The effects of TNF-α inhibitors on carbon tetrachloride-induced nephrotoxicity.

OBJECTIVES: Carbon tetrachloride (CCl4), employed in various industrial fields, can cause acute damage in renal tissues. This study investigated the therapeutic effect of the TNF-alpha inhibitor Infliximab on TGF-ß and apoptosis caused by acute kidney image induced by CCl4. METHODS: Twenty-four male Sprague-Dawley rats were assigned into control, CCl4, and CCl4+ Infliximab groups. The control group received an isotonic saline solution, and the CCl4 group 2 mL/kg CCl4 intraperitoneally (i.p). The CCl4+ Infliximab group was given 7 mg/kg Infliximab 24 hours after administration of 2 mL/kg CCl4. Kidney tissues were removed at the end of the experiment and subjected to histopathological and biochemical analysis. RESULTS: The application of CCl4 led to tubular necrosis, inflammation, vascular congestion, and increased Serum BUN and creatinine values. An increase in caspase-3 activity also occurred in the CCl4 group. However, Infliximab exhibited an ameliorating effect on kidney injury by causing a decrease in the number of apoptotic cells. Tissue ADA and TGF-ß values of the CCL4 group were significantly higher than the values of the control group (p = .001, p < .001 respectively) and CCL4+ Inf group (p = .004, p = .015, respectively). CONCLUSIONS: This study shows that Infliximab ameliorates nephrotoxicity by reducing lipid peroxidation, oxidative stress, and apoptosis in acute kidney damage developing in association with CCl4 administration. These findings are promising in terms of the ameliorating role of TNF-alpha inhibitors in acute kidney injury.

Proprotein convertase subtilisin/kexin type 9 is associated with atherosclerosis in patients with Behcet's disease.

OBJECTIVES: The incidence of cardiovascular disease is increased in patients with Behcet's disease (BD). Proprotein convertase subtilisin/kexin type 9 (PCSK9) causes the acceleration of atherosclerosis. We aimed to investigate whether there is a relationship between PCSK9 with carotid artery intima-media thickness (cIMT), a marker of subclinical atherosclerosis, and BD disease activity. METHODS: Fifty-eight patients with BD and 58 age-, gender-, and body mass index (BMI)-matched healthy control subjects were included in the study. The disease activity of the patients was estimated. Individuals' cIMT values were measured, and PCSK9 levels were studied. RESULTS: Patients with BD' cIMT (0.51 ± 0.1 vs 0.41 ± 0.1 mm, p < .001) and PCSK9 (623.2 ± 101.7 ± 10.1 vs 528.3 ± 242.7 ng/ml, p = .007), values were significantly higher than the control group. In stepwise regression analysis, there was an independent relationship between cIMT with PCSK9 (ß = 0.179, p < .050). There was no independent relationship between disease activities with PCSK9. Based on the ROC curve analysis, the PCSK9 optimal cutoff value for cIMT was 595.1 ng/ml, sensitivity 66.7%, specificity 64.7% (AUC = 0.672; 95% CI: 0.530-0.815, p = .040). CONCLUSION: There is a strong independent association between subclinical atherosclerosis and PCSK9 in patients with BD. There may be no independent association between PCSK9 and disease activity.

Strong relationship between cholesterol, low-density lipoprotein receptor, Na+/H+ exchanger, and SARS-COV-2: this association may be the cause of death in the patient with COVID-19.

Lipids have a wide variety and vital functions. Lipids play roles in energy metabolism, intracellular and extracellular signal traffic, and transport of fat-soluble vitamins. Also, they form the structure of the cell membrane. SARS-CoV-2 interacts with lipids since its genetic material contains lipid-enveloped ribonucleic acid (RNA). Previous studies have shown that total cholesterol, high-density lipoprotein, and low-density lipoprotein (LDL) levels are lower in patients with severe novel coronavirus disease 2019 (COVID-19) compared to patients with non-severe COVID-19.Na+/H+ Exchanger (NHE) is an important antiport that keeps the intracellular pH value within physiological limits. When the intracellular pH falls, NHE is activated and pumps H+ ions outward. However, prolonged NHE activation causes cell damage and atherosclerosis. Prolonged NHE activation may increase susceptibility to SARS-CoV-2 infection and severity of COVID-19.In COVID-19, increased angiotensin II (Ang II) due to angiotensin-converting enzyme-2 (ACE2) dysfunction stimulates NHE. Lipids are in close association with the NHE pump. Prolonged NHE activity increases the influx of H+ ions and free fatty acid (FFA) inward. Ang II also causes increased low-density lipoprotein receptor (LDLR) levels by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9). Thus, intracellular atheroma plaque formation is accelerated.Besides, SARS-CoV-2 may replicate more rapidly as intracellular cholesterol increases. SARS-CoV-2 swiftly infects the cell whose intracellular pH decreases with NHE activation and FFA movement. Novel treatment regimens based on NHE and lipids should be explored for the treatment of COVID-19.

Biochemical, Histopathological and Immunohistochemical Evaluation of the Protective and Therapeutic Effects of Thymoquinone against Ischemia and Ischemia/Reperfusion Injury in the Rat Ovary.

AIM: To evaluate the antioxidant effects of thymoquinone (TQ) and to investigate the biochemical, histopathological and immunohistochemical changes in experimental rat ovarian torsion. METHODS: A total of 48 female adult rats were used in this study and randomly divided into 7 groups: (1) sham operation; (2) bilateral 3-hour ovarian ischemia; (3) 3-hour ischemia and 3-hour reperfusion; (4) and (5) rats were administered 20 and 40 mg/kg of TQ, respectively, before 0.5 h of ischemia, and then 3 h of ovarian ischemia was applied; (6) and (7) 3-hour ovarian ischemia was applied; 2.5 h after the induction of ischemia, rats were administered the same doses of TQ; at the end of 3 h of ischemia, a 3-hour reperfusion was applied. Histologic changes under light microscopy, immunoreactivity for anticaspase-3 and serum levels of malondialdehyde, interleukin-6, catalase and glutathione peroxidase were noted and compared between the 7 groups. RESULTS: Ischemia and ischemia/reperfusion cause a deterioration of biochemical and histopathological parameters. Administration of TQ seems to reverse these alterations and alleviate the injury. Antioxidant defense mechanisms appear to be enhanced by the administration of TQ. CONCLUSION: TQ at different doses attenuates ovarian ischemia and ischemia/reperfusion injury in rats.

Evaluation of aortic stiffness in Gilbert syndrome patients: a protective effect of elevated bilirubin levels.

OBJECTIVE: Gilbert's syndrome (GS) is an autosomal recessive disease that is characterized by an increase in indirect bilirubin (IB). The incidence of atherosclerotic heart disease is decreased in GS. This study aimed to investigate the relation between pulse wave velocity (PWV) and the presence of GS. METHODS: The study included 58 GS patients (32 females, age; 27.12 ± 7.27 years, 26 males, age; 26.63 ± 5.84 years) admitted to the internal medicine clinic of the hospital. The control group included 58 healthy individuals (35 females [27.33 ± 8.06 years old, p=0.716] and 23 males [27.38 ± 6.91 years old, p=0.923]). PWV of both groups was measured from the right carotid and femoral arteries. RESULTS: Mean age of the GS group was 26.03 ± 8.22 years, while that of the healthy group was 26.60 ± 5.84 years. The GS group's diastolic blood pressure and PWV were significantly lower than those of the control group: 67.76 ± 8.59 mmHg vs 71.72 ± 7.28 mmHg; p=0.008, and 5.63 ± 1.12 m/s vs 6.18 ± 1.22 m/s; p=0.014 respectively. The GS group's high density lipoprotein (HDL) level was significantly higher than that of the control group: 1.4 ± 0.3 mmol/L vs 1.2 ± 0.3 mmol/L, p=0.029. CONCLUSION: This study found PWV among GS patients to be lower than that among non-smoking and aged-matched healthy controls.

Why have SGLT2 Inhibitors Failed to Achieve the Desired Success in COVID-19?

The SARS-CoV-2 virus emerged towards the end of 2019 and caused a major worldwide pandemic lasting at least 2 years, causing a disease called COVID-19. SARS-CoV-2 caused a severe infection with direct cellular toxicity, stimulation of cytokine release, increased oxidative stress, disruption of endothelial structure, and thromboinflammation, as well as angiotensin-converting enzyme 2 (ACE2) down-regulation-mediated renin-angiotensin system (RAS) activation. In addition to glucosuria and natriuresis, sodium-glucose transport protein 2 (SGLT2) inhibitors (SGLT2i) cause weight loss, a decrease in glucose levels with an insulin-independent mechanism, an increase in erythropoietin levels and erythropoiesis, an increase in autophagy and lysosomal degradation, Na+/H+-changer inhibition, prevention of ischemia/reperfusion injury, oxidative stress and they have many positive effects such as reducing inflammation and improving vascular function. There was great anticipation for SGLT2i in treating patients with diabetes with COVID-19, but current data suggest they are not very effective. Moreover, there has been great confusion in the literature about the effects of SGLT2i on COVID-19 patients with diabetes . Various factors, including increased SGLT1 activity, lack of angiotensin receptor blocker co-administration, the potential for ketoacidosis, kidney injury, and disruptions in fluid and electrolyte levels, may have hindered SGLT2i's effectiveness against COVID-19. In addition, the duration of use of SGLT2i and their impact on erythropoiesis, blood viscosity, cholesterol levels, and vitamin D levels may also have played a role in their failure to treat the virus. This article aims to uncover the reasons for the confusion in the literature and to unravel why SGLT2i failed to succeed in COVID-19 based on some solid evidence as well as speculative and personal perspectives.

Severe acute respiratory syndrome coronavirus 2 may cause liver injury via Na+/H+ exchanger.

The liver has many significant functions, such as detoxification, the urea cycle, gluconeogenesis, and protein synthesis. Systemic diseases, hypoxia, infections, drugs, and toxins can easily affect the liver, which is extremely sensitive to injury. Systemic infection of severe acute respiratory syndrome coronavirus 2 can cause liver damage. The primary regulator of intracellular pH in the liver is the Na+/H+ exchanger (NHE). Physiologically, NHE protects hepatocytes from apoptosis by making the intracellular pH alkaline. Severe acute respiratory syndrome coronavirus 2 increases local angiotensin II levels by binding to angiotensin-converting enzyme 2. In severe cases of coronavirus disease 2019, high angi-otensin II levels may cause NHE overstimulation and lipid accumulation in the liver. NHE overstimulation can lead to hepatocyte death. NHE overstimulation may trigger a cytokine storm by increasing proinflammatory cytokines in the liver. Since the release of proinflammatory cytokines such as interleukin-6 increases with NHE activation, the virus may indirectly cause an increase in fibrinogen and D-dimer levels. NHE overstimulation may cause thrombotic events and systemic damage by increasing fibrinogen levels and cytokine release. Also, NHE overstimulation causes an increase in the urea cycle while inhibiting vitamin D synthesis and gluconeogenesis in the liver. Increasing NHE3 activity leads to Na+ loading, which impairs the containment and fluidity of bile acid. NHE overstimulation can change the gut microbiota composition by disrupting the structure and fluidity of bile acid, thus triggering systemic damage. Unlike other tissues, tumor necrosis factor-alpha and angiotensin II decrease NHE3 activity in the intestine. Thus, increased luminal Na+ leads to diarrhea and cytokine release. Severe acute respiratory syndrome coronavirus 2-induced local and systemic damage can be improved by preventing virus-induced NHE overstimulation in the liver.

Relationship Between Serum Endocan Levels and Other Predictors of Endothelial Dysfunction in Obese Women.

Endocan, or endothelial cell-specific molecule-1 (ESM-1), is a potential inflammatory marker implicated in endothelial dysfunction. The purpose of this study was to determine the correlation between serum endocan levels and the presence and severity of endothelial dysfunction, and the relationships with serum intracellular adhesion molecule-1 (ICAM-1), adiponectin (a marker of inflammation), high sensitivity C-reactive protein (hsCRP) levels, and carotid intima-media thickness (cIMT) in obese subjects. Serum endocan, ICAM-1, adiponectin, hsCRP levels, and cIMT were evaluated in 76 obese women (BMI > 30 kg/m2) and 53 controls (BMI < 25 kg/m2). ICAM-1 (P = .01), hs-CRP (p < 0.001), and cIMT (p < .001) were significantly higher, while adiponectin (P = .006) was significantly lower, in obese women compared with the controls. Serum endocan levels were similar between the obese (470.5 ± 171.3 pg/mL) and controls (471.9 ± 146.3 pg/mL) (P = .732). There was no correlation between serum endocan values and the endothelial dysfunction markers, hsCRP (r = -.021), ICAM-1 (r = -.054), adiponectin (r = .113), or cIMT (r = -.060) in obesity. Endocan is not a suitable marker of endothelial dysfunction in the context of obesity. More research is required to evaluate the role of endocan in the regulation of inflammatory processes in obesity.

Effects of the Na+/H+ Ion Exchanger on Susceptibility to COVID-19 and the Course of the Disease.

The Na+/H+ ion exchanger (NHE) pumps Na+ inward the cell and H+ ion outside the cell. NHE activity increases in response to a decrease in intracellular pH, and it maintains intracellular pH in a narrow range. Patients with obesity, diabetes, and hypertension and the elderly are prone to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. The angiotensin II (Ang II) level is high in chronic diseases such as diabetes, hypertension, and obesity. Ang II is the main stimulator of NHE, and an increased Ang II level causes prolonged NHE activation in these patients. The long-term increase in NHE activity causes H+ ions to leave the cell in patients with diabetes, hypertension, and obesity. Increasing H+ ions outside the cell lead to an increase in oxidative stress and reactive oxygen species. H+ ion flows into the cell due to the increased oxidative stress. This vicious circle causes intracellular pH to drop. Although NHE is activated when intracellular pH decreases, there is prolonged NHE activation in chronic diseases such as aforementioned. Novel coronavirus disease 2019 (COVID-19) progression may be more severe and mortal in these patients. SARS-CoV-2 readily invades the cell at low intracellular pH and causes infection. The renin-angiotensin system and NHE play a vital role in regulating intracellular pH. The reduction of NHE activity or its prolonged activation may cause susceptibility to SARS-CoV-2 infection by lowering intracellular pH in patients with diabetes, hypertension, and obesity. Prolonged NHE activation in these patients with COVID-19 may worsen the course of the disease. Scientists continue to investigate the mechanism of the disease and the factors that affect its clinical progression.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be harmful in patients with diabetes during COVID-19 pandemic.

The novel coronavirus disease 2019 (COVID-19) outbreak once again demonstrated the importance of the renin-angiotensin system (RAS) in patients with diabetes. Activation of the RAS increases in patients with diabetes. The virus attaches to the ACE2 enzyme at low cytosolic pH values and enters into the cell and causes infection. Especially in the presence of diabetes mellitus and accompanying comorbid conditions such as hypertension, obesity, old age, and smoking, cytosolic pH is low, thus the virus easily may enter the cell by attaching to ACE2. ACEIs and ARBs lead to a reduction in angiotensin II level by increasing the ACE2 level, thus they cause a low cytosolic pH. Increased cardiac ACE2 levels due to ACEIs and ARBs can trigger cardiac arrhythmias and myocarditis by causing the virus to easily enter the heart tissue. There is ACE2 activity in the rostral ventrolateral medulla in the brain stem. The release of angiotensin 1-7 in the brain stem leads to the activation of the sympathetic nervous system. This activation causes systemic vasoconstriction and the patient's blood pressure increases. The most important event is the increased sympathetic activity via the central stimulation, this activity increases pulmonary capillary leaking, causing the ARDS. As the cytosolic pH, which is already low in patients with diabetes will decrease further with the mechanisms mentioned above, the viral load will increase and the infection will be exacerbated. As a result, the use of ACEIs and ARBs in patients with diabetes can lead to increased morbidity and mortality of COVID-19.

Can dapagliflozin have a protective effect against COVID-19 infection? A hypothesis.

It has been reported that frequent occurrence of COVID-19 infection in these patients is associated with low cytosolic pH. During virus infection, serum lactate dehydrogenase (LDH) level excessively rises. LDH is a cytosolic enzyme and the serum level increases as the cell break down. When anaerobic conditions develop, lactate formation increases from pyruvate. Cell pH is regulated by very complex mechanisms. When lactate increases in the extracellular area, this symporter carries lactate and H+ ion into the cell, and the intracellular pH quickly becomes acidic. Paradoxically, Na+/H+ exchanger activation takes place. While H+ ion is thrown out of the cell, Na+ and Ca+2 enter the cell. When Na+ and Ca+2 increase in the cell, the cells swell and die. Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor. Dapagliflozin has been reported to reduce lactate levels by various mechanisms. Also, it reduces oxygen consumption in tissues and causes the use of glucose in the aerobic pathway, thereby reducing lactate production. A lactate decrease in the environment reduces the activation of lactate/H+ symporter. Thus, the H ion pumping into the cell by this symporter is reduced and the cytosolic pH is maintained. Dapagliflozin also directly inhibits NHE. Thus, Na+ and Ca+2 flow to the cell are inhibited. Dapagliflozin provides the continuation of the structure and functions of the cells. Dapagliflozin can prevent the severe course of COVID-19 infection by preventing the lowering of cytosolic pH and reducing the viral load.