The analysis of the skeletal muscle metabolism is crucial for designing optimal exercise paradigms in type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease that commonly results from a high-calorie diet and sedentary lifestyle, leading to insulin resistance and glucose homeostasis perturbation. Physical activity is recommended as one first-line treatment in T2DM, but it leads to contrasted results. We hypothesized that, instead of applying standard exercise protocols, the prescription of personalized exercise programs specifically designed to reverse the potential metabolic alterations in skeletal muscle could result in better results. METHODS: To test this hypothesis, we drew the metabolic signature of the fast-twitch quadriceps muscle, based on a combined unbiased NMR spectroscopy and RT-qPCR study, in several T2DM mouse models of different genetic background (129S1/SvImJ, C57Bl/6J), sex and aetiology (high-fat diet (HFD) or HFD/Streptozotocin (STZ) induction or transgenic MKR (FVB-Tg Ckm-IGF1R*K1003R)1Dlr/J) mice. Three selected mouse models with unique muscular metabolic signatures were submitted to three different swimming-based programs, designed to address each metabolic specificity. RESULTS: We found that depending on the genetic background, the sex, and the mode of T2DM induction, specific muscular adaptations occurred, including depressed glycolysis associated with elevated PDK4 expression, shift to ß-oxidation, or deregulation of amino-acid homeostasis. Interestingly, dedicated swimming-based exercises designed to restore specific metabolic alterations in muscle were found optimal in improving systemic T2DM hallmarks, including a significant reduction in insulin resistance, the improvement of glucose homeostasis, and a delay in sensorimotor function alterations. CONCLUSION: The muscle metabolism constitutes an important clue for the design of precision exercises with potential clinical implications for T2DM patients.

C-peptide in diabetes: A player in a dual hormone disorder?

C-peptide, a byproduct of insulin synthesis believed to be biologically inert, is emerging as a multifunctional molecule. C-peptide serves an anti-inflammatory and anti-atherogenic role in type 1 diabetes mellitus (T1DM) and early T2DM. C-peptide protects endothelial cells by activating AMP-activated protein kinase α, thus suppressing the activity of NAD(P)H oxidase activity and reducing reactive oxygen species (ROS) generation. It also prevents apoptosis by regulating hyperglycemia-induced p53 upregulation and mitochondrial adaptor p66shc overactivation, as well as reducing caspase-3 activity and promoting expression of B-cell lymphoma-2. Additionally, C-peptide suppresses platelet-derived growth factor (PDGF)-beta receptor and p44/p42 mitogen-activated protein (MAP) kinase phosphorylation to inhibit vascular smooth muscle cells (VSMC) proliferation. It also diminishes leukocyte adhesion by virtue of its capacity to abolish nuclear factor kappa B (NF-kB) signaling, a major pro-inflammatory cascade. Consequently, it is envisaged that supplementation of C-peptide in T1DM might ameliorate or even prevent end-organ damage. In marked contrast, C-peptide increases monocyte recruitment and migration through phosphoinositide 3-kinase (PI-3 kinase)-mediated pathways, induces lipid accumulation via peroxisome proliferator-activated receptor γ upregulation, and stimulates VSMC proliferation and CD4+ lymphocyte migration through Src-kinase and PI-3K dependent pathways. Thus, it promotes atherosclerosis and microvascular damage in late T2DM. Indeed, C-peptide is now contemplated as a potential biomarker for insulin resistance in T2DM and linked to increased coronary artery disease risk. This shift in the understanding of the pathophysiology of diabetes from being a single hormone deficiency to a dual hormone disorder warrants a careful consideration of the role of C-peptide as a unique molecule with promising diagnostic, prognostic, and therapeutic applications.

Macrophage polarization and signaling in diabetic kidney disease: a catalyst for disease progression.

Diabetic kidney disease (DKD) is a serious complication of diabetes affecting millions of people worldwide. Macrophages, a critical immune cell type, are central players in the development and progression of DKD. In this comprehensive review, we delve into the intricate role of macrophages in DKD, examining how they can become polarized into proinflammatory M1 or anti-inflammatory M2 phenotypes. We explore the signaling pathways involved in macrophage recruitment and polarization in the kidneys, including the key cytokines and transcription factors that promote M1 and M2 polarization. In addition, we discuss the latest clinical studies investigating macrophages in DKD and explore the potential of hypoglycemic drugs for modulating macrophage polarization. By gaining a deeper understanding of the mechanisms that regulate macrophage polarization in DKD, we may identify novel therapeutic targets for this debilitating complication of diabetes. This review provides valuable insights into the complex interplay between macrophages and DKD, shedding light on the latest developments in this important area of research. This review aims to enhance understanding of the role that macrophages play in the pathogenesis of DKD.

Obstructive sleep apnea: Beyond the dogma of obesity!

Obstructive sleep apnea (OSA) has long been studied in patients with obesity and type 2 diabetes mellitus (T2DM), due to the fact that both disorders are commonly associated with an increased body mass index (BMI). However, a link between OSA and non-obese diabetic patients is still not very elaborated, nor heavily explored. In this review, we elucidate some proposed mechanisms for the link between OSA and diabetic patients both with and beyond obesity, shedding the light on the latter case. One such mechanism is oxidative stress, a phenomenon of reactive oxygen species (ROS) imbalance seen in both of the previously mentioned disorders. A plausible explanation for the OSA-induced ROS production is the repeating episodes of hypoxia and reperfusion and their effect on the mitochondrial electron transport chain. This paper explores the literature regarding ROS imbalance as the possible missing link between OSA and Diabetes Mellitus beyond obesity, while still mentioning other possible proposed mechanisms such as a dysregulated autonomic nervous system (ANS), as well as mechanical and craniofacial abnormalities. This paper also suggests a link between OSA and diabetic complications, while exploring the clinical progress made in treating the former disorder with anti-oxidant and hypo-glycemic drugs. If further investigated, these findings could help identify novel therapeutic interventions for the treatment of OSA and Diabetic patients.

Infection with Helicobacter pylori may predispose to atherosclerosis: role of inflammation and thickening of intima-media of carotid arteries.

Atherosclerosis is a major instigator of cardiovascular disease (CVD) and a main cause of global morbidity and mortality. The high prevalence of CVD calls for urgent attention to possible preventive measures in order to curb its incidence. Traditional risk factors of atherosclerosis, like age, smoking, diabetes mellitus, dyslipidemia, hypertension and chronic inflammation, are under extensive investigation. However, these only account for around 50% of the etiology of atherosclerosis, mandating a search for different or overlooked risk factors. In this regard, chronic infections, by Helicobacter pylori for instance, are a primary candidate. H. pylori colonizes the gut and contributes to several gastrointestinal diseases, but, recently, the potential involvement of this bacterium in extra-gastric diseases including CVD has been under the spotlight. Indeed, H. pylori infection appears to stimulate foam cell formation as well as chronic immune responses that could upregulate key inflammatory mediators including cytokines, C-reactive protein, and lipoproteins. These factors are involved in the thickening of intima-media of carotid arteries (CIMT), a hallmark of atherosclerosis. Interestingly, H. pylori infection was found to increase (CIMT), which along with other evidence, could implicate H. pylori in the pathogenesis of atherosclerosis. Nevertheless, the involvement of H. pylori in CVD and atherosclerosis remains controversial as several studies report no connection between H. pylori and atherosclerosis. This review examines and critically discusses the evidence that argues for a potential role of this bacterium in atherogenesis. However, additional basic and clinical research studies are warranted to convincingly establish the association between H. pylori and atherosclerosis.

NADPH oxidase 4 inhibition is a complementary therapeutic strategy for spinal muscular atrophy.

Introduction: Spinal muscular atrophy (SMA) is a fatal neurodegenerative disorder, characterized by motor neuron (MN) degeneration and severe muscular atrophy and caused by Survival of Motor Neuron (SMN) depletion. Therapies aimed at increasing SMN in patients have proven their efficiency in alleviating SMA symptoms but not for all patients. Thus, combinational therapies are warranted. Here, we investigated the involvement of NADPH oxidase 4 (NOX4) in SMA-induced spinal MN death and if the modulation of Nox4 activity could be beneficial for SMA patients. Methods: We analysed in the spinal cord of severe type SMA-like mice before and at the disease onset, the level of oxidative stress and Nox4 expression. Then, we tested the effect of Nox4 inhibition by GKT137831/Setanaxib, a drug presently in clinical development, by intrathecal injection on MN survival and motor behaviour. Finally, we tested if GKT137831/Setanaxib could act synergistically with FDA-validated SMN-upregulating treatment (nusinersen). Results: We show that NOX4 is overexpressed in SMA and its inhibition by GKT137831/Setanaxib protected spinal MN from SMA-induced degeneration. These improvements were associated with a significant increase in lifespan and motor behaviour of the mice. At the molecular level, GKT137831 activated the pro-survival AKT/CREB signaling pathway, leading to an increase in SMN expression in SMA MNs. Most importantly, we found that the per os administration of GKT137831 acted synergistically with a FDA-validated SMN-upregulating treatment. Conclusion: The pharmacological inhibition of NOX4 by GKT137831/Setanaxib is neuroprotector and could represent a complementary therapeutic strategy to fight against SMA.

A Portable Non-Invasive Electromagnetic Lesion-Optimized Sensing Device for the Diagnosis of Skin Cancer (SkanMD).

The article presented herein proposes an alternative skin cancer screening method that delivers non-invasive diagnosis and monitoring of skin lesions by leveraging electromagnetic waves with radio frequency technology and circuits. The proposed handheld device, named SkanMD, comprises a sensitive electromagnetic sensor, customized radio frequency wave analyzer circuits, and machine learning algorithms. The device is used in clinical studies that are performed on a total of 46 individuals that are composed of 18 patients with pre-diagnosed skin cancer, 10 individuals with benign nevi, 7 patients with arbitrary diseases, and 11 healthy individuals. These studies included the measurement of the reflection coefficient, S11, on multiple skin regions and recording the obtained complex values to build a Support Vector Machine (SVM)-based classification model. Due to the lesion-optimized sensor and the unified cross-patient classifier, our results differentiate between cancerous and non-cancerous skin lesions with a sensitivity that exceeds 92% and a specificity that exceeds 81.4%. These reported results are based on a limited population size study. They also demonstrate that SkanMD is a promising solution that could augment conventional diagnosis methods to greatly improve patient comfort and enable instantaneous and accurate diagnosis.

SGLT2 Inhibitor-Dapagliflozin Attenuates Diabetes-Induced Renal Injury by Regulating Inflammation through a CYP4A/20-HETE Signaling Mechanism.

Diabetic kidney disease (DKD) is a serious complication of diabetes, affecting millions of people worldwide. Inflammation and oxidative stress are key contributors to the development and progression of DKD, making them potential targets for therapeutic interventions. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a promising class of drugs, with evidence demonstrating that they can improve renal outcomes in people with diabetes. However, the exact mechanism by which SGLT2i exert their renoprotective effects is not yet fully understood. This study demonstrates that dapagliflozin treatment attenuates renal injury observed in type 2 diabetic mice. This is evidenced by the reduction in renal hypertrophy and proteinuria. Furthermore, dapagliflozin decreases tubulointerstitial fibrosis and glomerulosclerosis by mitigating the generation of reactive oxygen species and inflammation, which are activated through the production of CYP4A-induced 20-HETE. Our findings provide insights onto a novel mechanistic pathway by which SGLT2i exerts their renoprotective effects. Overall, and to our knowledge, the study provides critical insights into the pathophysiology of DKD and represents an important step towards improving outcomes for people with this devastating condition.

Urinary 20-HETE: A prospective Non-Invasive prognostic and diagnostic marker for diabetic kidney disease.

INTRODUCTION: The identification and validation of a non-invasive prognostic marker for early detection of diabetic kidney disease (DKD) can lead to substantial improvement in therapeutic decision-making. OBJECTIVES: The main objective of this study is to assess the potential role of the arachidonic acid (AA) metabolite 20-hydroxyeicosatetraenoic (20-HETE) in predicting the incidence and progression of DKD. METHODS: Healthy patients and patients with diabetes were recruited from the Hamad General Hospital in Qatar, and urinary 20-HETE levels were measured. Data analysis was done using the Statistical Package for Social Sciences (SPSS). RESULTS: Our results show that urinary 20-HETE-to-creatinine (20-HETE/Cr) ratios were significantly elevated in patients with DKD when compared to patients with diabetes who did not exhibit clinical signs of kidney injury (p < 0.001). This correlation was preserved in the multivariate linear regression accounting for age, diabetes, family history of kidney disease, hypertension, dyslipidemia, stroke and metabolic syndrome. Urinary 20-HETE/Cr ratios were also positively correlated with the severity of kidney injury as indicated by albuminuria levels (p < 0.001). A urinary 20-HETE/Cr ratio of 4.6 pmol/mg discriminated between the presence and absence of kidney disease with a sensitivity of 82.2 % and a specificity of 67.1%. More importantly, a 10-unit increase in urinary 20-HETE/Cr ratio was tied to a 10-fold increase in the risk of developing DKD, suggesting a 20-HETE prognostic efficiency. CONCLUSION: Taken together, our results suggest that urinary 20-HETE levels can potentially be used as non-invasive diagnostic and prognostic markers for DKD.

VEGF-A: A Novel Mechanistic Link Between CYP2C-Derived EETs and Nox4 in Diabetic Kidney Disease.

Diabetes is associated with decreased epoxyeicosatrienoic acid (EET) bioavailability and increased levels of glomerular vascular endothelial growth factor A (VEGF-A) expression. We examined whether a soluble epoxide hydrolase inhibitor protects against pathologic changes in diabetic kidney disease and whether the inhibition of the VEGF-A signaling pathway attenuates diabetes-induced glomerular injury. We also aimed to delineate the cross talk between cytochrome P450 2C (CYP2C)-derived EETs and VEGF-A. Streptozotocin-induced type 1 diabetic (T1D) rats were treated with 25 mg/L of 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) in drinking water for 6 weeks. In parallel experiments, T1D rats were treated with either SU5416 or humanized monoclonal anti-VEGF-A neutralizing antibody for 8 weeks. Following treatment, the rats were euthanized, and kidney cortices were isolated for further analysis. Treatment with AUDA attenuated the diabetes-induced decline in kidney function. Furthermore, treatment with AUDA decreased diabetes-associated oxidative stress and NADPH oxidase activity. Interestingly, the downregulation of CYP2C11-derived EET formation is found to be correlated with the activation of the VEGF-A signaling pathway. In fact, inhibiting VEGF-A using anti-VEGF or SU5416 markedly attenuated diabetes-induced glomerular injury through the inhibition of Nox4-induced reactive oxygen species production. These findings were replicated in vitro in rat and human podocytes cultured in a diabetic milieu. Taken together, our results indicate that hyperglycemia-induced glomerular injury is mediated by the downregulation of CYP2C11-derived EET formation, followed by the activation of VEGF-A signaling and upregulation of Nox4. To our knowledge, this is the first study to highlight VEGF-A as a mechanistic link between CYP2C11-derived EET production and Nox4. ARTICLE HIGHLIGHTS: Diabetes is associated with an alteration in cytochrome P450 2C11 (CYP2C11)-derived epoxyeicosatrienoic acid (EET) bioavailability. Decreased CYP2C11-derived EET bioavailability mediates hyperglycemia-induced glomerular injury. Decreased CYP2C11-derived EET bioavailability is associated with increased reactive oxygen species production, NADPH oxidase activity, and Nox4 expression in type 1 diabetes. Decreased CYP2C11-derived EET formation mediates hyperglycemia-induced glomerular injury through the activation of the vascular endothelial growth factor A (VEGF-A) signaling pathway. Inhibiting VEGF signaling using anti-VEGF or SU5416 attenuates type 1 diabetes-induced glomerular injury by decreasing NADPH oxidase activity and NOX4 expression.

Reduced methylation correlates with diabetic nephropathy risk in type 1 diabetes.

Diabetic nephropathy (DN) is a polygenic disorder with few risk variants showing robust replication in large-scale genome-wide association studies. To understand the role of DNA methylation, it is important to have the prevailing genomic view to distinguish key sequence elements that influence gene expression. This is particularly challenging for DN because genome-wide methylation patterns are poorly defined. While methylation is known to alter gene expression, the importance of this causal relationship is obscured by array-based technologies since coverage outside promoter regions is low. To overcome these challenges, we performed methylation sequencing using leukocytes derived from participants of the Finnish Diabetic Nephropathy (FinnDiane) type 1 diabetes (T1D) study (n = 39) that was subsequently replicated in a larger validation cohort (n = 296). Gene body-related regions made up more than 60% of the methylation differences and emphasized the importance of methylation sequencing. We observed differentially methylated genes associated with DN in 3 independent T1D registries originating from Denmark (n = 445), Hong Kong (n = 107), and Thailand (n = 130). Reduced DNA methylation at CTCF and Pol2B sites was tightly connected with DN pathways that include insulin signaling, lipid metabolism, and fibrosis. To define the pathophysiological significance of these population findings, methylation indices were assessed in human renal cells such as podocytes and proximal convoluted tubule cells. The expression of core genes was associated with reduced methylation, elevated CTCF and Pol2B binding, and the activation of insulin-signaling phosphoproteins in hyperglycemic cells. These experimental observations also closely parallel methylation-mediated regulation in human macrophages and vascular endothelial cells.

Low-quality protein modulates inflammatory markers and the response to lipopolysaccharide insult: the case of lysine.

The relationship between non-communicable diseases and eating behaviour has long been attributed to a surplus of food and energy. However, the increase in the prevalence of non-communicable disease and their underlying low-grade inflammatory milieu among people of low socio-economic status has highlighted the existence of a confounding factor. In this work, we aim to study the effect of lysine deficiency on some inflammatory markers in the absence or presence of an inflammatory insult (lipopolysaccharide (LPS)). For this purpose, thirty-two 5-week-old male Sprague Dawley rats were randomly distributed into four groups: (1) control diet, (2) control diet+LPS, (3) lysine-deficient diet and (4) lysine-deficient diet + LPS. Groups were only allowed their experimental diets for 4 weeks, during which LPS (50 µg/kg) or saline injections were administered intraperitoneally three times per week. The study showed that lysine deficiency blunted growth and body compartments development, decreased albumin production and elevated liver C-reactive protein (CRP) expression, independently of IL-6 and IL-1ß, the main precursors of CRP. Also, the insufficient levels of lysine in the diet increased hyperactivity and triggered an anxiety-like behaviour, exacerbated with LPS. This work presents evidence that various physiological changes are associated with the absence of a sufficient amount of lysine in the diet and can potentially increase the risk factor for diseases. Thus, the increment in non-communicable disease among the low socio-economic status populations, who heavily rely on cereals as a main source of protein, can be, at least partially, blamed on low lysine availability in diets.

Podocyturia: an earlier biomarker of cardiovascular outcomes.

Urinary podocin and nephrin mRNAs (podocyturia), as candidate biomarkers of endothelial/podocyte injury, were measured by quantitative PCR in Type II diabetics with normal albumin excretion rates (AER) at baseline, at 3-4 years, and at 7 years. Development of cardiovascular disease (CVD) was collected as outcome. Visit 1 podocyturia was significantly higher in subjects who subsequently developed CVD versus those who did not. Visit 1 AER terciles exhibited similar time to CVD, in contrast with stepwise and substantial increases in CVD events predicted by Visit 1 podocyturia terciles. Covariate-adjusted hazard ratios were highest for podocin, intermediate for nephrin mRNAs, and lowest for AER. Podocyturia was also measured in patients with and without significant coronary obstruction, and in 480 normoalbuminuric subjects at the enrolment visit to the Multi-Ethnic Study of Atherosclerosis (MESA). Podocyturia > 3 × 106 copies was associated with presence of obstructive coronary artery disease. In the MESA population, Visit 1 podocyturia was significantly higher in men, subjects with elevated BMI, and those with Type II DM. Conclusions: Podocyturia may be an earlier predictor of cardiovascular events than moderate albuminuria; it is significantly higher in patients with obstructive coronary artery disease, and in subjects with established risk factors for CVD.

Wearable flexible body matched electromagnetic sensors for personalized non-invasive glucose monitoring.

This work introduces novel body-matched, vasculature-inspired, quasi-antenna-arrays that act as electromagnetic sensors to instantaneously, continuously, and wirelessly sense glucose variations in the bloodstream. The proposed sensors are personalized, leverage electromagnetic waves, and are coupled with a custom machine-learning-based signal-processing module. These sensors are flexible, and embedded in wearable garments such as socks, which provide conformity to curved skin surfaces and movement resilience. The entire wearable system is calibrated against temperature, humidity, and movement resulting in high accuracy in glucose variations tracking. In-Vivo experiments on diabetic rats and pigs exhibit a 100% diagnostic accuracy over a wide range of glucose variations. Human trials on patients with diabetes and healthy individuals reveal a clinical accuracy of continuous glucose monitoring of 99.01% in twenty-eight subjects who underwent Oral Glucose Tolerance Tests. Hence, our approach ensures the continuous tracking of glucose variations from hypo-to-hyper glycemic levels with great fidelity.

SMPDL3b modulates radiation-induced DNA damage response in renal podocytes.

The kidneys are radiosensitive and dose-limiting organs for radiotherapy (RT) targeting abdominal and paraspinal tumors. Excessive radiation doses to the kidneys ultimately lead to radiation nephropathy. Our prior work unmasked a novel role for the lipid-modifying enzyme, sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b), in regulating the response of renal podocytes to radiation injury. In this study, we investigated the role of SMPDL3b in DNA double-strand breaks (DSBs) repair in vitro and in vivo. We assessed the kinetics of DSBs recognition and repair along with the ATM pathway and nuclear sphingolipid metabolism in wild-type (WT) and SMPDL3b overexpressing (OE) human podocytes. We also assessed the extent of DNA damage repair in SMPDL3b knock-down (KD) human podocytes, and C57BL6 WT and podocyte-specific SMPDL3b-knock out (KO) mice after radiation injury. We found that SMPDL3b overexpression enhanced DSBs recognition and repair through modulating ATM nuclear shuttling. OE podocytes were protected against radiation-induced apoptosis by increasing the phosphorylation of p53 at serine 15 and attenuating subsequent caspase-3 cleavage. SMPDL3b overexpression prevented radiation-induced alterations in nuclear ceramide-1-phosphate (C1P) and ceramide levels. Interestingly, exogenous C1P pretreatment radiosensitized OE podocytes by delaying ATM nuclear foci formation and DSBs repair. On the other hand, SMPDL3b knock-down, in vitro and in vivo, induced a significant delay in DSBs repair. Additionally, increased activation of apoptosis was induced in podocytes of SMPDL3b-KO mice compared to WT mice at 24 h post-irradiation. Together, our results unravel a novel role for SMPDL3b in radiation-induced DNA damage response. The current work suggests that SMPDL3b modulates nuclear sphingolipid metabolism, ATM nuclear shuttling, and DSBs repair.

Intestinal microbiota regulates diabetes and cancer progression by IL-1ß and NOX4 dependent signaling cascades.

Diabetes changes the host microbiota, a condition known as dysbiosis. Dysbiosis is an important factor for the pathogenesis of diabetes and colorectal cancer (CRC). We aimed at identifying the microbial signature associated with diabetes and CRC; and identifying the signaling mechanism altered by dysbiosis and leading to CRC progression in diabetes. MKR mice that can spontaneously develop type 2 diabetes were used. For CRC induction, another subset of mice was treated with azoxymethane and dextran sulfate sodium. To identify the role of microbiota, microbiota-depleted mice were inoculated with fecal microbial transplant from diabetic and CRC mice. Further, a mouse group was treated with probiotics. At the end of the treatment, 16S rRNA sequencing was performed to identify microbiota in the fecal samples. Blood was collected, and colons were harvested for molecular, anatomical, and histological analysis. Our results show that diabetes is associated with a microbial signature characterized by reduction of butyrate-forming bacteria. This dysbiosis is associated with gastrointestinal complications reflected by a reduction in colon lengths. These changes are reversed upon treatment with probiotics, which rectified the observed dysbiosis. Inoculation of control mice with diabetic or cancer microbiota resulted in the development of increased number of polyps. Our data also show that inflammatory cytokines (mainly interleukin (IL)-1ß) and NADPH oxidase (NOX)4 are over-expressed in the colon tissues of diabetic mice. Collectively our data suggest that diabetes is associated with dysbiosis characterized by lower abundance of butyrate-forming bacteria leading to over-expression of IL-1ß and NOX4 leading to gastrointestinal complications and CRC.

Role of AMPK/mTOR, mitochondria, and ROS in the pathogenesis of endometriosis.

Endometriosis is the presence of endometrial tissue outside the uterine cavity usually in the ovaries, fallopian tube, and pelvic cavity. It's a chronic enigmatic gynecological condition associated with dysmenorrhea, dyspareunia, pelvic pain, and infertility. Endometriosis lesions exist in a unique microenvironment characterized by increased concentrations of hormones, inflammation, and oxidative stress. This environment promotes cell survival through the binding of membrane receptors and subsequent cascading activation of intracellular kinases that stimulate a cellular response. In endometriosis, well-established signaling pathways, mTOR and AMPK, are altered via steroid hormones and other factors to promote cell growth, migration, and proliferation. This is accompanied by dysfunction in the mitochondria that increase energy production to sustain proliferation demands consequently leading to reactive oxygen species overproduction. This review aims to summarize the role of altered mTOR/AMPK signaling pathway, mitochondrial dysfunction, and reactive oxygen species overproduction along with providing therapeutic and diagnostic approaches. Highlighting these factors would provide a better understanding to reach a coherent theory for the pathogenesis of endometriosis.

Redox Balance in ß-Thalassemia and Sickle Cell Disease: A Love and Hate Relationship.

ß-thalassemia and sickle cell disease (SCD) are inherited hemoglobinopathies that result in both quantitative and qualitative variations in the ß-globin chain. These in turn lead to instability in the generated hemoglobin (Hb) or to a globin chain imbalance that affects the oxidative environment both intracellularly and extracellularly. While oxidative stress is not among the primary etiologies of ß-thalassemia and SCD, it plays a significant role in the pathogenesis of these diseases. Different mechanisms exist behind the development of oxidative stress; the result of which is cytotoxicity, causing the oxidation of cellular components that can eventually lead to cell death and organ damage. In this review, we summarize the mechanisms of oxidative stress development in ß-thalassemia and SCD and describe the current and potential antioxidant therapeutic strategies. Finally, we discuss the role of targeted therapy in achieving an optimal redox balance.

Influence of intermittent fasting on prediabetes-induced neuropathy: Insights on a novel mechanistic pathway.

Aims: Peripheral neuropathy (PN) is correlated with obesity and metabolic syndrome. Intermittent fasting (IF) has been described as the cornerstone in the management of obesity; however, its role in prediabetic complications is not well elucidated. Cytochromes P450 Monooxygenases (CYP450) are major sources of Reactive Oxygen Species (ROS) that orchestrate the onset and development of diabetic complications. One of the CYP-metabolites, Expoxyecosatetraenoic Acids (EETs), are considered to be negative regulators of ROS production. In this study, we elucidated the role of IF on ROS production and investigated its influence on prediabetes-induced PN. Methods: C57/BL6 control mice, prediabetic, prediabetic that underwent alternate day fasting with different diet composition, and prediabetic mice treated with EET-metabolizing sEH-inhibitor, AUDA. Body mass composition, metabolic, behavioral, and molecular tests were performed. Results: High-fat diet (HFD) led to an increase in NADPH-induced ROS production; that was due to an alteration in the epoxygenase pathway assessed by the decrease in CYP1a1/1a2 expression. IF reinstated the homeostatic levels of EETs in HFD-fed mice. Moreover, treatment with AUDA mimicked the beneficial effect observed with IF. Conclusion: IF and EETs bioavailability have a protective role in prediabetes-induced PN, suggesting a novel interventional strategy in the management of prediabetes and its associated complications.