The Renoprotective Mechanisms of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2i)-A Narrative Review.

Chronic kidney disease (CKD) is a noncommunicable condition that has become a major healthcare burden across the globe, often underdiagnosed and associated with low awareness. The main cause that leads to the development of renal impairment is diabetes mellitus and, in contrast to other chronic complications such as retinopathy or neuropathy, it has been suggested that intensive glycemic control is not sufficient in preventing the development of diabetic kidney disease. Nevertheless, a novel class of antidiabetic agents, the sodium-glucose cotransporter-2 inhibitors (SGLT2i), have shown multiple renoprotective properties that range from metabolic and hemodynamic to direct renal effects, with a major impact on reducing the risk of occurrence and progression of CKD. Thus, this review aims to summarize current knowledge regarding the renoprotective mechanisms of SGLT2i and to offer a new perspective on this innovative class of antihyperglycemic drugs with proven pleiotropic beneficial effects that, after decades of no significant progress in the prevention and in delaying the decline of renal function, start a new era in the management of patients with CKD.

Dose-dependent effects of acetaminophen and ibuprofen on mitochondrial respiration of human platelets.

Acetaminophen and ibuprofen are widely used over-the-counter medications to reduce fever, pain, and inflammation. Although both drugs are safe in therapeutic concentrations, self-medication is practiced by millions of aged patients with comorbidities that decrease drug metabolism and/or excretion, thus raising the risk of overdosage. Mitochondrial dysfunction has emerged as an important pathomechanism underlying the organ toxicity of both drugs. Assessment of mitochondrial oxygen consumption in peripheral blood cells is a novel research field Cu several applications, including characterization of drug toxicity. The present study, conducted in human platelets isolated from blood donor-derived buffy coat, was aimed at assessing the acute, concentration-dependent effects of each drug on mitochondrial respiration. Using the high-resolution respirometry technique, a concentration-dependent decrease of oxygen consumption in both intact and permeabilized platelets was found for either drug, mainly by inhibiting complex I-supported active respiration. Moreover, ibuprofen significantly decreased the maximal capacity of the electron transport system already from the lowest concentration. In conclusion, platelets from healthy donors represents a population of cells easily available, which can be routinely used in studies assessing mitochondrial drug toxicity. Whether these results can be recapitulated in patients treated with these medications is worth further investigation as potential peripheral biomarker of drug overdose.

Impairment of Mitochondrial Respiration in Metabolic Diseases: An Overview.

Mitochondrial dysfunction has emerged as a central pathomechanism in the setting of obesity and diabetes mellitus, linking these intertwined pathologies that share insulin resistance as a common denominator. High-resolution respirometry (HRR) is a state-of-the-art research method currently used to study mitochondrial respiration and its impairment in health and disease. Tissue samples, cells or isolated mitochondria are exposed to various substrate-uncoupler-inhibitor-titration protocols, which allows the measurement and calculation of several parameters of mitochondrial respiration. In this review, we discuss the alterations of mitochondrial bioenergetics in the main dysfunctional organs that contribute to the development of the obese and diabetic phenotypes in both animal models and human subjects. Herein we review data regarding the impairment of oxidative phosphorylation as integrated mitochondrial function assessed by means of HRR. We acknowledge the critical role of this method in determining the alterations in oxidative phosphorylation occurring in the early stages of metabolic pathologies. We conclude that there is a mutual two-way relationship between mitochondrial dysfunction and insulin insensitivity that characterizes these diseases.

Diabetes Mellitus and Other Predictors for the Successful Treatment of Metastatic Colorectal Cancer: A Retrospective Study.

Background and Objectives: In the last decades there has been an increasing body of research identifying the positive correlation between diabetes mellitus (DM) and solid malignancies, moreover, having shown DM as an independent risk factor for colorectal cancer (CRC). The aim of the present study was to assess the impact of DM on metastatic CRC (mCRC), and to identify possible predictive factors in the successful treatment of mCRC. Materials and Methods: 468 patients with mCRC were included in this retrospective, observational study. A total of 8669 oncological treatment cycles related to 988 distinct chemotherapy lines were analyzed. Data regarding lines of treatment and blood panel values were obtained from the Oncohelp Hospital database. Results: The presence of DM in male patients >70 years was a negative predictor (RR = 1.66 and a p = 0.05). DM seemed to have a detrimental effect in patients whose treatment included bevacizumab (median time to treatment failure -TTF- 94 days for DM+ cases compared to 114 days for DM-patients, p = 0.07). Analysis of treatments including bevacizumab based on DM status revealed lower values of mean TTF in DM+ female patients versus DM-(81.08 days versus 193.09 days, p < 0.001). It was also observed that DM+ patients had a higher mean TTF when undergoing anti-EGFR (epidermal growth factor) therapy (median TTF 143 days for DM+ patients versus 97.5 days for those without DM, p = 0.06). Conclusions: The favorable predictive factors identified were the inclusion of antiangiogenic agents, a higher hemoglobin value, a higher lymphocyte count, the inclusion of anti-EGFR treatment for DM+ patients, a higher creatinine, and a higher lymphocyte count in treatment lines that included anti-EGFR treatment. Unfavorable predictive factors were represented by the presence of DM in female patients undergoing antiangiogenic treatment, neutropenia in male patients, the association of oxaliplatin and antiangiogenic agents, and a higher monocyte count in the aforementioned treatment lines.

The Role of Nut and Seed Consumption in Colorectal Cancer: A Narrative Review.

Given the increased incidence of colorectal cancer worldwide, especially in developed and developing countries, is comes as no surprise that researchers are concentrating on methods to combat this public health issue, through investigating both lifestyle interventions and treatment options. Although treatment options are being constantly discovered and developed, researchers have also begun investigating the influence that nutrition and lifestyle have on CRC. Among the food categories, nuts and seeds boast numerous beneficial effects for cardiovascular health and metabolic balance and they contain a plethora of phytochemicals and antioxidants. The present narrative review aims to offer a broad perspective to date on the known effects of this consumption on colorectal cancer. For this purpose, articles were identified by conducting a search in the PubMed and Google Scholar databases, using search phrases such as ″nut intake and colorectal cancer″ and ″seed consumption and colorectal cancer", narrowing the search pool to those articles published between 2019 and 2022. The search returned eight relevant papers, all of which were validated by a second author. While the existing research is divided between those studies which have found no significant link between nut consumption and colorectal cancer protection and those which have, there is a consensus regarding the necessity for further research on this subject, as well as the possible mechanisms which might be involved in the protective effect observed by some researchers.

Impairment of mitochondrial respiration in platelets and placentas: a pilot study in preeclamptic pregnancies.

Preeclampsia (PE) is a major complication of pregnancy with partially elucidated pathophysiology. Placental mitochondrial dysfunction has been increasingly studied as major pathomechanism in both early- and late-onset PE. Impairment of mitochondrial respiration in platelets has recently emerged as a peripheral biomarker that may mirror organ mitochondrial dysfunction in several acute and chronic pathologies. The present study was purported to assess mitochondrial respiratory dys/function in both platelets and placental mitochondria in PE pregnancies. To this aim, a high-resolution respirometry SUIT (Substrate-Uncoupler-Inhibitor-Titration) protocol was adapted to assess complex I (glutamate + malate)- and complex II (succinate)-supported respiration. A decrease in all respiratory parameters (basal, coupled, and maximal uncoupled respiration) in peripheral platelets was found in preeclamptic as compared to healthy pregnancies. At variance, placental mitochondria showed a dichotomous behavior in preeclampsia in relation to the fetal birth weight. PE pregnancies with fetal growth restriction were associated with decreased in coupled respiration (oxidative phosphorylation/OXPHOS capacity) and maximal uncoupled respiration (electron transfer/ET capacity). At variance, these respiratory parameters were increased for both complex I- and II-supported respiration in PE pregnancies with normal weight fetuses. Large randomized controlled clinical studies are needed in order to advance our understanding of mitochondrial adaptive vs. pathological changes in preeclampsia.

Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Amiodarone Toxicity.

Amiodarone is a potent antiarrhythmic drug and displays substantial liver toxicity in humans. It has previously been demonstrated that amiodarone and its metabolite (desethylamiodarone, DEA) can inhibit mitochondrial function, particularly complexes I (CI) and II (CII) of the electron transport system in various animal tissues and cell types. The present study, performed in human peripheral blood cells, and one liver-derived human cell line, is primarily aimed at assessing the concentration-dependent effects of these drugs on mitochondrial function (respiration and cellular ATP levels). Furthermore, we explore the efficacy of a novel cell-permeable succinate prodrug in alleviating the drug-induced acute mitochondrial dysfunction. Amiodarone and DEA elicit a concentration-dependent impairment of mitochondrial respiration in both intact and permeabilized platelets via the inhibition of both CI- and CII-supported respiration. The inhibitory effect seen in human platelets is also confirmed in mononuclear cells (PBMCs) and HepG2 cells. Additionally, amiodarone elicits a severe concentration-dependent ATP depletion in PBMCs, which cannot be explained solely by mitochondrial inhibition. The succinate prodrug NV118 alleviates the respiratory deficit in platelets and HepG2 cells acutely exposed to amiodarone. In conclusion, amiodarone severely inhibits metabolism in primary human mitochondria, which can be counteracted by increasing mitochondrial function using intracellular delivery of succinate.

The Mental Status in Patients with Diabetes Mellitus Admitted to a Diabetes Clinic After Presenting in the Emergency Room: The Application of the SCL-90 Scale.

BACKGROUND: Diabetes mellitus (DM) is one of the most serious public health problems, involving increasing costs worldwide. The mental state of a person with DM is varied and ever-changing, such as stress, the pressure to always do everything by the book, sadness, anger, and even denial of the disease, all these are feelings patients with DM will experience throughout their life. AIM: The aim of our study was to assess the presence of mental and psychiatric disorders (anxiety, depressive states, paranoid ideation, phobia, obsessive-compulsive disorder) in a group of patients with DM after hospitalization in the Clinic for Diabetes, Nutrition, and Metabolic Diseases, for various exacerbations of the underlying condition, looking for possible correlations with other cardiovascular risk factors. PATIENTS AND METHODS: Clinical and biological parameters, the presence of acute and chronic complications of the diabetic patients have been evaluated. To assess mental health, the symptom checklist (SCL)-90 questionnaire was conducted for all admitted patients. RESULTS: We observed that the number of patients with obsessive-compulsive disorders was relatively high (23.3%), while depression was present in 17.1% of the patients. Also, 10.6% of patients had hostility and 15.6% had delusional ideation. The presence of psychiatric disorders was associated with a higher age (62 vs. 46.5 years; p <0.001), a longer diabetes duration (11 vs. 9 years; p <0.001), higher fasting glycemia (188 vs. 132 mg/dL; p <0.001) and postprandial glycemia (212 vs. 152 mg/dL; p <0.001), and triglycerides (125 vs. 110 mg/dL; p <0.001). Patients with altered mental status have shown statistically significantly more altered clinical and biological parameters compared to those without these mental disorders. CONCLUSION: Patients with DM represent a psychologically vulnerable population, which is why they should undergo early and regular screening for both psychological and psychiatric conditions, especially at admission.

Improvement of Platelet Respiration by Cell-Permeable Succinate in Diabetic Patients Treated with Statins.

Diabetes mellitus (DM) is the most severe metabolic disease that reached the level of a global pandemic and is associated with high cardiovascular morbidity. Statins are the first-line lipid-lowering therapy in diabetic patients with or without a history of atherosclerotic disease. Although well tolerated, chronic treatment may result in side effects that lead to treatment interruption. Mitochondrial dysfunction has emerged as a central pathomechanism in DM- and statin-induced side effects. Assessment of mitochondrial respiration in peripheral platelets has been increasingly used as a mirror of organ mitochondrial dysfunction. The present study aimed to assess the: (i) changes in mitochondrial respiration elicited by statins in patients with type 2 DM and (ii) the effects of cell-permeable succinate (NV118) on respiratory parameters in platelets harvested from these patients. No significant changes were found in global mitochondrial respiration of intact platelets isolated from diabetic patients treated with either atorvastatin or rosuvastatin. Similarly, no significant changes in mitochondrial respiration of permeabilized platelets were found between diabetic patients treated with atorvastatin and healthy controls. Acute ex vivo administration of NV118 significantly improved respiration in isolated platelets. These results prompt further research on the role of permeable succinate as a therapeutic alternative for improving mitochondrial function in metabolic pathologies and point to the role of peripheral platelets as a potential biomarker of treatment response.

Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Statin Toxicity.

Statins are the cornerstone of lipid-lowering therapy. Although generally well tolerated, statin-associated muscle symptoms (SAMS) represent the main reason for treatment discontinuation. Mitochondrial dysfunction of complex I has been implicated in the pathophysiology of SAMS. The present study proposed to assess the concentration-dependent ex vivo effects of three statins on mitochondrial respiration in viable human platelets and to investigate whether a cell-permeable prodrug of succinate (complex II substrate) can compensate for statin-induced mitochondrial dysfunction. Mitochondrial respiration was assessed by high-resolution respirometry in human platelets, acutely exposed to statins in the presence/absence of the prodrug NV118. Statins concentration-dependently inhibited mitochondrial respiration in both intact and permeabilized cells. Further, statins caused an increase in non-ATP generating oxygen consumption (uncoupling), severely limiting the OXPHOS coupling efficiency, a measure of the ATP generating capacity. Cerivastatin (commercially withdrawn due to muscle toxicity) displayed a similar inhibitory capacity compared with the widely prescribed and tolerable atorvastatin, but did not elicit direct complex I inhibition. NV118 increased succinate-supported mitochondrial oxygen consumption in atorvastatin/cerivastatin-exposed platelets leading to normalization of coupled (ATP generating) respiration. The results acquired in isolated human platelets were validated in a limited set of experiments using atorvastatin in HepG2 cells, reinforcing the generalizability of the findings.