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Rawaa El Sabbagh,1 Nadim S Azar,2,3 Assaad A Eid,3 Sami T Azar1 1Division of Endocrinology and Metabolism, American University of Beirut, Beirut, Lebanon; 2Department of Internal Medicine, American University of Beirut, Beirut, Lebanon; 3Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, LebanonCorrespondence: Sami T AzarDivision of Endocrinology and Metabolism, American University of Beirut Medical Center, Beirut, LebanonEmail sazar@aub.edu.lbAim: Immune checkpoint inhibitors are anti-cancer drugs associated with adverse events that result from releasing the immune system against self-antigens while attacking cancer cells. Thyroid dysfunctions are among the most common associated adverse events.Materials and Methods: We conducted a systematic search of the literature in 2 databases: PubMed and Medline. Articles that reported thyroid adverse events of immune checkpoint inhibitors were reviewed. Thyroid disorders include hyperthyroidism and hypothyroidism and are most commonly seen with programmed cell death protein 1 and programmed death-ligand 1 inhibitors.Conclusions: Thyroid disorders are common side effects seen with check point inhibitors and are treated, depending on the clinical situation, by adequate hormonal replacement, thionamides, corticosteroids or observation only. The use of high dose corticosteroids has not been established as a treatment of thyroid toxicities. Thyroid function tests screening should be a part of baseline laboratory testing of all patients undergoing treatment with immune checkpoint inhibitors.Keywords: immune check point inhibitors, thyroid dysfunction, anti-PD1, anti-PDL1

Objective: We investigated the role of cytochrome P450 of the 4A family (CYP4A), its metabolites, and NADPH oxidases both in reactive oxygen species (ROS) production and apoptosis of podocytes exposed to high glucose and in OVE26 mice, a model of type 1 diabetes.Research Design and Methods: Apoptosis, albuminuria, ROS generation, NADPH superoxide generation, CYP4A and Nox protein expression, and mRNA levels were measured in vitro and in vivo.Results: Exposure of mouse podocytes to high glucose resulted in apoptosis, with approximately one-third of the cells being apoptotic by 72 h. High-glucose treatment increased ROS generation and was associated with sequential upregulation of CYP4A and an increase in 20-hydroxyeicosatetraenoic acid (20-HETE) and Nox oxidases. This is consistent with the observation of delayed induction of NADPH oxidase activity by high glucose. The effects of high glucose on NADPH oxidase activity, Nox proteins and mRNA expression, and apoptosis were blocked by N-hydroxy-N'-(4-butyl-2-methylphenol) formamidine (HET0016), an inhibitor of CYP4A, and were mimicked by 20-HETE. CYP4A and Nox oxidase expression was upregulated in glomeruli of type 1 diabetic OVE26 mice. Treatment of OVE26 mice with HET0016 decreased NADPH oxidase activity and Nox1 and Nox4 protein expression and ameliorated apoptosis and albuminuria.Conclusions: Generation of ROS by CYP4A monooxygenases, 20-HETE, and Nox oxidases is involved in podocyte apoptosis in vitro and in vivo. Inhibition of selected cytochrome P450 isoforms prevented podocyte apoptosis and reduced proteinuria in diabetes. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) is a major complication of type 2 diabetes mellitus (T2DM) that leads to significant morbidity and mortality. The alteration in the signaling mechanism in diabetes leading to cardiomyopathy remains unclear. The purpose of this study is to investigate the role of tauopathy in myocardial dysfunction observed in T2DM. In that regard, diabetic Sprague Dawley rats were treated with intraperitoneal injections of lithium chloride (LiCl), inhibiting tau phosphorylation. Cardiac function was evaluated, and molecular markers of myocardial fibrosis and the TGF-β signaling were analyzed. T2DM rats exhibited a decline in ejection fraction and fractional shortening that revealed cardiac function abnormalities and increased myocardial fibrosis. These changes were associated with tau hyperphosphorylation. Treating diabetic rats with LiCl attenuated cardiac fibrosis and improved myocardial function. Inhibition of GSK-3β leads to the suppression of tau phosphorylation, which is associated with a decrease in TGF-β expression and regulation of the pro-inflammatory markers, suggesting that tau hyperphosphorylation is parallelly associated with fibrosis and inflammation in the diabetic heart. Our findings provide evidence of a possible role of tau hyperphosphorylation in the pathogenesis of DCM through the activation of TGF-β and by inducing inflammation. Targeting the inhibition of tau phosphorylation may offer novel therapeutic approaches to reduce DCM burden in T2DM patients.

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 β-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., (© 2024. The Author(s).)

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., (© 2024 Wiley Periodicals LLC.)

To investigate the effectiveness of AcceleDent Aura vibrating device on the rate of canine retraction. Thirty-two patients requiring extraction of upper first premolars and canine retraction were randomly allocated with a 1:1 ratio into either no-appliance group or the AcceleDent Aura appliance group. Canine retraction was done applying 150gm of retraction force using NiTi coil springs on 16 × 22 stainless steel archwires. The duration of the study was 4 months. Models were collected and digitized directly after extraction of upper first premolars and at monthly intervals during canine retraction for recording the monthly as well as the total distance moved by the canine. Digitized models were superimposed on the initial model and data were statistically analyzed. Anchorage loss, rotation, tipping, torque and root condition were evaluated using cone beam computed tomography imaging. Pain was evaluated by visual analog scale. No patients were dropped-out during this study. There was no statistically significant difference between both groups regarding the total distance travelled by the canine (P = 0.436), as well as the rate of canine retraction per month (P = 0.17). Root condition was the same for the two groups. Regarding the pain level, there was no statistically significant difference between the two groups at day 0 (P = 0.721), after 24 h (P = 0.882), after 72 h (P = 0.378) and after 7 days (P = 0.964). AcceleDent Aura was not able to accelerate orthodontic tooth movement. Pain level couldn't be reduced by vibrational force with an AcceleDent device during orthodontic treatment. Root condition was not affected by the vibrational forces., (© 2024. The Author(s).)

Background: The effect of gadolinium-based contrast agents (GBCA) on the spinal cord is not established, especially in patients with diabetes mellitus., Purpose: To investigate neuronal and myelin loss in the spinal cord when employing macrocyclic ionic Gadoterate Meglumine (Gd-DOTA) and non-ionic Gadobuterol (Gd-BT-DO3A) GBCA in rats with and without diabetes mellitus., Materials and Methods: This study was performed between November 2018 and February 2020. Sixty young Sprague Dawley white rats (n = 6/group) were given injections of two macrocyclic GBCA: 0.5 mmol/ml Gd-DOTA and 1 mmol/ml Gd-BT-DO3A, using volumes based of the recommended doses (0.1 ml and 0.2 ml) for 42 days in both healthy and diabetic rats. Control groups received saline injections. Morphological assessment of spinal cord tissues was performed on three spinal segments. Neuronal counts in the ventral horns and myelin sparing percentage in the white matter were determined and compared in each group employing one-way ANOVA and Dunnett test for each category followed by three-way factorial analysis., Results: Low neuronal count and myelin percentage-area were obtained in groups receiving 0.2 ml Gd-DOTA (p = .001;p = .002;p < .001 neurons; and p < .001;p = .007;p = .001 myelin %) and Gd-BT-DO3A (p = .01;p = .048;p = .006 neurons; p < .001;p = .01;p = .001 myelin %). Similarly, neuronal loss was seen in diabetics receiving low volume-injection (0.1 ml) of Gd-DOTA (p = .04;p = .03;p = .42), Gd-BT-DO3A (p = .002;p = .007;p = .01); or high volume-injection (0.2 ml) of Gd-DOTA (p = .001;p = .003;p = .01) or Gd-BT-DO3A (p < .001,p = .002;p = .002), with associated decrease in myelin sparing for each category with low dose Gd-DOTA (p < .001, p = .001; p. = 09),Gd-BT-DO3A (p = .003;p = .003;p = .007); or the higher dose counterparts of Gd-DOTA (p < .001; p < .00; p = .001) and Gd-BT-DO3A (p < .001, p < .001, p < .001). Damage was observed using the standard dose (equivalent of 0.1 mmol/kg for rats) of Gd-DOTA (0.2 ml) but not that of Gd-BT-DO3A (0.1 ml) in healthy rats., Conclusion: Multiple high-volume injections of gadoterate meglumine and gadobuterol are associated with neuronal and myelin injury in the spinal cord, more so in rats with diabetes mellitus., (Copyright © 2024. Published by Elsevier Inc.)

A negative impact of finasteride on fertility has been reported, in which over production of reactive oxygen species and apoptosis were implicated. Hesperidin, a plant-derived bioflavonoid with antioxidant and anti-apoptotic effects, may mitigate these adverse effects. In order to investigate the possible protective role of hesperidin against finasteride-induced seminiferous tubules toxicity in adult male Wistar rats, 60 rats were randomized into five groups (I-V) receiving distilled water, 0.5% sodium carboxymethylcellulose solution, hesperidin, finasteride, and combined hesperidin and finasteride respectively. Testicular weight, sperm count and motility were determined. Testicular tissue homogenates were prepared to measure the level of malondialdehyde (MDA), total antioxidant capacity (TAC), reduced glutathione (GSH) and the gene expression of caspase-3 and B-cell lymphoma 2 (Bcl2). Testes were processed for light and electron microscopic evaluation. Johnsen score was calculated. Administration of finasteride resulted in significantly decreased testicular weights, sperm count and motility, Johnsen score, tissue levels of TAC and GSH together with significant increase in tissue MDA. Gene expression revealed significantly increased caspase-3 and decreased Bcl2. Furthermore, finasteride disrupted the seminiferous tubules, causing degenerative changes affecting Sertoli cells and spermatogenic cells. Co-administration of hesperidin with finasteride resulted in improvement in testicular weights, TAC, GSH, Bcl2, Johnsen score, sperm count and motility as well as preservation of the structure of the seminiferous tubules. To conclude, hesperidin was found to have a protective potential on finasteride-induced oxidative stress, apoptosis and testicular structural damage., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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 (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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Aramouni, Assaf, Azar, Jabbour, Shaito, Sahebkar, Eid, Rizzo and Eid.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 El Khoury, Biondi, Bruneteau, Sapaly, Bendris, Bezier, Clerc, Akar, Weill, Eid and Charbonnier.)

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., (© 2023 by the American Diabetes Association.)

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.

This study examined the effect of varying concentrations of Ocimum basilicum aqueous extract, which was done via the green synthesis of Silver nanoparticles (AgNPs), on the identification of the most effective concentration for bacteria inhibitory activity. Different concentrations of the aqueous Ocimum basilicum extract (0.25, 0.50, 0.75 and 1.00 mM) were used as reducing and stabilizing agent to synthesize AgNPs by means of the reduction method. The crystal structure and morphology of the NPs were characterized UV-Vis spectra, X-ray diffraction (XRD) and scanning electron microscopy (SEM). The antibacterial efficacy of AgNPs was studied against E. coli ATCC 35218 using well diffusion, MIC, MBC, and time-kill curve. The dark yellow color of the Ocimum basilicum aqueous solution indicates the successful synthesis process of the AgNPs. UV-spectra of the AgNPs display a gradual increase of absorption in sequence with concentration increase of aqueous Ocimum basilicum extract solution from 0.25 to 1.00 mM. This, in turn, led to a shift in the wavelength from 488 to 497 nm, along with a change in the nanoparticle size from 52 to 8 nm. The tests also showed a high activity of the particles against bacteria (E. coli), ranging between 15.6 and 62.5 µg/ml. Based on AgNPs, it was confirmed that an aqueous Ocimum basilicum extract can be used as an effective, reducing and stabilizing agent for the synthesis of different sizes of AgNPs based on the solvent concentration. The AgNPs also proved to be effective in inhibiting and killing bacteria., (© 2023. The Author(s).)

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.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Production and hosting by Elsevier B.V.)

Background: Treatment of horizontal forehead lines with botulium toxin type A is a common procedure that helps achieve a youthful and rejuvenated look. Adequate knowledge of the anatomy and an individualized treatment approach is the key to successful treatment outcome., Aim: To evaluate the cosmetic outcome following treatment of dynamic forehead wrinkles by locking the line of convergence using botulinum toxin type A., Patients and Methods: Fifty female patients with dynamic forehead wrinkles were included. The line of convergence was identified, and injection points were determined. Patients received injections of botulinum toxin type A in the upper part of the frontalis along the line of convergence. Patients were evaluated before injection and the response was evaluated after 2 weeks and after 3 months of injection., Results: Post-treatment significant decrease in dynamic wrinkle scale was detected. The distance between the medial and lateral canthi and their corresponding lower brow margins on maximum brow elevation was also significantly decreased after treatment. Meanwhile, the validated brow positioning score revealed no significant change in the resting brow position when pre-and post-treatment scores were compared., Conclusions: Treating forehead wrinkles by injecting botulinum toxin along the line of convergence is an effective technique that requires less overall amount of toxin, improves the appearance of the wrinkles and minimizes the risk of development of side effects., (© 2022 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Introduction: Synthetic mid-urethral slings (MUSs) are the gold standard treatment for female stress urinary incontinence (SUI). Recently, there have been reports of serious adverse events with synthetic tapes such as urethral erosion, vaginal erosion, and mesh infection. Tension-free vaginal flap (TVF) operation has been proven to be successful as a natural alternative to synthetic slings. We propose our novel technique, the transobturator tension-free vaginal flap (TO-TVF), utilizing native vaginal tissue and being suspended via transobturator route., Methods: This prospective study was conducted on 72 female patients with SUI, presenting at Alexandria University Hospital. Patients were randomized into 2 groups, group 1: 37 patients subjected to TO-TVF and group 2: 35 patients to conventional transobturator tape (TOT). In TO-TVF, a rectangular vaginal wall flap is created. A polypropylene monofilament mesh is sutured to each edge of the vaginal flap. This is inserted like conventional outside-in TOT. Patients were subjected to PGI and UDI-6 questionnaires and urodynamic study before and 6 months postoperatively., Results: Both groups showed comparable and significant improvements in questionnaires. Mean operative time for TO-TVF and conventional TOT was 26.31 ± 5.2 min and 21.8 ± 3.1 min, respectively. Cure rate was 89% in group 1 and 91.4% in group 2, which was not statistically significant. No significant intraoperative complications were encountered. We had no cases of vaginal or urethral erosion in both groups., Conclusions: TO-TVF is a cost-effective, feasible, safe, and effective surgical alternative to synthetic MUS. Synthetic mesh tissue anchoring properties are maintained for better adjustment of tension. However, long-term follow-up on a large cohort of patients is still needed., (© 2023 S. Karger AG, Basel.)

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 × 10 6 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., (© 2022. The Author(s).)

Background: Reduced sirtuin 1 (Sirt1) expression in psoriasis was previously reported, and its activation was associated with disease improvement. Narrow-band ultraviolet B (NB-UVB) downregulates several pro-inflammatory cytokines such as interferon-γ (IFN-γ) and influences keratinocyte differentiation in psoriasis., Objectives: The aim of this study was to study the in vivo influence NB-UVB treatment on Sirt1 expression in psoriatic skin in relation to disease improvement and IFN-γ expression., Methods: Twenty-six patients with chronic plaque psoriasis were evaluated, and psoriasis area severity index (PASI) was calculated. Skin biopsies were taken from lesional skin of the patients before and after 3 months of treatment with NB-UVB and from 26 controls, where the distribution and immunohistochemistry (IHC) scores of Sirt1 and IFN-γ were determined., Results: After 3 months of treatment, Sirt1 distribution and epidermal IHC score were significantly higher, whereas Sirt1 dermal IHC score and IFN-γ distribution, epidermal and dermal IHC scores were significantly lower than the pre-treatment values. Before and after 3 months of NB-UVB therapy, PASI showed a significant negative correlation with Sirt1 distribution and epidermal IHC score; and a significant positive correlation with interferon-γ distribution and epidermal IHC score. Moreover, Sirt1 distributions were negatively correlated with the corresponding interferon-γ distributions. Conclusions The detected upregulation of epidermal Sirt1 following NB-UVB therapy possibly represents another mechanism by which NB-UVB can act in psoriasis and also highlights the role of Sirt1 upregulation in psoriasis treatment., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (Copyright © 2022. Published by Elsevier Inc.)

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., (© 2022 Federation of American Societies for Experimental Biology.)

Significance: Despite the many efforts put into understanding diabetic nephropathy (DN), direct treatments for DN have yet to be discovered. Understanding the mechanisms behind DN is an essential step in the development of novel therapeutic regimens. The mammalian target of rapamycin (mTOR) pathway has emerged as an important candidate in the quest for drug discovery because of its role in regulating growth, proliferation, as well as protein and lipid metabolism. Recent Advances: Kidney cells have been found to rely on basal autophagy for survival and for conserving kidney integrity. Recent studies have shown that diabetes induces renal autophagy deregulation, leading to kidney injury. Hyper-activation of the mTOR pathway and oxidative stress have been suggested to play a role in diabetes-induced autophagy imbalance. Critical Issues: A detailed understanding of the role of mTOR signaling in diabetes-associated complications is of major importance in the search for a cure. In this review, we provide evidence that mTOR is heavily implicated in diabetes-induced kidney injury. We suggest possible mechanisms through which mTOR exerts its negative effects by increasing insulin resistance, upregulating oxidative stress, and inhibiting autophagy. Future Directions: Both increased oxidative stress and autophagy deregulation are deeply embedded in DN. However, the mechanisms controlling oxidative stress and autophagy are not well understood. Although Akt/mTOR signaling seems to play an important role in oxidative stress and autophagy, further investigation is required to uncover the details of this signaling pathway. Antioxid. Redox Signal. 37, 802-819.

Introduction: Vitiligo is an acquired disease of complex pathogenesis, in which the immunologic attack to the skin and hair follicle melanocytes leads to areas of depigmentation and leukotrichia, respectively., Objectives: To study the dermoscopic features of the hair changes in vitiligo lesions in comparison to perilesional control areas and in relation to disease duration., Methods: Forty-seven patients with both old and recent vitiligo lesions were included. Dermoscopic features of hair within the lesions were examined and compared to those in perilesional non depigmented skin of the same patient., Results: Hair density (P < 0.001), terminal hair rate (P = 0.011), terminal to vellus hair ratio (P = 0.029) and mean hair shaft thickness (P = 0.031) were significantly decreased, whereas vellus hair rate (P = 0.011) was significantly increased in old vitiligo lesions compared to their respective control areas. The frequency of broken hair was significantly higher in old lesions (P < 0.001), while that of upright re-growing hair was significantly higher in recent lesions (P = 0.016)., Conclusions: Hair involvement in vitiligo lesions is not only limited to the development of leukotrichia. Other subtle changes in hair density, anagen and telogen hair rates, and mean hair thickness can be detected. These changes may serve as objective clues to the duration of the lesions., Competing Interests: Competing interests: None., (©2022 Anbar et al.)

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., (© 2022. The Author(s).)

Background: Carboxytherapy is a minimally invasive, relatively safe modality that has been used for the treatment of dark circles; however, different flow rates and different injection techniques have been described in the literature., Aim: To study the effect of the flow rate on the therapeutic outcome of carboxytherapy in infraorbital dark circles., Methods: Eighty patients with infraorbital dark circles were divided into two equal groups: Group A received carboxytherapy at a flow rate of 30 ml/min, and group B received carboxytherapy at a flow rate of 60 ml/min. Patients received weekly sessions for 6 weeks, and the treatment response was evaluated 6 weeks after the last treatment session., Results: Significant improvement of the dark circles was detected in both treatment groups. However, no significant difference in the treatment response was found when both flow rates were compared. The frequency of development of side effects was significantly higher in the group receiving CO 2 at a flow rate of 60 ml/min. No significant difference in the overall post-treatment patient satisfaction between the two groups was detected., Conclusion: Carboxytherapy is an effective therapeutic modality for infraorbital dark circles. Lower flow rates achieve therapeutic responses similar to higher flow rates but with fewer side effects., (© 2021 Wiley Periodicals LLC.)

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)-1β) 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-1β and NOX4 leading to gastrointestinal complications and CRC., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Significance: Reactive oxygen species (ROS) contribute to multiple aspects of peripheral nervous system (PNS) biology ranging from physiological processes ( e.g. , axonal outgrowth and regeneration) to pathophysiology ( e.g. , nerve degeneration). Although ROS are derived from multiple sources, NADPH oxidase (Nox) family members are dedicated to ROS generation. Noxs are expressed in the PNS, and their overexpression is associated with detrimental effects on nerve function and contributes, at least in part, to peripheral neuropathies. Recent Advances: Of the seven members, studies mostly focused on Nox1, Nox2, and Nox4, which are expressed in the PNS in a cell-specific manner. We have also recently identified human Nox5 in sural nerve biopsies. When maintained at homeostatic levels, Noxs regulate several aspects of peripheral nerve health, most notably neurite outgrowth and axonal regeneration following nerve lesion. While Nox2 and Nox4 dysregulation is a major source of oxidative stress in PNS disorders, including neuropathic pain and diabetic peripheral neuropathy, recent evidence also implicates Nox1 and Nox5. Critical Issues: Although there is compelling evidence for a direct role of Noxs on nerve function, little is known about their subcellular localization, intercellular regulation, and interaction. These, together with redox signaling, are considered crucial components of nerve redox status. In addition, the lack of isoform-specific inhibitors limits conclusions about the physiological role of Noxs in the PNS and their therapeutic potential in peripheral neuropathies. Future Directions: Future research using isoform-specific genetic and pharmacological approaches are therefore needed to better understand the significance of Nox enzymes in PNS (patho) physiology. Antioxid. Redox Signal. 37, 613-630.

Diabetic Peripheral Neuropathy (DPN), highly prevalent among patients with diabetes, is characterized by peripheral nerve dysfunction. Reactive Oxygen Species (ROS) overproduction has been suggested to orchestrate diabetic complications including DPN. Untargeted antioxidant therapy has exhibited limited efficacy, highlighting a critical need to explore ROS sources altered in a cell-specific manner in DPN. Cytochromes P450 (CYP) enzymes are prominent sources of ROS. Particularly, the 20-HETE synthase, CYP4A, is reported to mediate diabetes-induced renal, retinal, and cardiovascular injuries. This work investigates the role of CYP4A/20-HETE in DPN and their mechanisms of action. Non-obese type 2 Diabetic mice (MKR) were used and treated with a CYP4A-inhibitor (HET0016) or AMPK-activator (Metformin). Peripheral nerves of MKR mice reflect increased CYP4A and 20-HETE levels, concurrent with altered myelin proteins and sensorimotor deficits. This was associated with increased ROS production and altered Beclin-1 and LC3 protein levels, indicative of disrupted autophagic responses in tandem with AMPK inactivation. AMPK activation via Metformin restored nerve integrity, reduced ROS production, and regulated autophagy. Interestingly, similar outcomes were revealed upon HET0016 treatment whereby ROS production, autophagic responses, and AMPK signaling were normalized in diabetic mice. Altogether, the results highlight hyperglycemia-mediated oxidative injury in DPN through a novel CYP4A/20-HETE/AMPK pathological axis. PERSPECTIVE: To our knowledge, this is the first study to highlight the role of CYPs/20-HETE-induced oxidative injury in the pathogenesis of diabetic peripheral neuropathy. Targeting the identified pathological axis CYP4A/20-HETE/AMPK may be of clinical potential in predicting and alleviating peripheral nerve injury in patients with Type 2 Diabetes Mellitus., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

β-thalassemia and sickle cell disease (SCD) are inherited hemoglobinopathies that result in both quantitative and qualitative variations in the β-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 β-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 β-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.

Background: NB-UVB has long been the vitiligo management pillar with capability of achieving the main treatment outcomes; repigmentation and stabilization. Its stabilizing effect in dark skin has been debatable. However, randomized controlled trials regarding NB-UVB ability to control disease activity are lacking., Purpose: To assess stabilizing effect of NB-UVB in comparison to systemic corticosteroids, the mainstay in vitiligo stabilization, in skin photo-types (III-V)., Methods: This is a multicenter, placebo-controlled, randomized, prospective study. Eighty patients with active nonsegmental vitiligo (NSV) (Vitiligo disease activity (VIDA) ≥2) were randomized to either NB-UVB and placebo (NB-placebo) or NB-UVB and dexamethasone oral mini-pulse (OMP) therapy (NB-OMP) for 6 months. Sixty four patients completed the study, 34 in the NB-OMP group and 30 in the NB-placebo group. Patients were evaluated fortnightly according to presence or absence of symptoms/signs of activity., Results: In spite of earlier control of disease activity observed in the NB-OMP group, it was comparable in both groups by the end of the study period. Disease activity prior to therapy, but not extent, was found to influence control of activity in both groups. Thus, NB-UVB is a safe sole therapeutic tool in vitiligo management. Not only does it efficiently achieve repigmentation, but also it is a comparable stabilizing tool for systemic corticosteroids in spite of slightly delayed control., Conclusion: NB-UVB is the only well-established vitiligo therapy that can be used solely whenever corticosteroids are contraindicated or immune-suppression is unjustified. Nonetheless, its combination with corticosteroids expedites response and improves compliance., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., Competing Interests: Authors report no conflict of interest., (© 2022 The Authors.)

P ingestion has been found to alter energy balance, while regular physical exercise (E) was reported to be associated with energy compensation. However, it is not clear whether dietary P would affect energy compensation following structured E. Two experiments were performed, low P (LP) (0·1, 0·2 and 0·3 %P) and high P (HP) (0·3 , 0·6 and 1·2 %P) diets. In each experiment, male rats were randomly divided into three groups (n 8), in which a sedentary or a moderate-intensity exercise routine (30 min 5 d a week) was implemented. Energy intake (EI); efficiency and stores; body measures and total energy expenditure (TEEx) were monitored for 6 weeks. In the LP experiment, EI and weight gain were the lowest in the 0·1 and 0·2 %P as compared with the 0·3 %P. In the HP experiment, EI was highest in the high P (0·6 and 1·2 %P) groups, while weight gain was reduced. In both experiments, exercise was able to reduce body fat accumulation and to maintain a higher % lean body mass. In the LP diets experiment, the similarity in TEEx between the sedentary and exercising groups suggests the probability of a reduction in normal daily activities, which indicates the presence of compensation for the energy expended during exercise by a subsequent reduction in EE. In contrast, the elevated TEEx in the HP exercising groups (0·6 and 1·2 %P) argue against the presence of energy compensation. In conclusion, high dietary P decreases the body's capability to compensate for the energy deficit induced by E, consequently maintaining an elevated TEEx.

Inflammatory skin diseases are highly prevalent, yet their impacts on patients' quality of life (QoL) are not addressed. In this cross-sectional study, the Arabic version of Skindex-16 was used to evaluate the symptomatic, emotional, and functional distress of patients with inflammatory skin disorders attending several outpatient dermatology clinics in Egypt and Saudi Arabia. Patients with ≥50% of the symptoms score, ≥50% of the emotions score, and ≥33% of the functioning score were considered having poor QoL. A total of 1,310 patients aged 30 ± 13 years (70.6% from Egypt and 29.4% from Saudi Arabia) were included in this study. Of them, 1,192 patients had inflammatory skin diseases, and 118 had facial nevi, who served as controls. Patients with inflammatory skin diseases had significantly worse QoL than those with nevi. Autoimmune bullous disease group showed the highest prevalence poor symptoms (56.8%), poor emotions (75.7%), and poor functioning (83.8%) of QoL. Women with acne and psoriasis were more likely to have poor symptoms than men (16.3% vs. 4.7% and 52.7% vs. 25.3%, respectively). In conclusion, inflammatory skin diseases had profound negative effects on patients' QoL. Age, sex, education, and marital status of patients can affect their perception of QoL.

Diabetic kidney disease (DKD), a serious diabetic complication, results in podocyte loss and proteinuria through NADPH oxidases (NOX)-mediated ROS production. DUOX1 and 2 are NOX enzymes that require calcium for their activation which enters renal cells through the pivotal TRPC channels. Hypoglycemic drugs such as liraglutide can interfere with this deleterious mechanism imparting reno-protection. Herein, we aim to investigate the reno-protective effect of GLP1 receptor agonist (GLP1-RA), via its effect on TRPC6 and NADPH oxidases. To achieve our aim, control or STZ-induced T1DM Sprague-Dawley rats were used. Rats were treated with liraglutide, metformin, or their combination. Functional, histological, and molecular parameters of the kidneys were assessed. Our results show that treatment with liraglutide, metformin or their combination ameliorates DKD by rectifying renal function tests and protecting against fibrosis paralleled by restored mRNA levels of nephrin, DUOX1 and 2, and reduced ROS production. Treatment with liraglutide reduces TRPC6 expression, while metformin treatment shows no effect. Furthermore, TRPC6 was found to be directly interacting with nephrin, and indirectly interacting with DUOX1, DUOX2 and GLP1-R. Our findings suggest that treatment with liraglutide may prevent the progression of diabetic nephropathy by modulating the crosstalk between TRPC6 and NADPH oxidases.

Patients undergoing radiotherapy (RT) for various tumors localized in the abdomen or pelvis often suffer from radiation nephrotoxicity as collateral damage. Renal podocytes are vulnerable targets for ionizing radiation and contribute to radiation-induced nephropathies. Our prior work previously highlighted the importance of the lipid-modifying enzyme sphingomyelinase acid phosphodiesterase like 3b (SMPDL3b) in modulating the radiation response in podocytes and glomerular endothelial cells. Hereby, we investigated the interplay between SMPDL3b and oxidative stress in mediating radiation injury in podocytes. We demonstrated that the overexpression of SMPDL3b in cultured podocytes (OE) reduced superoxide anion generation and NADPH oxidase activity compared to wild-type cells (WT) post-irradiation. Furthermore, OE podocytes showed downregulated levels of NOX1 and NOX4 after RT. On the other hand, treatment with the NOX inhibitor GKT improved WTs' survival post-RT and restored SMPDL3b to basal levels. in vivo , the administration of GKT restored glomerular morphology and decreased proteinuria in 26-weeks irradiated mice. Taken together, these results suggest a novel role for NOX-derived reactive oxygen species (ROS) upstream of SMPDL3b in modulating the response of renal podocytes to radiation., Competing Interests: AF is an inventor on pending or issued patents (PCT/US11/56272, PCT/US12/62594, PCT/US2019/041730, PCT/US2019/032215, PCT/US13/36484, and PCT 62/674,897) aimed to diagnosing or treating proteinuric kidney diseases and stands to gain royalties from their 20 future commercialization of these patents. AF is Vice-President of L&F Health LLC and is a consultant for ZyVersa Therapeutics, Inc. ZyVersa Therapeutics, Inc has licensed worldwide rights to develop and commercialize hydroxypropyl-beta-cyclodextrin from LF Research for the treatment of kidney disease. AF is the founder of LipoNexT LLC. AF is supported by Hoffman-La Roche and by Boehringer Ingelheim. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Azzam, Francis, Youssef, Mroueh, Daher, Eid, Fornoni, Marples and Zeidan.)

Obesity is a risk factor for erectile dysfunction and atherosclerosis. Lipocalin-2 is an adipocytokine with proinflammatory properties involved in several disorders with metabolic alterations. Our aim was to study the relation of serum lipocalin-2 and carotid artery intima-media thickness (CIMT) to obesity in erectile dysfunction. Serum lipocalin-2 and CIMT were measured in 25 obese and 25 nonobese eugonadal patients over forty with venogenic erectile dysfunction and 25 healthy controls. Their relation to different patient- and disease-related parameters was studied. Results revealed lipocalin-2 to be significantly higher in obese compared with nonobese patients and with controls, and in nonobese patients compared with controls. CIMT was lower in controls compared with both obese and nonobese patients. In obese and nonobese patients, lipocalin-2 was positively correlated with disease duration, body mass index, waist circumference and end-diastolic velocity. Lipocalin-2 was negatively correlated with the short form of the international index of erectile function scores in both groups. In conclusion, the elevated lipocalin-2 in obese and to a lesser extent in nonobese patients and its association with disease severity points to its potential value as a diagnostic marker and a possible therapeutic target that could ameliorate the metabolic derangement associated with erectile dysfunction., (© 2021 Wiley-VCH GmbH.)

Diabetic cardiomyopathy (DCM) is a well-established complication of type 1 and type 2 diabetes associated with a high rate of morbidity and mortality. DCM is diagnosed at advanced and irreversible stages. Therefore, it is of utmost need to identify novel mechanistic pathways involved at early stages to prevent or reverse the development of DCM. In vivo experiments were performed on type 1 diabetic rats (T1DM). Functional and structural studies of the heart were executed and correlated with mechanistic assessments exploring the role of cytochromes P450 metabolites, the 20-hydroxyeicosatetraenoic acids (20-HETEs) and epoxyeicosatrienoic acids (EETs), and their crosstalk with other homeostatic signaling molecules. Our data displays that hyperglycemia results in CYP4A upregulation and CYP2C11 downregulation in the left ventricles (LV) of T1DM rats, paralleled by a differential alteration in their metabolites 20-HETEs (increased) and EETs (decreased). These changes are concomitant with reductions in cardiac outputs, LV hypertrophy, fibrosis, and increased activation of cardiac fetal and hypertrophic genes. Besides, pro-fibrotic cytokine TGF-ß overexpression and NADPH (Nox4) dependent-ROS overproduction are also correlated with the observed cardiac functional and structural modifications. Of interest, these observations are attenuated when T1DM rats are treated with 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA), which blocks EETs metabolism, or N-hydroxy-N'-(4-butyl-2-methylphenol)Formamidine (HET0016), which inhibits 20-HETEs formation. Taken together, our findings confer pioneering evidence about a potential interplay between CYP450-derived metabolites and Nox4/TGF-β axis leading to DCM. Pharmacologic interventions targeting the inhibition of 20-HETEs synthesis or the activation of EETs synthesis may offer novel therapeutic approaches to treat DCM., Competing Interests: Declaration of Competing Interest All authors declare that they have no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Patients with diabetes are more vulnerable to the detrimental respiratory effects of combustible cigarette smoke (CS) when compared to the general population. Electronic cigarettes (ECIG) and heated tobacco products (HTP) are marketed as less harmful alternatives to CS. In this study, we compared the effects of acute ECIG, HTP and CS exposure on the lungs of type II diabetes versus non-diabetic mice in an animal model., Methods: Type II Diabetic (Diab) and Non-Diabetic (Non-Diab) mice were divided into Control, ECIG, HTP and CS groups. Animals were exposed for 6 hrs./day to either air, ECIG, HTP or CS for seven days. Lung injury was determined by a) histopathology, b) wet to dry ratio, c) albumin concentration in bronchoalveolar lavage fluid, d) expression of TNF-α, IL-6, and IL-1 β, e) reactive oxygen species production (ROS), and f) assessment of cellular apoptosis., Results: Lung histology revealed increased edema and inflammatory cells in diabetic mice exposed to ECIG, HTP and CS. The expression of Inflammatory mediators was, in general, more significant in the Diabetic groups as well. TNF-α expression, for example, was upregulated in Diab + ECIG but not in Non-Diab + ECIG. ROS was significantly increased in Diab + CS, less in Non-Diab + CS and weakly noted in ECIG + Diab. Significant albumin leak was observed in Diab and Non-Diab HTP-exposed animals. CS exposure worsened lung injury in Diab when compared to Non-Diab mice., Conclusion: Comorbid medical conditions like diabetes may amplify ill effects of CS, ECIG or HTP exposure., Competing Interests: The authors have declared that no competing interests exist.

Objective: To evaluate the feasibility and outcomes of porcine submucosal allograft (Biodesign Sinonasal Repair Graft [Cook Medical, Bloomington, IN]) in oral cavity and oropharynx reconstruction after ablative surgery., Methods: We conducted a prospective and retrospective review of patients who underwent Biodesign Sinonasal Repair Graft reconstruction for oral and oropharyngeal surgical defects at a single institution between 2018 and 2020. A total of 11 patients were included in the study. Data points included their perioperative medical and demographic data, immediate postoperative course, and follow-up visits at 10 days and at 2 months. The clinicopathologic characteristics of their disease, postoperative esthetic, and functional outcomes were recorded and analyzed., Results: Eleven procedures have been performed, and all patients received Biodesign reconstruction either immediately after ablation or after they failed a previous reconstruction. None of the patients had bone exposure. The subsites included oral tongue ( n  = 6), floor of the mouth ( n  = 3), buccal mucosa ( n  = 1), and soft palate ( n  = 1). In all cases, the operations and the postoperative course were uneventful. The mean defect size was 22 cm 2 . The median start of oral intake was at 2 days postoperatively. The Biodesign graft healed well in all patients with no total graft loss. There was one complication that required revision surgery due to obstruction of Wharton's duct by the Biodesign material., Conclusions: Biodesign can be a viable option for small and medium-sized oral and oropharyngeal defects in patients who are medically unfit or do not want to undergo a free flap surgery., Level of Evidence: 4., Competing Interests: None of the authors declare any financial interest in this article. Dr. M. Boyd Gillespie, MSc declares having consulted with Cook Biomedical on sleep surgery devices from September 2017 till February 2020, none since., (© 2021 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC. on behalf of The Triological Society.)

The emergence of immune checkpoint inhibitors in the arsenal of cancer immunotherapy was a breakthrough which provided hope to many cancer patients. However, not long has passed since their discovery that some adverse effects were associated with these promising therapeutic agents. Immune checkpoint inhibitors dysregulate host immunity and may precipitate autoimmune diseases including diabetes mellitus. In this review, we go beyond the case reports towards understanding the underlying mechanisms by which Programmed cell death 1 (PD-1) and Programmed death ligand-1 (PD-L1) inhibitors precipitate diabetes. We discuss the role of PD-1/PD-L1 in autoimmunity and the use of mice models to describe their involvement in diabetes. We also reviewed the genetic anomalies in PD-1/PD-L1genes and their link to diabetes. Finally, we present the studies conducted to identify patients at risk of developing autoimmune diseases as an adverse effect for PD-1/PD-L1 use. Understanding these issues can guide researchers to find a way to circumvent the autoimmune adverse reactions seen with PD-1/PD-L1 inhibitors without affecting their antitumor activity., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Diabetic nephropathy is a major health challenge with considerable economic burden and significant impact on patients' quality of life. Despite recent advances in diabetic patient care, current clinical practice guidelines fall short of halting the progression of diabetic nephropathy to end-stage renal disease. Moreover, prior literature reported manifestations of renal dysfunction in early stages of metabolic impairment prior to the development of hyperglycemia indicating the involvement of alternative pathological mechanisms apart from those typically triggered by high blood glucose. Here, we extend our prior research work implicating localized inflammation in specific adipose depots in initiating cardiovascular dysfunction in early stages of metabolic impairment. Non-obese prediabetic rats showed elevated glomerular filtration rates and mild proteinuria in absence of hyperglycemia, hypertension, and signs of systemic inflammation. Isolated perfused kidneys from these rats showed impaired renovascular endothelial feedback in response to vasopressors and increased flow. While endothelium dependent dilation remained functional, renovascular relaxation in prediabetic rats was not mediated by nitric oxide and prostaglandins as in control tissues, but rather an upregulation of the function of epoxy eicosatrienoic acids was observed. This was coupled with signs of peri-renal adipose tissue (PRAT) inflammation and renal structural damage. A two-week treatment with non-hypoglycemic doses of metformin or pioglitazone, shown previously to ameliorate adipose inflammation, not only reversed PRAT inflammation in prediabetic rats, but also reversed the observed functional, renovascular, and structural renal abnormalities. The present results suggest that peri-renal adipose inflammation triggers renal dysfunction early in the course of metabolic disease., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Immunotherapy is now a recognized treatment option for several types of cancer. However, some cancer patients treated with immune checkpoint inhibitors (ICIs) are subject to immune-related adverse events, including induced diabetes mellitus. The exact role and molecular/genetic action of ICIs in diabetes are still not well understood. Elucidating the underlying mechanisms in a proper fashion would allow better refining of biomarkers that would help diagnose patients at risk of altered immune system homeostasis, but would also hold the potential of new therapeutic options for diabetes. In the present narrative review, we propose to discuss the case of autoimmune diabetes following treatment with ICIs and the role of ICIs in the pathophysiology of diabetes. We also present some scarce available data on interesting potential immune therapies for diabetes.

Immunomodulatory approaches are defined as all interventions that modulate and curb the immune response of the host rather than targeting the disease itself with the aim of disease prevention or treatment. A better understanding of the immune system continues to offer innovative drug targets and methods for immunomodulatory interventions. Cardiorenal syndrome is a clinical condition that defines disorders of the heart and kidneys, both of which communicate with one another through multiple pathways in an interdependent relationship. Cardiorenal syndrome denotes the confluence of heart-kidney relationships across numerous interfaces. As such, a dysfunctional heart or kidney has the capacity to initiate disease in the other organ via common hemodynamic, neurohormonal, immunological, and/or biochemical feedback pathways. Understanding how immunomodulatory approaches are implemented in diabetes-induced cardiovascular and renal diseases is important for a promising regenerative medicine, which is the process of replacing cells, tissues or organs to establish normal function. In this article, after a brief introduction on the immunomodulatory approaches in diseases, we will be reviewing the epidemiology and classifications of cardiorenal syndrome. We will be emphasizing on the hemodynamic factors and non-hemodynamic factors linking the heart and the kidneys. In addition, we will be elaborating on the immunomodulatory pathways involved in diabetes-induced cardiorenal syndrome namely, RAS, JAK/STAT, and oxidative stress. Moreover, we will be addressing possible therapeutic approaches that target the former pathways in an attempt to modulate the immune system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ammar, Nahlawi, Shayya, Ghadieh, Azar, Harb and Eid.)

Oxidative damage by reactive oxygen species (ROS) is one of the main contributors to cell injury and tissue damage in thalassemia patients. Recent studies suggest that ROS generation in non-transfusion-dependent (NTDT) patients occurs as a result of iron overload. Among the different sources of ROS, the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes and cytochrome P450 (CYP450) have been proposed to be major contributors for oxidative stress in several diseases. However, the sources of ROS in patients with NTDT remain poorly understood. In this study, Hbb th3/+ mice, a mouse model for β-thalassemia, were used. These mice exhibit an unchanged or decreased expression of the major NOX isoforms, NOX1, NOX2 and NOX4, when compared to their C57BL/6 control littermates. However, a significant increase in the protein synthesis of CYP4A and CYP4F was observed in the Hbb th3/+ mice when compared to the C57BL/6 control mice. These changes were paralleled by an increased production of 20-hydroxyeicosatetraenoic acid (20-HETE), a CYP4A and CYP4F metabolite. Furthermore, these changes corroborate with onset of ROS production concomitant with liver injury. To our knowledge, this is the first report indicating that CYP450 4A and 4F-induced 20-HETE production mediates reactive oxygen species overgeneration in Hbb th3/+ mice through an NADPH-dependent pathway.