SARS-CoV-2 infection and diabetes: Pathophysiological mechanism of multi-system organ failure

Since the discovery of the coronavirus disease 2019 outbreak, a vast majority of studies have been carried out that confirmed the worst outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in people with preexisting health conditions, including diabetes, obesity, hypertension, cancer, and cardiovascular diseases. Likewise, diabetes itself is one of the leading causes of global public health concerns that impose a heavy global burden on public health as well as socio-economic development. Both diabetes and SARS-CoV-2 infection have their independent ability to induce the pathogenesis and severity of multi-system organ failure, while the co-existence of these two culprits can accelerate the rate of disease progression and magnify the severity of the disease. However, the exact pathophysiology of multi-system organ failure in diabetic patients after SARS-CoV-2 infection is still obscure. This review summarized the organ-specific possible molecular mechanisms of SARS-CoV-2 and diabetes-induced pathophysiology of several diseases of multiple organs, including the lungs, heart, kidneys, brain, eyes, gastrointestinal system, and bones, and sub-sequent manifestation of multi-system organ failure

Tissue-specific role and associated downstream signaling pathways of adiponectin

According to the World Health Organization, metabolic syndrome (MetS) can be defined as a pathological condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. The incidence of MetS keeps rising, as at least 35% of the USA population suffers from MetS. One of the worst comorbidities of metabolic syndrome are cardiovascular diseases that significantly amplifies the mortality associated with this syndrome. There is an urgent need to understand the pathophysiology of MetS to find novel diagnosis, treatment and management to mitigate the MetS and associated complications. Altered circulatory adiponectin levels have been implicated in MetS. Adiponectin has numerous biologic functions including antioxidative, anti-nitrative, anti-inflammatory, and cardioprotective effects. Being a pleiotropic hormone of multiple tissues, tissue-specific key signaling pathways of adiponectin will help finding specific target/s to blunt the pathophysiology of metabolic syndrome and associated disorders. The purpose of this review is to elucidate tissue-specific signaling pathways of adiponectin and possibly identify potential therapeutic targets for MetS as well as to evaluate the potential of adiponectin as a biomarker/therapeutic option in MetS

Diabetic Aldehyde Dehydrogenase 2 Mutant (ALDH2*2) Mice Are More Susceptible to Cardiac Ischemic-Reperfusion Injury Due to 4-Hydroxy-2-Nonenal Induced Coronary Endothelial Cell Damage

Background: Aldehyde dehydrogenase-2 (ALDH2), a mitochondrial enzyme, detoxifies reactive aldehydes such as 4-hydroxy-2-nonenal (4HNE). A highly prevalent E487K mutation in ALDH2 (ALDH2*2) in East Asian people with intrinsic low ALDH2 activity is implicated in diabetic complications. 4HNE-induced cardiomyocyte dysfunction was studied in diabetic cardiac damage; however, coronary endothelial cell (CEC) injury in myocardial ischemia-reperfusion injury (IRI) in diabetic mice has not been studied. Therefore, we hypothesize that the lack of ALDH2 activity exacerbates 4HNE-induced CEC dysfunction which leads to cardiac damage in ALDH2*2 mutant diabetic mice subjected to myocardial IRI. Methods and Results: Three weeks after diabetes mellitus (DM) induction, hearts were subjected to IRI either in vivo via left anterior descending artery occlusion and release or ex vivo IRI by using the Langendorff system. The cardiac performance was assessed by conscious echocardiography in mice or by inserting a balloon catheter in the left ventricle in the ex vivo model. Just 3 weeks of DM led to an increase in cardiac 4HNE protein adducts and, cardiac dysfunction, and a decrease in the number of CECs along with reduced myocardial ALDH2 activity in ALDH2*2 mutant diabetic mice compared with their wild-type counterparts. Systemic pretreatment with Alda-1 (10 mg/kg per day), an activator of both ALDH2 and ALDH2*2, led to a reduction in myocardial infarct size and dysfunction, and coronary perfusion pressure upon cardiac IRI by increasing CEC population and coronary arteriole opening. Conclusions: Low ALDH2 activity exacerbates 4HNE-mediated CEC injury and thereby cardiac dysfunction in diabetic mouse hearts subjected to IRI, which can be reversed by ALDH2 activation

Critical role of SIK3 in mediating high salt and IL-17 synergy leading to breast cancer cell proliferation

Chronic inflammation is a well-known precursor for cancer development and proliferation. We have recently demonstrated that high salt (NaCl) synergizes with sub-effective interleukin (IL)-17 to induce breast cancer cell proliferation. However, the exact molecular mechanisms mediating this effect are unclear. In our current study, we adopted a phosphoproteomic-based approach to identify salt modulated kinase-proteome specific molecular targets. The phosphoprotemics based binary comparison between heavy labelled MCF-7 cells treated with high salt (Δ0.05 M NaCl) and light labelled MCF-7 cells cultured under basal conditions demonstrated an enhanced phosphorylation of Serine-493 of SIK3 protein. The mRNA transcript and protein expression analysis of SIK3 in MCF-7 cells demonstrated a synergistic enhancement following co-treatment with high salt and sub-effective IL-17 (0.1 ng/mL), as compared to either treatments alone. A similar increase in SIK3 expression was observed in other breast cancer cell lines, MDA-MB-231, BT20, and AU565, while non-malignant breast epithelial cell line, MCF10A, did not induce SIK3 expression under similar conditions. Biochemical studies revealed mTORC2 acted as upstream mediator of SIK3 phosphorylation. Importantly, cell cycle analysis by flow cytometry demonstrated SIK3 induced G0/G1-phase release mediated cell proliferation, while SIK3 silencing abolished this effect. Also, SIK3 induced pro-inflammatory arginine metabolism, as evidenced by upregulation of the enzymes iNOS and ASS-1, along with downregulation of anti-inflammatory enzymes, arginase-1 and ornithine decarboxylase. Furthermore, gelatin zymography analysis has demonstrated that SIK3 induced expression of tumor metastatic CXCR4 through MMP-9 activation. Taken together, our data suggests a critical role of SIK3 in mediating three important hallmarks of cancer namely, cell proliferation, inflammation and metastasis. These studies provide a mechanistic basis for the future utilization of SIK3 as a key drug discovery target to improve breast cancer therapy

Exposure to the Dioxin-like Pollutant PCB 126 Afflicts Coronary Endothelial Cells via Increasing 4-Hydroxy-2 Nonenal: A Role for Aldehyde Dehydrogenase 2

Exposure to environmental pollutants, including dioxin-like polychlorinated biphenyls (PCBs), play an important role in vascular inflammation and cardiometabolic diseases (CMDs) by inducing oxidative stress. Earlier, we demonstrated that oxidative stress-mediated lipid peroxidation derived 4-hydroxy-2-nonenal (4HNE) contributes to CMDs by decreasing the angiogenesis of coronary endothelial cells (CECs). By detoxifying 4HNE, aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme, enhances CEC angiogenesis. Therefore, we hypothesize that ALDH2 activation attenuates a PCB 126-mediated 4HNE-induced decrease in CEC angiogenesis. To test our hypothesis, we treated cultured mouse CECs with 4.4 µM PCB 126 and performed spheroid and aortic ring sprouting assays, the ALDH2 activity assay, and Western blotting for the 4HNE adduct levels and real-time qPCR to determine the expression levels of Cyp1b1 and oxidative stress-related genes. PCB 126 increased the gene expression and 4HNE adduct levels, whereas it decreased the ALDH2 activity and angiogenesis significantly in MCECs. However, pretreatment with 2.5 µM disulfiram (DSF), an ALDH2 inhibitor, or 10 µM Alda 1, an ALDH2 activator, before the PCB 126 challenge exacerbated and rescued the PCB 126-mediated decrease in coronary angiogenesis by modulating the 4HNE adduct levels respectively. Finally, we conclude that ALDH2 can be a therapeutic target to alleviate environmental pollutant-induced CMDs

Exposure to the Dioxin-like Pollutant PCB 126 Afflicts Coronary Endothelial Cells via Increasing 4-Hydroxy-2 Nonenal: A Role for Aldehyde Dehydrogenase 2

Exposure to environmental pollutants, including dioxin-like polychlorinated biphenyls (PCBs), play an important role in vascular inflammation and cardiometabolic diseases (CMDs) by inducing oxidative stress. Earlier, we demonstrated that oxidative stress-mediated lipid peroxidation derived 4-hydroxy-2-nonenal (4HNE) contributes to CMDs by decreasing the angiogenesis of coronary endothelial cells (CECs). By detoxifying 4HNE, aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme, enhances CEC angiogenesis. Therefore, we hypothesize that ALDH2 activation attenuates a PCB 126-mediated 4HNE-induced decrease in CEC angiogenesis. To test our hypothesis, we treated cultured mouse CECs with 4.4 µM PCB 126 and performed spheroid and aortic ring sprouting assays, the ALDH2 activity assay, and Western blotting for the 4HNE adduct levels and real-time qPCR to determine the expression levels of Cyp1b1 and oxidative stress-related genes. PCB 126 increased the gene expression and 4HNE adduct levels, whereas it decreased the ALDH2 activity and angiogenesis significantly in MCECs. However, pretreatment with 2.5 µM disulfiram (DSF), an ALDH2 inhibitor, or 10 µM Alda 1, an ALDH2 activator, before the PCB 126 challenge exacerbated and rescued the PCB 126-mediated decrease in coronary angiogenesis by modulating the 4HNE adduct levels respectively. Finally, we conclude that ALDH2 can be a therapeutic target to alleviate environmental pollutant-induced CMDs

Expression of the 5-HT2C receptor in chicken

Serotonin 2C (5-HT2C) receptors are G protein-coupled receptors which are expressed on GABAergic, glutamatergic, and dopaminergic neurons. 5-HT2C receptors have been identified as important regulators of obesity in humans and animals. It is well known that 5-HT2C receptor expression levels are inversely proportional to the obesity of any individual. To date, no research has examined the expression levels of the 5-HT2C receptor on birds with high fat content. The aim of our current research is to evaluate the expression levels of the 5-HT2C receptor in broiler chickens when fed a low fat versus high fat diet. Materials and methods: In order to perform the experiment, we raised a total of 200 birds (100 males and 100 females) with two main groups: birds fed a high fat diet (HFD) (10 replications for a total of 100 birds) and birds fed a low fat diet (LFD) (100 birds with 10 replications). Birds in the HFD and LFD groups will be fed high energy ratios containing 11.65% fat and low energy ratios containing 5.62% fat respectively. The brains of the birds were collected every two weeks until eight weeks of age (WOA). The 5-HT2C receptor mRNA expression in the hypothalamus of chicken brains were identified by RT-qPCR reactions based on threshold cycle (Ct) values of the samples. Results: The expression of hypothalamic 5-HT2C receptor mRNA was higher in the LFD group of birds compared to the HFD group of birds with significant differences at 6 and 8 WOA. However, there were no significant differences in 5-HT2C receptor mRNA expression levels between male and female birds in either of the diet groups of birds. Conclusion: Both diet and age have significant effects on the expression of hypothalamic 5-HT2C receptor in birds. The LFD increases the expression levels of hypothalamic 5-HT2C receptor after 4 weeks of continuous feeding. On the contrary, HFD gradually decreases the expression levels of hypothalamic 5-HT2C receptor mRNA from two to six WOA

Aldehyde dehydrogenase 2 inhibition potentiates 4-hydroxy-2-nonenal induced decrease in angiogenesis of coronary endothelial cells

Coronary endothelial cell (EC) dysfunction including defective angiogenesis is reported in cardiac diseases. 4-Hydroxynonenal (4HNE) is a lipid peroxidation product, which is increased in cardiac diseases and implicated in cellular toxicity. Aldehyde dehydrogenase (ALDH) 2 is a mitochondrial enzyme that metabolizes 4HNE and reduces 4HNE-mediated cytotoxicity. Thus, we hypothesize that ALDH2 inhibition potentiates 4HNE-mediated decrease in coronary EC angiogenesis in vitro. To test our hypothesis, first, we treated the cultured mouse coronary EC (MCEC) lines with 4HNE (25, 50, and 75 μM) for 2 and 4 hours. Next, we pharmacologically inhibited ALDH2 by disulfiram (DSF) (2.5 μM) before challenging the cells with 4HNE. In this study, we found that 4HNE attenuated tube formation which indicates decreased angiogenesis. Next, we found that 4HNE has significantly downregulated the expressions of vascular endothelial growth factor receptor (VEGFR) 2 (P \u3c .05 for mRNA and P = .005 for protein), Sirtuin 1 (SIRT 1) (P \u3c 0.0005 for mRNA), and Ets-related gene (ERG) (P \u3c 0.0001 for mRNA and P \u3c 0.005 for protein) in MCECs compared with control. ALDH 2 inhibition by DSF potentiated 4HNE-induced decrease in angiogenesis (P \u3c 0.05 vs 4HNE at 2 h and P \u3c 0.0005 vs 4HNE at 4 h) by decreasing the expressions of VEGFR2 (P \u3c 0.005 for both mRNA and protein), SIRT 1 (P \u3c 0.05), and ERG (P \u3c 0.005) relative to 4HNE alone. Thus, we conclude that ALDH2 acts as a proangiogenic signaling molecule by alleviating the antiangiogenic effects of 4HNE in MCECs

A role for aldehyde dehydrogenase (ALDH) 2 in angiotensin II-mediated decrease in angiogenesis of coronary endothelial cells

Diabetes-induced coronary endothelial cell (CEC) dysfunction contributes to diabetic heart diseases. Angiotensin II (Ang II), a vasoactive hormone, is upregulated in diabetes, and is reported to increase oxidative stress in CECs. 4-hydroxy-2-nonenal (4HNE), a key lipid peroxidation product, causes cellular dysfunction by forming adducts with proteins. By detoxifying 4HNE, aldehyde dehydrogenase (ALDH) 2 reduces 4HNE mediated proteotoxicity and confers cytoprotection. Thus, we hypothesize that ALDH2 improves Ang II-mediated defective CEC angiogenesis by decreasing 4HNE-mediated cytotoxicity. To test our hypothesis, we treated the cultured mouse CECs (MCECs) with Ang II (0.1, 1 and 10 μM) for 2, 4 and 6 h. Next, we treated MCECs with Alda-1 (10 μM), an ALDH2 activator or disulfiram (2.5 μM)/ALDH2 siRNA (1.25 nM), the ALDH2 inhibitors, or blockers of angiotensin II type-1 and 2 receptors i.e. Losartan and PD0123319 respectively before challenging MCECs with 10 μM Ang II. We found that 10 μM Ang II decreased tube formation in MCECs with in vitro angiogenesis assay (P \u3c .0005 vs control). 10 μM Ang II downregulated the levels of vascular endothelial growth factor receptor 1 (VEGFR1) (p \u3c .005 for mRNA and P \u3c .05 for protein) and VEGFR2 (p \u3c .05 for mRNA and P \u3c .005 for protein) as well as upregulated the levels of angiotensin II type-2 receptor (AT2R) (p \u3c .05 for mRNA and P \u3c .005 for protein) and 4HNE-adducts (P \u3c .05 for protein) in cultured MCECs, compared to controls. ALDH2 inhibition with disulfiram/ALDH2 siRNA exacerbated 10 μM Ang II-induced decrease in coronary angiogenesis (P \u3c .005) by decreasing the levels of VEGFR1 (P \u3c .005 for mRNA and P \u3c .05 for protein) and VEGFR2 (P \u3c .05 for both mRNA and protein) and increasing the levels of AT2R (P \u3c .05 for both mRNA and protein) and 4HNE-adducts (P \u3c .05 for protein) relative to Ang II alone. AT2R inhibition per se improved angiogenesis in MCECs. Additionally, enhancing ALDH2 activity with Alda 1 rescued Ang II-induced decrease in angiogenesis by increasing the levels of VEGFR1, VEGFR2 and decreasing the levels of AT2R. In summary, ALDH2 can be an important target in reducing 4HNE-induced proteotoxicity and improving angiogenesis in MCECs. Finally, we conclude ALDH2 activation can be a therapeutic strategy to improve coronary angiogenesis to ameliorate cardiometabolic diseases

4-hydroxy-2-nonenal decreases coronary endothelial cell migration: Potentiation by aldehyde dehydrogenase 2 inhibition

4-hydroxynonenal (4HNE) is a reactive aldehyde, which is involved in oxidative stress associated pathogenesis. The cellular toxicity of 4HNE is mitigated by aldehyde dehydrogenase (ALDH) 2. Thus, we hypothesize that ALDH2 inhibition exacerbates 4HNE-induced decrease in coronary endothelial cell (EC) migration in vitro. To test our hypothesis, we pharmacologically inhibited ALDH2 in cultured mouse coronary ECs (MCECs) by disulfiram (DSF) (2.5 μM) before challenging the cells with different doses of 4HNE (25, 50 and 75 μM) for 4, 12, 16 and 24 h. We evaluated MCEC migration by scratch wound migration assay. 4HNE attenuated MCEC migration significantly relative to control (P \u3c .05), which was exacerbated with DSF pretreatment (P \u3c .05). DSF pretreatment exacerbated 4HNE-induced decrease in ALDH2 activity in MCECs. Next, we showed that 75 μM 4HNE significantly decreased the intracellular mRNA levels of vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), focal adhesion kinase (FAK) and other promigratory genes compared to control, which were further decreased by DSF pretreatment. 75 μM 4HNE also decreased the protein levels of VEGFR2, FAK, phospho-FAK, Src and paxillin in MCECs. Thus, we conclude that ALDH2 inhibition potentiates 4HNE-induced decrease in MCECs migration in vitro