Search Results (21)

Background/Objectives: α-carbonic anhydrase (α-TcCA) has emerged as a promising drug target in T. cruzi, the causative agent of Chagas disease in the Americas. Sulfonamides, known inhibitors of CAs, bind to the zinc ion on the enzyme’s active site. This study proposes the repositioning of sulfonamide-based drugs to identify new trypanocidal agents. Method: Ligand-based virtual screening and molecular docking analysis were performed on FDA-approved drugs targeting α-TcCA. These compounds were evaluated in vitro and ex vivo against the A1 and NINOA strains, followed by enzymatic assays. Results: Four sulfonylureas were selected: glimepiride (Glim), acetohexamide (Ace), gliclazide (Glic), and tolbutamide (Tol). Ace and Tol had half-maximal inhibitory concentration (IC₅₀) values similar or better than reference drugs against the NINOA strain in the epimastigote and trypomastigote stages, while Glic and Glim had the highest activity against the A1 strain (epimastigotes and amastigotes). Notably, Ace had the highest trypanocidal activity against all stages in NINOA, with IC₅₀ values of 6.5, 46.5, and 46 μM for epimastigotes, trypomastigotes, and amastigotes, respectively. Additionally, Ace inhibited α-TcCA with K_I = 5.6 μM, suggesting that its trypanocidal effect is associated to the enzyme inhibition. Conclusions: This study supports the repositioning of FDA-approved sulfonamide-based hypoglycaemic agents as trypanocidal compounds. Future studies should focus on structural modifications to improve selectivity. Integrating docking, parasitological, and enzymatic data is crucial for optimizing drug candidates for Chagas disease. Full article

Diabetes-related cognitive impairment (DCI) is a severe complication of type 2 diabetes mellitus (T2DM), with limited understanding of its molecular mechanisms hindering effective therapeutic development. This study identified SERPINA3 as a potential therapeutic target for DCI through integrated machine learning and molecular docking analyses. Transcriptomic data from cortical neuronal samples of T2DM patients were analysed using support vector machine recursive feature elimination (SVM-RFE) and least absolute shrinkage and selection operator (LASSO) regression, revealing SERPINA3 as a significantly upregulated gene in DCI. Experimental validation via Western blot confirmed elevated SERPINA3 protein levels in DCI patient plasma. Molecular docking demonstrated the stable binding of sulfonylurea hypoglycaemic agents, such as gliclazide and glimepiride, to SERPINA3, with binding energies of −6.8 and −6.6 kcal/mol, respectively. These findings suggest that SERPINA3 plays a pivotal role in DCI pathogenesis and that sulfonylurea drugs may exert neuroprotective effects through SERPINA3-mediated pathways. This study provides novel insights into the molecular mechanisms of DCI and highlights the potential of SERPINA3-targeted therapies for early intervention and treatment. Further research is warranted to validate these findings in larger cohorts and explore their clinical applicability. Full article

Gracilaria species, a widely distributed genus of red macroalgae, have gathered significant attention for their diverse medical applications attributable to their bioactive sulphated polysaccharides (SPs). This review examines the global narrative of various Gracilaria SP applications in terms of their therapeutic potential and mechanistic insights into the use of these SPs against a range of medical conditions, including cancer, inflammation, neurodegenerative disorders, diabetes, and immune dysfunctions. SPs extracted from G. lemaneiformis and G. fisheri have demonstrated potent anti-tumour activities by inducing apoptosis through various mechanisms, including the upregulation of CD8⁺ T cells and IL-2, inhibition of EGFR/MAPK/ERK signalling pathways, and activation of the Fas/FasL pathway. Selenium nanoparticles (SeNPs) conjugated with SPs further enhanced the targeted delivery and efficacy of these SPs against glioblastoma by the downregulation of ROS followed by the activation of p53, MAPK, and AKT pathways. The anti-inflammatory properties of SPs are evidenced by key suppressive inflammatory markers like NO, TNF-α, IL-1β, and IL-6 in mutant rodent models. SPs from G. cornea and G. birdiae effectively reduce neutrophil migration and vascular permeability, offering potential treatments for acute inflammation and conditions such as colitis by modulating pathways involving COX-2 and NF-κB. Neuroprotective effects by SPs (from G. cornea and G. gracili) studied in 6-OHDA-induced rats, which mitigate oxidative stress and enhance neuronal cell viability, facilitate the management of neurodegenerative diseases like Parkinson’s and Alzheimer’s. Regarding the hypoglycaemic effect, SPs from G. lemaneiformis exhibit a glucose-modulating response by improving insulin regulation, inhibiting α-amylase activity, repairing pancreatic β-cells, and modulating lipid metabolism. Moreover, immunomodulatory activities of Gracilaria-derived SPs include the stimulation of macrophages, T-cell proliferation, and cytokine production, underscoring their potential as functional food and immunotherapeutic agents. Recently, Gracilaria-derived SPs have been found to modulate gut microbiota, promote SCFA production, and enhance gut microbials, suggesting their potential as prebiotic agents (G. rubra and G. lemaneiformis). This review highlights the multifaceted medical applications of Gracilaria sulphated polysaccharides, providing detailed mechanistic insights and suggesting avenues for future clinical translation and therapeutic innovations. Full article

Non-alcoholic metabolic-associated steatohepatitis (MASH) is a condition characterized by increasingly high prevalence and incidence, and also represents an important unmet medical need when it comes to effective pharmacotherapy. In this work, we aimed to explore the therapeutic possibilities of the synergistic combined use of glycyrrhizinic acid (GA) and phosphatidylcholine (PC) to prevent experimental MASH. Adult C57Bl/6 mice were used to model dietary/toxic MASH and treated orally by either GA (34.3 mg/kg/d) or a GA + PC combination (34.3 + 158.1 mg/kg/d) for 3 months. Animal locomotion, behaviour, short-term memory, physical performance, neuromuscular joint function, blood biochemistry, and oxidative stress marker levels were evaluated, followed by histological examination of the liver, skeletal muscle and sciatic nerve with tissue ammonia and lipid content determination. Real-time polymerase chain reaction was used to measure the relative expression of several pathogenetic transcript markers. GA and PC showed moderate additive synergism in their anti-inflammatory, antioxidant, hypoammonaemic, hypoglycaemic, and pro-cognitive activities. Differential effects of the agents were seen in regard to anxiety- and depression-like behaviour as well as gene expression. Our results indicate partial pharmacological synergism between GA and PC and validate further research of its potential clinical applications. Full article

Diabetes mellitus is a chronic disease that, untreated or poorly controlled, can lead to serious complications, reducing life expectancy and quality. Diabetic patients are more likely to develop infections, including many common infections, but also pathognomonic ones such as emphysematous pyelonephritis, malignant otitis externa, mucormycosis and Fournier’s gangrene. Considering the fact that diabetic patients experience more frequently urinary tract infections (UTIs) with a worse prognosis than non-diabetic people, we conducted a review study based on data in the literature, following the particularities of UTIs in this group of patients, the risk factors, the mechanisms involved and the challenges in their management. The findings highlight that UTI in diabetic patients have some particularities, including a more frequent evolution to bacteremia, increased hospitalizations, and elevated rates of recurrence and mortality than non-diabetic patients. The possible risk factors identified seem to be female gender, pregnancy, older age, UTI in the previous six months, poor glycemic control and duration of diabetes. The mechanisms involved are related to glucosuria and bladder dysfunction, factors related to bacterial strains and host response. The bacterial strains involved in UTIs in diabetic patients and their antibiotic susceptibility profile are, with some exceptions, similar to those in non-diabetic people; however, the antimicrobial agents should be carefully chosen and the duration of the treatment should be as those required for a complicated UTI. The data related to the risk of developing UTIs in patients treated with SGLT-2 inhibitors, a new class of oral hypoglycaemic agents with cardiovascular and renal benefits, are controversial; overall, it was evidenced that UTIs occurred at the initiation of the treatment, recurrent infection was uncommon and the majority of UTIs responded to treatment with standard antibiotics. Moreover, interruption or discontinuation of SGLT-2 inhibitor as a result of UTI was rare and SGLT-2 inhibitors did not increase the risk of severe infections such as urosepsis and pyelonephritis. Full article

Background: Type 2 diabetes mellitus (T2DM) is an ongoing, risky, and costly health problem that therefore always requires new treatment options. Moreover, although several drugs are available, only 36% of patients achieve glycaemic control, and patient adherence is a major obstacle. With monotherapy, T2DM and its comorbidities/complications often cannot be managed, and the concurrent administration of several hypoglycaemic drugs is required, which increases the risk of side effects. In fact, despite the efficacy of the drugs currently on the market, they generally come with serious side effects. Therefore, scientific research must always be active in the discovery of new therapeutic agents. Discussion: The present review highlights some of the recent discoveries regarding marine natural products that can modulate the various targets that have been identified as crucial in the establishment of T2DM disease and its complications, with a focus on the compounds isolated from marine invertebrates. The activities of these metabolites are illustrated and discussed. Objectives. The paper aims to capture the relevant evidence of the great chemical diversity of marine natural products as a key tool that can advance understanding in the T2DM research field, as well as in antidiabetic drug discovery. The variety of chemical scaffolds highlighted by the natural hits provides not only a source of chemical probes for the study of specific targets involved in the onset of T2DM, but is also a helpful tool for the development of drugs that are capable of acting via novel mechanisms. Thus, it lays the foundation for the design of multiple ligands that can overcome the drawbacks of polypharmacology. Full article

Frailty in older people with diabetes is viewed as one homogeneous category. We previously suggested that frailty is not homogeneous and spans across a metabolic spectrum that starts with an anorexic malnourished (AM) frail phenotype and ends with a sarcopenic obese (SO) phenotype. We aimed to investigate the metabolic characteristics of frail older people with diabetes reported in the current literature to explore whether they fit into two distinctive metabolic phenotypes. We performed systematic review of studies published over the last 10 years and reported characteristics of frail older people with diabetes mellitus. A total of 25 studies were included in this systematic review. Fifteen studies reported frail patients’ characteristics that could fit into an AM phenotype. This phenotype is characterised by low body weight, increased prevalence of malnutrition markers such as low serum albumin, low serum cholesterol, low Hb, low HbA1c, and increased risk of hypoglycaemia. Ten studies reported frail patients’ characteristics that describe a SO phenotype. This phenotype is characterised by increased body weight, increased serum cholesterol, high HbA1c, and increased blood glucose levels. Due to significant weight loss in the AM phenotype, insulin resistance decreases, leading to a decelerated diabetes trajectory and reduced hypoglycaemic agent use or deintensification of therapy. On the other hand, in the SO phenotype, insulin resistance increases leading to accelerated diabetes trajectory and increased hypoglycaemic agent use or intensification of therapy. Current literature suggests that frailty is a metabolically heterogeneous condition that includes AM and SO phenotypes. Both phenotypes have metabolically distinctive features, which will have a different effect on diabetes trajectory. Therefore, clinical decision-making and future clinical studies should consider the metabolic heterogeneity of frailty. Full article

The global prevalence of comorbid diabetes and frailty is increasing due to increasing life expectancy. Frailty appears to be a metabolically heterogeneous condition that may affect the clinical decision making on the most appropriate glycaemic target and the choice of the most suitable hypoglycaemic agent for each individual. The metabolic profile of frailty appears to span across a spectrum that starts at an anorexic malnourished (AM) frail phenotype on one end and a sarcopenic obese (SO) phenotype on the other. The AM phenotype is characterised by significant weight loss and less insulin resistance compared with the SO phenotype, which is characterised by significant obesity and increased insulin resistance. Therefore, due to weight loss, insulin therapy may be considered as an early option in the AM frail phenotype. Insulin-related weight gain and the anabolic properties of insulin may be an advantage to this anorexic phenotype. There is emerging evidence to support the idea that insulin may improve the muscle function of older people with diabetes, although this evidence still needs further confirmation in future large-scale prospective studies. Long acting insulin analogues have a lower risk of hypoglycaemia, comapred to intermediate acting insulins. Additionally their simple once daily regimen makes it more appropriate in frail older patients. Future research on the availability of new once-weekly insulin analogues is appealing. The goals of therapy are to achieve relaxed targets, avoid hypoglycaemia and to focus on the maintenance of quality of life in these vulnerable patients. Full article

In this study, we aim to explore the beneficial therapeutic impacts of dapagliflozin (Dapa), a highly potent, reversible, and selective sodium–glucose cotransporter-2 inhibitor, and liraglutide (Lira), a glucagon-like peptide-1 (GLP-1) receptor agonist, as hypoglycaemic agents for the management of diabetes mellitus (DM), as well as their combination against DM-induced complications, including hepato-renal injury. Indeed, the progression of DM was found to be associated with significant hepatic and renal injury, as confirmed by the elevated biochemical indices of hepatic and renal functions, as well as histopathological examination. Dapa, Lira, and their combination effectively attenuated DM-induced hepatic and renal injury, as confirmed by the recovery of hepatic and renal functional biomarkers. The administration of both drugs significantly reduced the tissue contents of MDA and restored the contents of GSH and catalase activity. Moreover, NF-κB and TNF-α expression at the protein and gene levels was significantly reduced in the liver and the kidney. This was in parallel with the significant reduction in the caspase-3 content in the liver and the kidney, as well as suppressed cleaved caspase-3 expression in the hepatic and renal specimens, as confirmed by immune–histochemical analysis. Notably, the combined Dapa/Lira treatment demonstrated an additive superior hepato-renal protective impact compared with the use of either drug alone. Thus, it appears that Dapa and Lira, through the coordinated modulation of oxidative, inflammatory, and apoptotic signalling, confer a significant hepato-renal protective impact against DM-induced complications and tissue injury. Full article

The COVID-19 pandemic has led to a dramatic rise in the incidence of rhino-orbito-cerebral mucormycosis (ROCM) in India. The purpose of our report is to describe the prevalence of ROCM in the context of SARS-CoV-2 infection during the second Indian COVID-19 wave, as well as its diagnostics proceeding, and to discuss the challenges met in the time frame from the suspected diagnosis to the therapeutic decision in such patients. We conducted a retrospective multicentre case series study at six centres of Sudhalkar and Raghudeep group of hospitals in India. ROCM was confirmed in 38 (2.5%) of the 1546 patients admitted with SARS-CoV-2 infection. The average time to establish a diagnosis was 16 days. In total, 19 (50%) patients suffered from type 2 diabetes and were mostly treated with hypoglycaemic agents (in 90% of cases). The standard of care for SARS-CoV-2 management included systemic steroids therapy, intravenous remdesivir for 5 days, and concomitant prophylactic antibiotic therapy following admission. The median (IQR) blood glucose levels in all patients during the course of hospitalisation was 320 (250.5–375) mg/dl. A total of 16% of patients had an irreparable functional loss, and the mortality was 5%. We may hypothesise that excessive administration of antibiotics that profoundly affects human microbiota, coupled with poorly controlled glycaemia and unprotocolised haphazard steroid administration, contribute to a favourable setting for mucormycosis infections. Full article

Diabetes is a metabolic disease that affected 9.3% of adults worldwide in 2019. Its co-occurrence is suspected to increase mortality from COVID-19. The treatment of diabetes is mainly based on the long-term use of pharmacological agents, often expensive and causing unpleasant side effects. There is an alarming increase in the number of pharmaceuticals taken in Europe. The aim of this paper is to concisely collect information concerning the few antidiabetic or hypoglycaemic raw plant materials that are present in the consciousness of Europeans and relatively easily accessible to them on the market and sometimes even grown on European plantations. The following raw materials are discussed in this mini-review: Morus alba L., Cinnamomum zeylanicum J.Presl, Trigonella foenum-graecum L., Phaseolus vulgaris L., Zingiber officinale Rosc., and Panax ginseng C.A.Meyer in terms of scientifically tested antidiabetic activity and the presence of characteristic biologically active compounds and their specific properties, including antioxidant properties. The characteristics of these raw materials are based on in vitro as well as in vivo studies: on animals and in clinical studies. In addition, for each plant, the possibility to use certain morphological elements in the light of EFSA legislation is given. Full article

In France, around 5% of the general population are taking drug treatments for diabetes mellitus (mainly type 2 diabetes mellitus, T2DM). Although the management of T2DM has become more complex, most of these patients are managed by their general practitioner and not a diabetologist for their antidiabetics treatments; this increases the risk of potentially inappropriate prescriptions (PIPs) of hypoglycaemic agents (HAs). Inappropriate prescribing can be assessed by approaches that are implicit (expert judgement based) or explicit (criterion based). In a mixed, multistep process, we first systematically reviewed the published definitions of PIPs for HAs in patients with T2DM. The results will be used to create the first list of explicit definitions. Next, we will complete the definitions identified in the systematic review by conducting a qualitative study with two focus groups of experts in the prescription of HAs. Lastly, a Delphi survey will then be used to build consensus among participants; the results will be validated in consensus meetings. We developed a method for determining explicit definitions of PIPs for HAs in patients with T2DM. The resulting explicit definitions could be easily integrated into computerised decision support tools for the automated detection of PIPs. Full article

Mushrooms are considered a valuable food due to their unique taste, nutritional properties, and biological effects [¹]. They are a source of several classes of phytochemicals, including phenols, terpenoids, steroids, and polysaccharides that demonstrate a wide range of biological activities [²]. Obesity is a metabolic disorder, which results from the excessive accumulation of body fat, associated with several comorbidities, including cardiovascular diseases, hypertension, various types of cancer, and type 2 diabetes mellitus [³]. Several natural compounds possess the ability to reduce body weight and to prevent diet-induced obesity by inhibiting enzymes that interfere with the hydrolysis and absorption of dietary carbohydrates and lipids, such as alpha-amylase, alpha-glucosidase, and pancreatic lipase [⁴,⁵]. This study was constructed to investigate the hypoglycaemic and hypolipidemic activity of Leccinum duriusculum and Lanmaoa fragrans (=Boletus fragrans) from Calabria (southern Italy), two symbiotic edible mushrooms belonging to the Boletaceae family, growing the former in poplar tree forests and the latter in a mycorrhizal association with oaks. Both mushrooms were dried and exhaustively extracted by maceration with n-hexane, dichloromethane, and methanol. Extracts were investigated for their inhibitory activity against alpha-amylase, alpha-glucosidase, and lipase [6]. The best results against alpha-glucosidase and alpha-amylase were obtained with L. duriusculum methanol and dichloromethane extracts, respectively. The methanol extracts of both species exhibited the most promising results in inhibiting lipase (IC₅₀ of 35.02 and 22.40 μg/mL, for L. duriusculum and L. fragrans, respectively, vs. IC₅₀ of 37.63 μg/mL for the positive control orlistat). These data provided evidence that both species are able to inhibit key enzymes that interfere with the hydrolysis and absorption of dietary carbohydrates and lipids, suggesting their potential use for the development of new potential agents for the management of obesity and type 2 diabetes mellitus. However, further research is required to confirm these effects in vivo. Full article

Atherosclerosis is a multifactorial vascular disease that leads to inflammation and stiffening of the arteries and decreases their elasticity due to the accumulation of calcium, small dense Low Density Lipoproteins (sdLDL), inflammatory cells, and fibrotic material. A review of studies pertaining to cardiometabolic risk factors, lipids alterations, hypolipidemic agents, nutraceuticals, hypoglycaemic drugs, atherosclerosis, endothelial dysfunction, and inflammation was performed. There are several therapeutic strategies including Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) inhibitors, inclisiran, bempedoic acid, Glucagon-Like Peptide-1 Receptor agonists (GLP-1 RAs), and nutraceuticals that promise improvement in the atheromatous plaque from a molecular point of view, because have actions on the exposure of the LDL-Receptor (LDL-R), on endothelial dysfunction, activation of macrophages, on lipid oxidation, formations on foam cells, and deposition extracellular lipids. Atheroma plaque reduction both as a result of LDL-Cholesterol (LDL-C) intensive lowering and reducing inflammation and other residual risk factors is an integral part of the management of atherosclerotic disease, and the use of valid therapeutic alternatives appear to be appealing avenues to solving the problem. Full article

This study aimed to determine the effect of applying stimulatory agents to liquid cultured Inonotus obliquus on the simultaneous accumulation of exo-polysaccharides (EPS) and their monosaccharide composition. Different stimulatory agents (VB₆, VB₁, betulin and birch extract) were investigated for their effects on active exo-polysaccharides by submerged fermentation of I. obliquus. The mycelial biomass, reducing sugar content, EPS yield and α-glucosidase inhibition rate were determined, and the EPS obtained was analyzed for monosaccharide composition. The results showed that the addition of all the four stimulatory agents could significantly increase the inhibitory activity against α-glucosidase of EPS than the control, whereas EPS from 4 μg/mL VB₁-containing medium had the best effect with an estimated IC₅₀ value 24.34 μg/mL. Among the four stimulatory agents, VB₆ gave maximum production of mycelial biomass and EPS at the concentration of 4 μg/mL with a increase of 50.79% and 114.46%, respectively. In addition, betulin had a significant effect on increasing the EPS yield and activity, and birch extract had a significantly stimulatory effect on the mycelial growth and the polysaccharides activity, only slightly worse than VB₆ and VB₁. Moreover, the addition of different stimulatory agents changed the monosaccharide composition of polysaccharides, which had a correlation with polysaccharide activity. Full article