Evidence that tirzepatide protects against diabetes-related cardiac damages.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective antidiabetic drugs with potential cardiovascular benefits. Despite their well-established role in reducing the risk of major adverse cardiovascular events (MACE), their impact on heart failure (HF) remains unclear. Therefore, our study examined the cardioprotective effects of tirzepatide (TZT), a novel glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist. METHODS: A three-steps approach was designed: (i) Meta-analysis investigation with the primary objective of assessing major adverse cardiovascular events (MACE) occurrence from major randomized clinical trials.; (ii) TZT effects on a human cardiac AC16 cell line exposed to normal (5 mM) and high (33 mM) glucose concentrations for 7 days. The gene expression and protein levels of primary markers related to cardiac fibrosis, hypertrophy, and calcium modulation were evaluated. (iii) In silico data from bioinformatic analyses for generating an interaction map that delineates the potential mechanism of action of TZT. RESULTS: Meta-analysis showed a reduced risk for MACE events by TZT therapy (HR was 0.59 (95% CI 0.40-0.79, Heterogeneity: r2 = 0.01, I2 = 23.45%, H2 = 1.31). In the human AC16 cardiac cell line treatment with 100 nM TZT contrasted high glucose (HG) levels increase in the expression of markers associated with fibrosis, hypertrophy, and cell death (p < 0.05 for all investigated markers). Bioinformatics analysis confirmed the interaction between the analyzed markers and the associated pathways found in AC16 cells by which TZT affects apoptosis, fibrosis, and contractility, thus reducing the risk of heart failure. CONCLUSION: Our findings indicate that TZT has beneficial effects on cardiac cells by positively modulating cardiomyocyte death, fibrosis, and hypertrophy in the presence of high glucose concentrations. This suggests that TZT may reduce the risk of diabetes-related cardiac damage, highlighting its potential as a therapeutic option for heart failure management clinical trials. Our study strongly supports the rationale behind the clinical trials currently underway, the results of which will be further investigated to gain insights into the cardiovascular safety and efficacy of TZT.

Myocardial sodium-glucose cotransporter 2 expression and cardiac remodelling in patients with severe aortic stenosis: The BIO-AS study.

AIM: Cardiac remodelling plays a major role in the prognosis of patients with aortic stenosis (AS) and could impact the benefits of aortic valve replacement. Our study aimed to evaluate the expression of sodium-glucose cotransporter 2 (SGLT2) gene and protein in patients with severe AS stratified in high gradient (HG) and low flow-low gradient (LF-LG) AS and its association with cardiac functional impairments. METHODS AND RESULTS: Gene expression and protein levels of main biomarkers of cardiac fibrosis (galectin-3, sST2, serpin-4, procollagen type I amino-terminal peptide, procollagen type I carboxy-terminal propeptide, collagen, transforming growth factor [TGF]-ß), inflammation (growth differentiation factor-15, interleukin-6, nuclear factor-κB [NF-κB]), oxidative stress (superoxide dismutase 1 [SOD1] and 2 [SOD2]), and cardiac metabolism (sodium-hydrogen exchanger, peroxisome proliferator-activated receptor [PPAR]-α, PPAR-γ, glucose transporter 1 [GLUT1] and 4 [GLUT4]) were evaluated in blood samples and heart biopsies of 45 patients with AS. Our study showed SGLT2 gene and protein hyper-expression in patients with LF-LG AS, compared to controls and HG AS (p < 0.05). These differences remained significant even after adjusting for age, gender, body mass index, history of diabetes mellitus, arterial hypertension, and coronary artery disease. SGLT2 gene expression was positively correlated with: (i) TGF-ß (r = 0.72, p < 0.001) and collagen (r = 0.73, p < 0.001) as markers of fibrosis; (ii) NF-κB (r = 0.36, p < 0.01) and myocardial interleukin-6 (r = 0.68, p < 0.001) as markers of inflammation: (iii) SOD2 (r = -0.38, p < 0.006) as a marker of oxidative stress; (iv) GLUT4 (r = 0.33, p < 0.02) and PPAR-α (r = 0.36, p < 0.01) as markers of cardiac metabolism. CONCLUSION: In patients with LF-LG AS, SGLT2 gene and protein were hyper-expressed in cardiomyocytes and associated with myocardial fibrosis, inflammation, and oxidative stress.

Tirzepatide prevents neurodegeneration through multiple molecular pathways.

BACKGROUND: Several evidence demonstrated that glucagon-like peptide 1 receptor agonists (GLP1-RAs) reduce the risk of dementia in type 2 diabetes patients by improving memory, learning, and overcoming cognitive impairment. In this study, we elucidated the molecular processes underlying the protective effect of Tirzepatide (TIR), a dual glucose-dependent insulinotropic polypeptide receptor agonist (GIP-RA)/ GLP-1RA, against learning and memory disorders. METHODS: We investigated the effects of TIR on markers of neuronal growth (CREB and BDNF), apoptosis (BAX/Bcl2 ratio) differentiation (pAkt, MAP2, GAP43, and AGBL4), and insulin resistance (GLUT1, GLUT4, GLUT3 and SORBS1) in a neuroblastoma cell line (SHSY5Y) exposed to normal and high glucose concentration. The potential role on DNA methylation of genes involved in neuroprotection and epigenetic modulators of neuronal growth (miRNA 34a), apoptosis (miRNA 212), and differentiation (miRNA 29c) was also investigated. The cell proliferation was detected by measuring Ki-67 through flow cytometry. The data were analysed by SPSS IBM Version 23 or GraphPad Prism 7.0 software and expressed as the means ± SEM. Differences between the mean values were considered significant at a p-value of < 0.05. GraphPad Prism software was used for drawing figures. RESULTS: For the first time, it was highlighted: (a) the role of TIR in the activation of the pAkt/CREB/BDNF pathway and the downstream signaling cascade; (b) TIR efficacy in neuroprotection; (c) TIR counteracting of hyperglycemia and insulin resistance-related effects at the neuronal level. CONCLUSIONS: We demonstrated that TIR can ameliorate high glucose-induced neurodegeneration and overcome neuronal insulin resistance. Thus, this study provides new insight into the potential role of TIR in improving diabetes-related neuropathy.

Peptides from Marine-Derived Fungi: Chemistry and Biological Activities.

Marine natural products are well-recognized as potential resources to fill the pipeline of drug leads to enter the pharmaceutical industry. In this circumstance, marine-derived fungi are one of the unique sources of bioactive secondary metabolites due to their capacity to produce diverse polyketides and peptides with unique structures and diverse biological activities. The present review covers the peptides from marine-derived fungi reported from the literature published from January 1991 to June 2023, and various scientific databases, including Elsevier, ACS publications, Taylor and Francis, Wiley Online Library, MDPI, Springer, Thieme, Bentham, ProQuest, and the Marine Pharmacology website, are used for a literature search. This review focuses on chemical characteristics, sources, and biological and pharmacological activities of 366 marine fungal peptides belonging to various classes, such as linear, cyclic, and depsipeptides. Among 30 marine-derived fungal genera, isolated from marine macro-organisms such as marine algae, sponges, coral, and mangrove plants, as well as deep sea sediments, species of Aspergillus were found to produce the highest number of peptides (174 peptides), followed by Penicillium (23 peptides), Acremonium (22 peptides), Eurotium (18 peptides), Trichoderma (18 peptides), Simplicillium (17 peptides), and Beauveria (12 peptides). The cytotoxic activity against a broad spectrum of human cancer cell lines was the predominant biological activity of the reported marine peptides (32%), whereas antibacterial, antifungal, antiviral, anti-inflammatory, and various enzyme inhibition activities ranged from 7% to 20%. In the first part of this review, the chemistry of marine peptides is discussed and followed by their biological activity.

Targeting redox imbalance in neurodegeneration: characterizing the role of GLP-1 receptor agonists.

Reactive oxygen species (ROS) have emerged as essential signaling molecules regulating cell survival, death, inflammation, differentiation, growth, and immune response. Environmental factors, genetic factors, or many pathological condition such as diabetes increase the level of ROS generation by elevating the production of advanced glycation end products, reducing free radical scavengers, increasing mitochondrial oxidative stress, and by interfering with DAG-PKC-NADPH oxidase and xanthine oxidase pathways. Oxidative stress, and therefore the accumulation of intracellular ROS, determines the deregulation of several proteins and caspases, damages DNA and RNA, and interferes with normal neuronal function. Furthermore, ROS play an essential role in the polymerization, phosphorylation, and aggregation of tau and amyloid-beta, key mediators of cognitive function decline. At the neuronal level, ROS interfere with the DNA methylation pattern and various apoptotic factors related to cell death, promoting neurodegeneration. Only few drugs are able to quench ROS production in neurons. The cross-linking pathways between diabetes and dementia suggest that antidiabetic medications can potentially treat dementia. Among antidiabetic drugs, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been found to reduce ROS generation and ameliorate mitochondrial function, protein aggregation, neuroinflammation, synaptic plasticity, learning, and memory. The incretin hormone glucagon-like peptide-1 (GLP-1) is produced by the enteroendocrine L cells in the distal intestine after food ingestion. Upon interacting with its receptor (GLP-1R), it regulates blood glucose levels by inducing insulin secretion, inhibiting glucagon production, and slowing gastric emptying. No study has evidenced a specific GLP-1RA pathway that quenches ROS production. Here we summarize the effects of GLP-1RAs against ROS overproduction and discuss the putative efficacy of Exendin-4, Lixisenatide, and Liraglutide in treating dementia by decreasing ROS.

Targeting high glucose-induced epigenetic modifications at cardiac level: the role of SGLT2 and SGLT2 inhibitors.

BACKGROUND: Sodium-glucose co-transporters (SGLT) inhibitors (SGLT2i) showed many beneficial effects at the cardiovascular level. Several mechanisms of action have been identified. However, no data on their capability to act via epigenetic mechanisms were reported. Therefore, this study aimed to investigate the ability of SGLT2 inhibitors (SGLT2i) to induce protective effects at the cardiovascular level by acting on DNA methylation. METHODS: To better clarify this issue, the effects of empagliflozin (EMPA) on hyperglycemia-induced epigenetic modifications were evaluated in human ventricular cardiac myoblasts AC16 exposed to hyperglycemia for 7 days. Therefore, the effects of EMPA on DNA methylation of NF-κB, SOD2, and IL-6 genes in AC16 exposed to high glucose were analyzed by pyrosequencing-based methylation analysis. Modifications of gene expression and DNA methylation of NF-κB and SOD2 were confirmed in response to a transient SGLT2 gene silencing in the same cellular model. Moreover, chromatin immunoprecipitation followed by quantitative PCR was performed to evaluate the occupancy of TET2 across the investigated regions of NF-κB and SOD2 promoters. RESULTS: Seven days of high glucose treatment induced significant demethylation in the promoter regions of NF-kB and SOD2 with a consequent high level in mRNA expression of both genes. The observed DNA demethylation was mediated by increased TET2 expression and binding to the CpGs island in the promoter regions of analyzed genes. Indeed, EMPA prevented the HG-induced demethylation changes by reducing TET2 binding to the investigated promoter region and counteracted the altered gene expression. The transient SGLT2 gene silencing prevented the DNA demethylation observed in promoter regions, thus suggesting a role of SGLT2 as a potential target of the anti-inflammatory and antioxidant effect of EMPA in cardiomyocytes. CONCLUSIONS: In conclusion, our results demonstrated that EMPA, mainly acting on SGLT2, prevented DNA methylation changes induced by high glucose and provided evidence of a new mechanism by which SGLT2i can exert cardio-beneficial effects.

Anti-inflammatory role of SGLT2 inhibitors as part of their anti-atherosclerotic activity: Data from basic science and clinical trials.

Atherosclerosis is a progressive inflammatory disease leading to mortality and morbidity in the civilized world. Atherosclerosis manifests as an accumulation of plaques in the intimal layer of the arterial wall that, by its subsequent erosion or rupture, triggers cardiovascular diseases. Diabetes mellitus is a well-known risk factor for atherosclerosis. Indeed, Type 2 diabetes mellitus patients have an increased risk of atherosclerosis and its associated-cardiovascular complications than non-diabetic patients. Sodium-glucose co-transport 2 inhibitors (SGLT2i), a novel anti-diabetic drugs, have a surprising advantage in cardiovascular effects, such as reducing cardiovascular death in a patient with or without diabetes. Numerous studies have shown that atherosclerosis is due to a significant inflammatory burden and that SGLT2i may play a role in inflammation. In fact, several experiment results have demonstrated that SGLT2i, with suppression of inflammatory mechanism, slows the progression of atherosclerosis. Therefore, SGLT2i may have a double benefit in terms of glycemic control and control of the atherosclerotic process at a myocardial and vascular level. This review elaborates on the anti-inflammatory effects of sodium-glucose co-transporter 2 inhibitors on atherosclerosis.

Curcumin-Based Nanoformulations: A Promising Adjuvant towards Cancer Treatment.

Throughout the United States, cancer remains the second leading cause of death. Traditional treatments induce significant medical toxic effects and unpleasant adverse reactions, making them inappropriate for long-term use. Consequently, anticancer-drug resistance and relapse are frequent in certain situations. Thus, there is an urgent necessity to find effective antitumor medications that are specific and have few adverse consequences. Curcumin is a polyphenol derivative found in the turmeric plant (Curcuma longa L.), and provides chemopreventive, antitumor, chemo-, and radio-sensitizing properties. In this paper, we summarize the new nano-based formulations of polyphenolic curcumin because of the growing interest in its application against cancers and tumors. According to recent studies, the use of nanoparticles can overcome the hydrophobic nature of curcumin, as well as improving its stability and cellular bioavailability in vitro and in vivo. Several strategies for nanocurcumin production have been developed, each with its own set of advantages and unique features. Because the majority of the curcumin-based nanoformulation evidence is still in the conceptual stage, there are still numerous issues impeding the provision of nanocurcumin as a possible therapeutic option. To support the science, further work is necessary to develop curcumin as a viable anti-cancer adjuvant. In this review, we cover the various curcumin nanoformulations and nanocurcumin implications for therapeutic uses for cancer, as well as the current state of clinical studies and patents. We further address the knowledge gaps and future research orientations required to develop curcumin as a feasible treatment candidate.

Anthraquinones and Their Analogues from Marine-Derived Fungi: Chemistry and Biological Activities.

Anthraquinones are an interesting chemical class of polyketides since they not only exhibit a myriad of biological activities but also contribute to managing ecological roles. In this review article, we provide a current knowledge on the anthraquinoids reported from marine-derived fungi, isolated from various resources in both shallow waters such as mangrove plants and sediments of the mangrove habitat, coral reef, algae, sponges, and deep sea. This review also tentatively categorizes anthraquinone metabolites from the simplest to the most complicated scaffolds such as conjugated xanthone-anthraquinone derivatives and bianthraquinones, which have been isolated from marine-derived fungi, especially from the genera Apergillus, Penicillium, Eurotium, Altenaria, Fusarium, Stemphylium, Trichoderma, Acremonium, and other fungal strains. The present review, covering a range from 2000 to 2021, was elaborated through a comprehensive literature search using the following databases: ACS publications, Elsevier, Taylor and Francis, Wiley Online Library, MDPI, Springer, and Thieme. Thereupon, we have summarized and categorized 296 anthraquinones and their derivatives, some of which showed a variety of biological properties such as enzyme inhibition, antibacterial, antifungal, antiviral, antitubercular (against Mycobacterium tuberculosis), cytotoxic, anti-inflammatory, antifouling, and antioxidant activities. In addition, proposed biogenetic pathways of some anthraquinone derivatives are also discussed.

Uncommon Terpenoids from Salvia Species: Chemistry, Biosynthesis and Biological Activities.

The search for new bioactive compounds from plant sources has been and continues to be one of the most important fields of research in drug discovery. However, Natural Products research has continuously evolved, and more and more has gained a multidisciplinary character. Despite new developments of methodologies and concepts, one intriguing aspect still persists, i.e., different species belonging to the same genus can produce different secondary metabolites, whereas taxonomically different genera can produce the same compounds. The genus Salvia L. (Family Lamiaceae) comprises myriad distinct medicinal herbs used in traditional medicine worldwide that show different pharmacological activities due to the presence of a variety of interesting specialized metabolites, including mono-, sesqui-, di-, sester-, tri-, tetra-, and higher terpenoids as well as phenylpropanoids, phenolic acid derivatives, lignans, flavonoids, and alkaloids. We herein summarize the research progress on some uncommon terpenoids, isolated from members of the genus Salvia, which are well recognized for their potential pharmacological activities. This review also provides a current knowledge on the biosynthesis and occurrence of some interesting phytochemicals from Salvia species, viz. C23-terpenoids, sesterterpenoids (C25), dammarane triterpenoids (C30), and uncommon triterpenoids (C20+C10). The study was carried out by searching various scientific databases, including Elsevier, ACS publications, Taylor and Francis, Wiley Online Library, MDPI, Springer, Thieme, and ProQuest. Therefore, 106 uncommon terpenoids were identified and summarized. Some of these compounds possessed a variety of pharmacological properties, such as antibacterial, antiviral, antiparasitic, cytotoxic and tubulin tyrosine ligase inhibitory activities. Due to the lack of pharmacological information for the presented compounds gathered from previous studies, biological investigation of these compounds should be reinvestigated.

Inhibitory effects of selected antibiotics on the activities of α-amylase and α-glucosidase: In-vitro, in-vivo and theoretical studies.

Antibiotics are effective drugs that are used to treat infectious diseases either by killing bacteria or slowing down their growth. The well-adapted structural features of antibiotics for the inhibition/activation of enzymes include several available hydrogen bond (H-bond) acceptors and donors, flexible backbone and hydrophobic nature. The substrates of α-amylase and α-glucosidase, known as key absorbing enzymes, have functional groups (OH groups) rembling antibiotics. Given the possibility of developing in diabetics and the significant association between diabetes and infection, the present study was conducted to investigate the influences of tetracycline (TET), kanamycin (KANA), lincomycin (LIN), erythromycin (ERM) and azithromycin (AZM) on α-glucosidase and α-amylase activities with calculating IC50 and Ki values. Also, the efficacy of antibiotics after oral administration was evaluated by analysis of blood glucose concentrations in rats, as well as a molecular docking analysis was explored. α-glucosidase and α-amylase activities were inhibited in a dose dependent fashion by TET with an IC50 of 38.7 ±â€¯1.4 and 47.8 ±â€¯3.2 µM respectively, by KANA with an IC50 of 46.2 ±â€¯1.6 and 65.1 ±â€¯1.6, by LIN with an IC50 of 59.1 ±â€¯2.1 and 51.3 ±â€¯4.1, by ERM with an IC50 of 94.9 ±â€¯4.7 and 65.7 ±â€¯3.8 and by AZM with an IC50 of 69.4 ±â€¯4.4 and 103.6 ±â€¯6.2. Moreover, the Ki values of TET were calculated as 4.4 ±â€¯0.6 and 8.4 ±â€¯0.8 µM for α-glucosidase and α-amylase in a competitive-mode and mixed-mode inhibition. In addition, to communicate with the active site of α-glucosidase and α-amylase respectively, TET presented a binding energy of -9.8 and -8.8 kcal/mol, KANA -7.9 and -7.1, LIN -7.8 and -6.7, ERM -6.8 and -6.4, and AZM -6.4 and -7.5 kcal/mol. In-vivo studies also suggested a decrease in the blood glucose concentration after administering TET compared to the positive controls (P < 0.01). The results obtained from the present research can therefore help the scientific community explore the possible interconnection between the clinical side-effects of antibiotics and their α-glucosidase and α-amylase inhibitory properties, as the target enzymes in hypoglycemia conditions.