known from wet lab data. • We identified 196 approved drugs that could be repurposed for COVID-19 and 102 approved drugs that could be repurposed for SARS. • We also provide the mechanisms of actions of identified drugs using an artificial neural network. In the past 20 years, there have been several infectious disease outbreaks in humans for which the causative agent has been a zoonotic coronavirus. Novel infectious disease outbreaks, as illustrated by the current coronavirus disease 2019 (COVID-19) pandemic, demand a rapid response in terms of identifying effective treatments for seriously ill patients. The repurposing of approved drugs from other therapeutic areas is one of the most practical routes through which to approach this. Here, we present a systematic network-based drug repurposing methodology, which interrogates virus–human, human protein–protein and drug–protein interactome data. We identified 196 approved drugs that are appropriate for repurposing against COVID-19 and 102 approved drugs against a related coronavirus, severe acute respiratory syndrome (SARS-CoV). We constructed a protein–protein interaction (PPI) network based on disease signatures from COVID-19 and SARS multi-omics datasets. Analysis of this PPI network uncovered key pathways. Of the 196 drugs predicted to target COVID-19 related pathways, 44 (hypergeometric p-value: 1.98e−04) are already in COVID-19 clinical trials, demonstrating the validity of our approach. Using an artificial neural network, we provide information on the mechanism of action and therapeutic value for each of the identified drugs, to facilitate their rapid repurposing into clinical trials. [ABSTRACT FROM AUTHOR]

Keywords: drug mechanism; SGLT2 inhibitor; type 2 diabetes EN drug mechanism SGLT2 inhibitor type 2 diabetes 757 762 6 03/11/22 20220401 NES 220401 PEER REVIEW The peer review history for this article is available at https://publons.com/publon/10.1111/dom.14627. The fractional excretion rates (%) of glucose, Na, K, Cl, Ca, and P were calculated using the following formula: urine solute × serum Cr / serum solute × urine Cr. Drug mechanism, SGLT2 inhibitor, type 2 diabetes 7 Clar C, Gill JA, Court R, Waugh N. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. [Extracted from the article]

Triple combination FCR (fludarabine, cyclophosphamide and rituximab) is often used as front-line treatment for chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma. Results from our laboratory indicate that 2-FaraAMP (fludarabine) has multiple mechanisms of cytotoxicity that include accumulation of isoforms and phosphorylated derivatives of p53, and induction of the unfolded protein response (UPR). Using protein pull-downs with Dynabeads coated with p53 antibody, we have found that 2-FaraA (fludarabine nucleoside) induces major changes in the p53 interactome in human Raji lymphoma and IM9 multiple myeloma cells. These changes are likely driven by DNA strand breaks induced by 2-FaraA that activate protein kinases such as ATM, ATR and Chk1. [ABSTRACT FROM AUTHOR]

An appropriate therapeutic index is crucial for drug discovery and development since narrow therapeutic index (NTI) drugs with slight dosage variation may induce severe adverse drug reactions or potential treatment failure. To date, the shared characteristics underlying the targets of NTI drugs have been explored by several studies, which have been applied to identify potential drug targets. However, the association between the drug therapeutic index and the related disease has not been dissected, which is important for revealing the NTI drug mechanism and optimizing drug design. Therefore, in this study, two classes of disease (cancers and cardiovascular disorders) with the largest number of NTI drugs were selected, and the target property of the corresponding NTI drugs was analyzed. By calculating the biological system profiles and human protein–protein interaction (PPI) network properties of drug targets and adopting an AI-based algorithm, differentiated features between two diseases were discovered to reveal the distinct underlying mechanisms of NTI drugs in different diseases. Consequently, ten shared features and four unique features were identified for both diseases to distinguish NTI from NNTI drug targets. These computational discoveries, as well as the newly found features, suggest that in the clinical study of avoiding narrow therapeutic index in those diseases, the ability of target to be a hub and the efficiency of target signaling in the human PPI network should be considered, and it could thus provide novel guidance in the drug discovery and clinical research process and help to estimate the drug safety of cancer and cardiovascular disease.

The cardio‐renal benefits of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors are well established. In 2016, we postulated that these benefits are attributable, in part, to the occurrence of chronic low‐grade ketonaemia and a shift in myocardial and renal fuel metabolism away from fat oxidation, which is energy inefficient, towards ketone oxidation, which is more energy efficient. This shift improves myocardial and renal function and can potentially translate into lower rates of progression to heart failure and end‐stage kidney disease in patients with and without diabetes. There is now evidence that, in addition to being an efficient fuel substrate, ketones also have antiinflammatory and antioxidative benefits on the heart and the kidney. In addition, ketones have positive effects on mitochondrial biogenesis and function, and on erythropoiesis, and thereby are potentially able to further ameliorate the proinflammatory and hypoxic milieu in those with heart and kidney failure, independent of hyperglycaemia. In the present review, we propose a novel hypothesis to link the pleiotropic effects of low‐grade ketonaemia to the cardio‐renal benefits seen with SGLT2 inhibitors. [ABSTRACT FROM AUTHOR]

Aim: To present an overview of exendin(9‐39)NH2 usage as a scientific tool in humans and provide recommendations for dosage and infusion regimes. Methods: We systematically searched the literature on exendin(9‐39)NH2 and included for review 44 clinical studies reporting use of exendin(9‐39)NH2 in humans. Results: Exendin(9‐39)NH2 binds to the orthosteric binding site of the glucagon‐like peptide‐1 (GLP‐1) receptor with high affinity. The plasma elimination half‐life of exendin(9‐39)NH2 after intravenous administration is ~30 minutes, requiring ~2.5 hours of constant infusion before steady‐state plasma concentrations can be expected. Studies utilizing infusions with exendin(9‐39)NH2 in humans have applied varying regimens (priming with a bolus or constant infusion) and dosages (continuous infusion rate range 30‐900 pmol/kg/min) with subsequent differences in effects. Administration of exendin(9‐39)NH2 in healthy individuals, patients with diabetes, obese patients, and patients who have undergone bariatric surgery significantly increases fasting and postprandial levels of glucose and glucagon, but has inconsistent effects on circulating concentrations of insulin and C‐peptide, gastric emptying, appetite sensations, and food intake. Importantly, exendin(9‐39)NH2 induces secretion of all L cell products (ie, in addition to GLP‐1, also peptide YY, glucagon‐like peptide‐2, oxyntomodulin, and glicentin) complicating use of exendin(9‐39)NH2 as a tool to study the isolated effect of GLP‐1. Conclusions: Exendin(9‐39)NH2 is selective for the GLP‐1 receptor, with numerous and complex whole‐body effects. To obtain GLP‐1 receptor blockade in humans, we recommend an initial high‐dose infusion, followed by a continuous infusion rate aiming at a ratio of exendin(9‐39)NH2 to GLP‐1 of 2000:1. Highlights Exendin(9‐39)NH2 is a competitive antagonist of the human GLP‐1 receptor.Exendin(9‐39)NH2 has been used as a tool to delineate human GLP‐1 physiology since 1998.Exendin(9‐39)NH2 induces secretion of GLP‐1 and other L cell products.Reported effects of exendin(9‐39)NH2 on insulin levels and food intake are inconsistent.Here, we provide recommendations for the use of exendin(9‐39)NH2 in clinical studies. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and insulin resistance. The dual sodium‐glucose co‐transporter 1/2 inhibitor (SGLT1/2i) licogliflozin (LIK066) ameliorates hyperinsulinism in patients with diabetes and obesity. This study examines the effect of licogliflozin on androgens in women with PCOS. In a multicentre, randomized, placebo‐controlled, double‐blind, 2‐week trial, patients with PCOS received licogliflozin 50 mg or placebo three times a day (TID). Changes in free testosterone (FT), other androgens and variables of insulin resistance were analysed. Concentration of FT did not change (TRLIK066:TRPCB [FT]: 0.88; 90% CI: 0.70‐1.11; P =.353). Licogliflozin reduced androstendione (A4) by 19% (TRLIK066:TRPCB [A4]: 0.81; 90% CI: 0.68‐0.99; P =.089) and dehydroepiandrosteron sulphate (DHEAS) by 24% (TRLIK066:TRPCB [DHEAS]: 0.76; 90% CI: 0.65‐0.89; P =.008). Hyperinsulinaemia was reduced by 70% by licogliflozin (highest insulin concentration [MAXI]; TRLIK066:TRPCB [MAXI]: 0·26; 90% CI:0.20‐0.34; P <.001 and area under the curve insulin [AUCI]; TRLIK066:TRPCB [AUCI]: 0.32; 90% CI: 0.25‐0.41; P <.001). Diarrhoea and nausea occurred as common adverse events. Dual inhibition of SGLT1/2 ameliorates hyperinsulinaemia and hyperandrogenaemia in women with PCOS. Licogliflozin may represent a promising novel treatment option for PCOS. [ABSTRACT FROM AUTHOR]

The incretin hormones glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) have their main physiological role in augmenting insulin secretion after their nutrient‐induced secretion from the gut. A functioning entero‐insular (gut‐endocrine pancreas) axis is essential for the maintenance of a normal glucose tolerance. This is exemplified by the incretin effect (greater insulin secretory response to oral as compared to "isoglycaemic" intravenous glucose administration due to the secretion and action of incretin hormones). GIP and GLP‐1 have additive effects on insulin secretion. Local production of GIP and/or GLP‐1 in islet α‐cells (instead of enteroendocrine K and L cells) has been observed, and its significance is still unclear. GLP‐1 suppresses, and GIP increases glucagon secretion, both in a glucose‐dependent manner. GIP plays a greater physiological role as an incretin. In type 2‐diabetic patients, the incretin effect is reduced despite more or less normal secretion of GIP and GLP‐1. While insulinotropic effects of GLP‐1 are only slightly impaired in type 2 diabetes, GIP has lost much of its acute insulinotropic activity in type 2 diabetes, for largely unknown reasons. Besides their role in glucose homoeostasis, the incretin hormones GIP and GLP‐1 have additional biological functions: GLP‐1 at pharmacological concentrations reduces appetite, food intake, and—in the long run—body weight, and a similar role is evolving for GIP, at least in animal studies. Human studies, however, do not confirm these findings. GIP, but not GLP‐1 increases triglyceride storage in white adipose tissue not only through stimulating insulin secretion, but also by interacting with regional blood vessels and GIP receptors. GIP, and to a lesser degree GLP‐1, play a role in bone remodelling. GLP‐1, but not GIP slows gastric emptying, which reduces post‐meal glycaemic increments. For both GIP and GLP‐1, beneficial effects on cardiovascular complications and neurodegenerative central nervous system (CNS) disorders have been observed, pointing to therapeutic potential over and above improving diabetes complications. The recent finding that GIP/GLP‐1 receptor co‐agonists like tirzepatide have superior efficacy compared to selective GLP‐1 receptor agonists with respect to glycaemic control as well as body weight has renewed interest in GIP, which previously was thought to be without any therapeutic potential. One focus of this research is into the long‐term interaction of GIP and GLP‐1 receptor signalling. A GLP‐1 receptor antagonist (exendin [9‐39]) and, more recently, a GIP receptor agonist (GIP [3‐30] NH2) and, hopefully, longer‐acting GIP receptor agonists for human use will be helpful tools to shed light on the open questions. A detailed knowledge of incretin physiology and pathophysiology will be a prerequisite for designing more effective incretin‐based diabetes drugs. [ABSTRACT FROM AUTHOR]

Aim: To investigate the glucosuric, renal and haemodynamic effects of licogliflozin, a dual sodium‐glucose co‐transporter‐1 and sodium‐glucose co‐transporter‐2 inhibitor, in patients with chronic kidney disease (CKD). Methods: This multiple‐dose, parallel‐group, phase II mechanistic study randomized 53 participants (aged 18–78 years, body mass index ≤ 50 kg/m2) with varying degrees of CKD or normal renal function to treatment with licogliflozin (50 mg once daily) or placebo for 7 days. The effects of licogliflozin on 24‐h urinary glucose excretion (UGE24), renal function, haemodynamics, pharmacokinetics and safety were assessed. Results: Licogliflozin treatment for 7 days significantly (p <.01) increased UGE24 from baseline in participants with normal renal function (adjusted mean change: 41.8 [33.6, 49.9] g) or with mild (32.6 [24.1, 41.0] g), moderate A (35.7 [28.6, 42.9] g) or moderate B (20.3 [13.1, 27.5] g) CKD, but not in severe (6.2 [−0.71, 13.18] g) CKD. Licogliflozin reduced urinary electrolytes (sodium, potassium and chloride), blood pressure and urinary volume to varying extents among different groups. Significant increases in renin (p <.05), angiotensin II (p <.05) and aldosterone (p <.01) levels were observed. Adverse events were generally mild, and most commonly included diarrhoea (94%), flatulence (68%) and abdominal pain (21%). Conclusion: Licogliflozin treatment results in significantly increased UGE and favourable changes in urinary electrolytes and haemodynamics in patients with varying degrees of CKD (estimated glomerular filtration rate ≥ 45 mL/min/1.73 m2). [ABSTRACT FROM AUTHOR]

Aim: To investigate the tolerability, pharmacokinetics (PK) and postprandial triglyceride (TG) response of single, escalating oral doses of a selective 5‐hydroxytryptamine‐2c (5‐HT2c) agonist in subjects with overweight/obesity and apply mechanistic population pharmacokinetic‐pharmacodynamic modelling to identify a plausible drug mechanism of action. Materials and Methods: This phase 1, single‐centre, double‐blind, randomized, placebo‐controlled, four‐period, two‐alternating cohorts study evaluated single escalating oral doses ranging from 5 to 130 mg of LY2140112 (LY) in subjects with overweight/obesity (body mass index: 27–39 kg/m2). Postprandial TG response (total TG, chylomicrons and very low‐density lipoprotein particles [VLDL]‐V6) following a high‐fat meal were assessed for 11 h postmeal for each dose level. The PK profile was assessed for 96 h postdose. Drug exposure and TG concentrations in chylomicrons and VLDL‐V6 were used to characterize the drug mechanism of action using non‐linear mixed‐effect modelling. Results: Seventeen subjects entered the study and 16 subjects received at least one dose of LY. LY2140112 was generally well tolerated up to 75 mg. The PK of LY were described by a two‐compartment model with first‐order elimination. The 100 and 130 mg dose levels of LY significantly reduced the postprandial TG of VLDL‐V6 by approximately 50%, while total TG and chylomicrons were not significantly different from placebo. The application of a published lipokinetic model successfully described the postprandial TG response in this study and indicated that LY reduced the conversion of TGs from chylomicron to VLDL‐V6. Conclusions: LY significantly reduced the postprandial TG of VLDL‐V6 following a single dose, when food consumption was controlled. The data indicate that a selective 5‐HT2c agonist alters lipid metabolism, beyond the reported reduction in satiety. The application of a semi‐physiological lipokinetic model enabled identification of a plausible drug mechanism of action of LY. [ABSTRACT FROM AUTHOR]

Aims: To assess the therapeutic potential of fatty acid synthase (FASN) inhibition with FT‐4101, a potent, selective, orally bioavailable, small‐molecule by (a) evaluating the dose−response of single FT‐4101 doses (3, 6 and 9 mg) on hepatic de novo lipogenesis (DNL) in healthy participants (Study 1) and (b) demonstrating the safety, tolerability and efficacy on hepatic steatosis after 12 weeks of FT‐4101 dosing in patients with non‐alcoholic fatty liver disease (NAFLD; Study 2). Materials and Methods: In Study 1, three sequential cohorts of healthy men (n = 10/cohort) were randomized to receive a single dose of FT‐4101 (n = 5/cohort) or placebo (n = 5/cohort) followed by crossover dosing after 7 days. Hepatic DNL was assessed during fructose stimulation from 13C‐acetate incorporation. In Study 2, men and women with NAFLD (n = 14) randomly received 12 weeks of intermittent once‐daily dosing (four cycles of 2 weeks on‐treatment, followed by 1 week off‐treatment) of 3 mg FT‐4101 (n = 9) or placebo (n = 5). Steady‐state DNL based on deuterated water labelling, hepatic steatosis using magnetic resonance imaging‐proton density fat fraction and sebum lipids and circulating biomarkers were assessed. Results: Single and repeat dosing of FT‐4101 were safe and well tolerated. Single FT‐4101 doses inhibited hepatic DNL dose‐dependently. Twelve weeks of 3 mg FT‐4101 treatment improved hepatic steatosis and inhibited hepatic DNL. Decreases in sebum sapienate content with FT‐4101 at week 11 were not significant compared to placebo and rebounded at week 12. Biomarkers of liver function, glucose and lipid metabolism were unchanged. Conclusions: Inhibition of FASN with 3 mg FT‐4101 safely reduces hepatic DNL and steatosis in NAFLD patients. [ABSTRACT FROM AUTHOR]

Naltrexone/bupropion (NB) is a US Food and Drug Administration‐approved antiobesity medication. Clinical trials have shown variable weight loss, with responders and non‐responders. NB is believed to act on central dopaminergic pathways to suppress appetite. The Taq1A polymorphism near DRD2 (rs1800497) is associated with the density of striatal dopamine D2 receptors, with individuals carrying the A allele (AA or AG; termed A1+) having 30%‐40% fewer dopamine binding sites than those who do not carry the A allele (GG; termed A1‐). We performed a pilot study to assess the association of the rs1800497 ANKK1 c.2137G > A (p.Glu713Lys) variant with weight loss with NB treatment in 33 subjects. Mean (SD) weight loss was 5.9% (3.2%) for the A1+ genotype group (n = 15) and 4.2% (4.2%) for the A1‐ genotype group (n = 18). The mean weight loss for the A1+ genotype group was significantly greater than the predefined clinically significant 4% weight‐loss target (one‐sample t‐test, P =.035), whereas the mean weight loss for the A1‐ genotype group was not (P =.85). Individuals with the A1+ genotype appear to respond better to NB than A1‐ individuals. [ABSTRACT FROM AUTHOR]

Hydroxychloroquine (HCQ) is a kind of synthetic 4-aminoquinoline antimalarial drugs. In recent years, other pharmacological effects of HCQ, such as immunomodulatory, immunosuppression, anti-inflammation, vascular endothelium protection, anti-thrombus, improving metabolic syndrome, and anti-infection, have been gradually known. At present, HCQ is a first-line drug for systemic lupus erythematosus. And in many guidelines for the treatment of autoimmune diseases, HCQ is recommended during whole pregnancy and lactation. This review mainly expounds the mechanism and research progress of HCQ in reproductive immunology, including pregnancy complicated with autoimmune diseases, such as systemic lupus erythematosus, antiphospholipid syndrome and Sjogren's syndrome, as well as unexplained recurrent spontaneous abortion and recurrent implantation failure, and explores the safety and application prospect of HCQ in reproductive immunology. [ABSTRACT FROM AUTHOR]

Metformin is the initial medication recommended for the treatment of type 2 diabetes mellitus (T2DM). In addition to diabetes treatment, the function of metformin also can be anti-aging, antiviral, and anti-inflammatory. Nevertheless, further exploration is required to fully understand its mode of operation. Historically, the liver has been acknowledged as the main location where metformin reduces glucose levels, however, there is increasing evidence suggesting that the gastrointestinal tract also plays a significant role in its action. In the gastrointestinal tract, metformin effects glucose uptake and absorption, increases glucagon-like peptide-1 (GLP-1) secretion, alters the composition and structure of the gut microbiota, and modulates the immune response. However, the side effects of it cannot be ignored such as gastrointestinal distress in patients. This review outlines the impact of metformin on the digestive system and explores potential explanations for variations in metformin effectiveness and adverse effects like gastrointestinal discomfort., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cheng, Ren, Jia, Wang and Cong.)

Abstract The concept of antibody microarrays is one of the most versatile approaches within multiplexed immunoassay technologies. These types of arrays have increasingly become an attractive tool for the exploratory detection and study of protein abundance, function, pathways, and potential drug targets. Due to the properties of the antibody microarrays and their potential use in basic research and clinical analytics, various types of antibody microarrays have already been developed. In spite of the growing number of studies utilizing this technique, few reviews about antibody microarray technology have been presented to reflect the quality and future uses of the generated data. In this review, we provide a summary of the recent applications of antibody microarray techniques in basic biology and clinical studies, providing insights into the current trends and future of protein analysis.

Aim: To test the hypothesis that glucokinase activators (GKAs) induce hepatic adaptations that alter intra-hepatocyte metabolite homeostasis. Methods: C57BL/6 mice on a standard rodent diet were treated with a GKA (AZD1656) acutely or chronically. Hepatocytes were isolated from the mice after 4 or 8 weeks of treatment for analysis of cellular metabolites and gene expression in response to substrate challenge. Results: Acute exposure of mice to AZD1656 or a liver-selective GKA (PF- 04991532), before a glucose tolerance test, or challenge of mouse hepatocytes with GKAs ex vivo induced various Carbohydrate response element binding protein (ChREBP) target genes, including Carbohydrate response element binding protein beta isoform (ChREBP-β), Gckr and G6pc. Both glucokinase activation and ChREBP target gene induction by PF-04991532 were dependent on the chirality of the molecule, confirming a mechanism linked to glucokinase activation. Hepatocytes from mice treated with AZD1656 for 4 or 8 weeks had lower basal glucose 6-phosphate levels and improved ATP homeostasis during high substrate challenge. They also had raised basal ChREBP-β mRNA and AMPK-α mRNA (Prkaa1, Prkaa2) and progressively attenuated substrate induction of some ChREBP target genes and Prkaa1 and Prkaa2. Conclusions: Chronic GKA treatment of C57BL/6 mice for 8 weeks activates liver ChREBP and improves the resilience of hepatocytes to compromised ATP homeostasis during high-substrate challenge. These changes are associated with raised mRNA levels of ChREBP-β and both catalytic subunits of AMP-activated protein kinase. [ABSTRACT FROM AUTHOR]

Aim: Type 1 diabetes (T1D) is a chronic autoimmune disease leading to progressive loss of pancreatic beta cells. Interferon (IFN)‐α plays a critical role in the crosstalk between pancreatic beta cells and the immune system in early insulitis. In human beta cells IFNα signals through JAK1 and TYK2, leading to endoplasmic reticulum stress, inflammation and HLA class I overexpression. IFNα, acting synergistically with IL‐1β, induces apoptosis. Polymorphisms in TYK2 that decrease its activity are associated with protection against T1D, and we hypothesized that pharmacological inhibitors that specifically target TYK2 could protect human beta cells against the deleterious effects of IFNα. Materials and Methods: Two TYK2 inhibitors provided by Nimbus Lakshmi were tested in human insulin‐producing EndoC‐βH1 cells and human islets to evaluate their effect on IFNα signalling, beta‐cell function and susceptibility to viral infection using RT‐qPCR, western blot, immunofluorescence, ELISA and nuclear dyes. Results: The two TYK2 inhibitors tested prevented IFNα‐induced human beta‐cell gene expression in a dose‐dependent manner. They also protected human islets against IFNα + IL‐1β‐induced apoptosis. Importantly, these inhibitors did not modify beta‐cell function or their survival following infection with the potential diabetogenic coxsackieviruses CVB1 and CVB5. Conclusions: The two TYK2 inhibitors tested inhibit the IFNα signalling pathway in human beta cells, decreasing its pro‐inflammatory and pro‐apoptotic effects without sensitizing the cells to viral infection. The preclinical findings could pave the way for future clinical trials with TYK2 inhibitors for the prevention and treatment of type 1 diabetes. [ABSTRACT FROM AUTHOR]

Aim: To explore the relationship between baseline uric acid (UA) levels and long‐term cardiovascular events in adults with type 2 diabetes (T2D) and to determine whether the cardioprotective effects of fenofibrate are partly mediated through its UA‐lowering effects. Methods: Data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial were utilized, comprising 9795 adults with T2D randomly allocated to treatment with fenofibrate or matching placebo. Plasma UA was measured before and after a 6‐week, active fenofibrate run‐in phase in all participants. Cox proportional hazards models were used to explore the relationships between baseline UA, pre‐to‐post run‐in reductions in UA and long‐term cardiovascular outcomes. Results: Mean baseline plasma UA was 0.33 mmol/L (SD 0.08). Baseline UA was a significant predictor of long‐term cardiovascular events, with every 0.1 mmol/L higher UA conferring a 21% increase in event rate (HR 1.21, 95% CI 1.13‐1.29, P <.001). This remained significant after adjustment for treatment allocation, cardiovascular risk factors and renal function. The extent of UA reduction during fenofibrate run‐in was also a significant predictor of long‐term cardiovascular events, with every 0.1 mmol/L greater reduction conferring a 14% lower long‐term risk (HR 0.86, 95% CI 0.76‐0.97, P =.015). This effect was not modified by treatment allocation (Pinteraction =.77). Conclusions: UA is a strong independent predictor of long‐term cardiovascular risk in adults with T2D. Although greater reduction in UA on fenofibrate is predictive of lower cardiovascular risk, this does not appear to mediate the cardioprotective effects of fenofibrate. [ABSTRACT FROM AUTHOR]

Multi-Drug Resistant (MDR) and Extensively Drug-Resistant (XDR) in Tuberculosis (TB) is still a big threat worldwide, as it remains one of the leading causes of death. The main reason behind this is the Mycobacterium tuberculosis bacteria (Mtb) is being resistant towards first line drug (FLD). This is because of the mutation in certain genes like katG, pncA, rpoB, embABC. To have a better understanding of the mechanism behind the susceptibility and resistivity of drugs involved in FLD, we propose a graphical approach of modeling the whole process by using Petri net. The analysis of the model helps in improving the new drug techniques on the way to decrease the rate of MDR-TB and XDR-TB. [ABSTRACT FROM AUTHOR]

Aims: To investigate the mechanism of action of 55P0251, a novel multiflorine‐derived substituted quinazolidine that augments insulin release and lowers blood glucose in rodents, but does not act via mechanisms addressed by any antidiabetic agent in clinical use. Materials and Methods: Using male mice, we determined the effects of 55P0251 on glucose tolerance, insulin secretion from isolated islets and blood oxygen saturation, including head‐to‐head comparison of 55P0251 to its inverted enantiomer 55P0250, as well as to other anti‐hyperglycaemic multiflorine derivatives discovered in our programme. Results: 55P0251 was clearly superior to its inverted enantiomer in the glucose tolerance test (area under the curve: 11.3 mg/kg 55P0251, 1.19 ± 0.04 min*mol/L vs 55P0250, 1.80 ± 0.04 min*mol/L; P <.0001). For insulin release in vitro, this superiority became visible only under concomitant adrenergic background stimulation (glucose‐stimulated insulin release, fmol*islet−1*30 min−1: without α2‐adrenoceptor agonist: 500 μmol/L 55P0251, 390 ± 34, vs 55P0250, 459 ± 40, nonsignificant; with α2‐adrenoceptor agonist: 250 μmol/L 55P0251, 138 ± 9, vs 55P0250, 21 ± 6; P <.0001). Since receptor binding assays suggested antagonism at α2A‐adrenoceptors as a potential mechanism of action, we measured oxygen saturation in capillary blood from the tail as a surrogate of vasoconstriction, which supported α2‐antagonistic action in vivo (90 mg/kg 55P0251, 83 ± 3%, vs 55P0250, 57 ± 3%; P <.0001). Lack of association between glucose‐lowering activities and α2A‐adrenoceptor binding affinity arising from comparison of multiflorine derivatives was attributed to differences in their pharmacokinetic properties. Conclusions: Our findings suggest that 55P0251 and related multiflorine derivatives are to be categorized as α2‐adrenoceptor antagonists with potential to lower blood glucose by blocking α2A‐adrenoceptors on pancreatic β cells. [ABSTRACT FROM AUTHOR]

Evidence clearly shows a chemopreventive effect for aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) on colorectal cancer and probably other cancer types; however, data on the risk-benefit profile for cancer prevention are insufficient and no definitive recommendations can be made. Aspirin has emerged as the most likely NSAID for use in chemoprevention because of its known cardiovascular benefit and available safety and efficacy data. Other traditional NSAIDs, particularly sulindac, and selective COX-2 inhibitors are now given to patients at high risk of colorectal cancer, although these drugs do not provide cardioprotection. More studies of aspirin and cancer prevention are needed to define the lowest effective dose, the age at which to initiate therapy, the optimum treatment duration, and the subpopulations for which the benefits of chemoprevention outweigh the risks of adverse side-effects. Although it might be possible to answer some of these questions with longer follow-up of existing clinical trials, randomised controlled trials with new study designs will be needed. Future projects should investigate the effects of aspirin treatment on multiple organ systems. Cancers of interest are colorectal, breast, prostate, lung, stomach, and oesophageal. The main side-effect of aspirin is peptic ulcers; therefore coadministration of aspirin with a proton-pump inhibitor is an attractive option and is under investigation in the AspECT trial.

Increased polyamine synthesis and inflammation have long been associated with colon carcinogenesis in both preclinical models and in humans. Recent experimental studies suggest that polyamines may be mechanistically involved in colonic inflammatory processes. Genetic epidemiology results indicate that a single nucleotide polymorphism influencing the expression of a polyamine biosynthetic gene is associated with both risk of colon polyp occurrence and recurrence, and the response to aspirin as a polyp preventive agent. A prospective, randomized, placebo-controlled clinical trial of combination difluoromethylornithine, a selective inhibitor of polyamine synthesis, and sulindac, a nonsteroidal anti-inflammatory drug, found that the 3-year treatment was associated with a 70% reduction of recurrence of all adenomas, and over a 90% reduction of recurrence of advanced and/or multiple adenomas, without evidence of serious toxicities. This proof-of-principle trial indicates that targeting polyamine synthesis and inflammation can be an effective strategy for preventing the occurrence of the advanced and/or multiple adenomas that are most closely associated with the development of colon cancers in humans.

Prostate cancer is a major health issue, and prevention of prostate cancer and/or its progression will yield benefits for men. Difluoromethylornithine (DFMO) is an antiproliferative agent, inhibiting ornithine decarboxylase, the first enzyme in the polyamine pathway, and has been studied as a therapeutic and chemopreventive agent. The prostate has high levels of tissue polyamines and has shown sensitivity to DFMO both in vitro and in vivo.Eighty-one men participated in a 1-year randomized trial of placebo or DFMO. Prostate volume determination and biopsy of the prostate for histology and polyamine content were done at baseline and after 12 months. Other biomarker variables were assessed, including total and free prostate-specific antigen and prostate-specific antigen doubling time.Compared with baseline, men receiving DFMO had a smaller increase in prostate volume (0.14 cm(3)) than those on placebo (2.95 cm(3); P = 0.0301) at 1 year. In addition, DFMO caused a 60.8% reduction of prostate putrescine levels compared with a 139.5% increase in the placebo arm (P = 0.0014). Stratification by ornithine decarboxylase genotype showed that DFMO reduced prostate volume (P = 0.029) and putrescine levels (P = 0.0053) in the AA + GA group but not in the GG group. There were no grade 3 or 4 toxicities. There was no clinical ototoxicity, with one subclinical grade 2 hearing decline on audiogram.In this randomized placebo-controlled trial, DFMO induced a decrease of prostate putrescine levels and rate of prostate growth. The potential of this compound for prostate cancer or hyperplasia should be further studied.

New insights into cancer cell-specific biological pathways are urgently needed to promote development of rationally targeted therapeutics. Reactive oxygen species (ROS) and their role in cancer cell response to growth factor signaling and hypoxia are emerging as verdant areas of exploration on the road to discovering cancer's Achilles heel. One of the distinguishing and near-universal hallmarks of cancer growth is hypoxia. Unregulated cellular proliferation leads to formation of cellular masses that extend beyond the resting vasculature, resulting in oxygen and nutrient deprivation. The resulting hypoxia triggers a number of critical adaptations that enable cancer cell survival, including apoptosis suppression, altered glucose metabolism, and an angiogenic phenotype. Ironically, recent investigations suggest that oxygen depletion stimulates mitochondria to elaborate increased ROS, with subsequent activation of signaling pathways, such as hypoxia inducible factor 1alpha, that promote cancer cell survival and tumor growth. Because mitochondria are key organelles involved in chemotherapy-induced apoptosis induction, the relationship between mitochondria, ROS signaling, and activation of survival pathways under hypoxic conditions has been the subject of increased study. Insights into mechanisms involved in ROS signaling may offer novel avenues to facilitate discovery of cancer-specific therapies. Preclinical and clinical evaluation of agents that modify ROS signaling in cancer offers a novel avenue for intervention. This review will cover recent work in ROS-mediated signaling in cancer cells and its potential as a target for developmental therapeutics.