Manganese-Induced Nephrotoxicity Is Mediated through Oxidative Stress and Mitochondrial Impairment

Manganese (Mn) is an essential element that is incorporated in various metabolic pathways and enzyme structures. On the other hand, a range of adverse effects has been described in association with Mn overexposure. Mn is a well-known neurotoxic agent in mammals. Renal injury is another adverse effect associated with Mn intoxication. No precise mechanism for Mn nephrotoxicity has been identified so far. The current study was designed to evaluate the potential mechanisms of Mn-induced renal injury. Rats were treated with Mn (20 and 40 mg/mL, respectively, in drinking water) for 30 consecutive days. Markers of oxidative stress, as well as several mitochondrial indices, were assessed in the kidney tissue. Renal injury was evident in Mn-treated animals, as judged by a significant increase in serum BUN and creatinine. Moreover, urinalysis revealed a significant increase in urine glucose, phosphate, and protein in Mn-treated rats. Kidney histopathological alterations, including tubular atrophy, interstitial inflammation, and necrosis, were also detected in Mn-treated animals. Biomarkers of oxidative stress, including an increment in reactive oxygen species (ROS), lipid peroxidation, and oxidized glutathione (GSSG), were detected in Mn-treated groups. On the other hand, kidney glutathione (GSH) stores and total antioxidant capacity were depleted in Mn groups. Mn exposure was associated with significant mitochondrial depolarization, decreased mitochondrial dehydrogenases activity, mitochondrial permeabilization, and depletion of adenosine triphosphate (ATP) content. These data highlight oxidative stress and mitochondrial impairment as potential mechanisms involved in Mn-induced renal injury

Amino Acid-Containing Krebs-Henseleit Buffer Protects Rat Liver in a Long-Term Organ Perfusion Model

Background: The liver is vulnerable to the toxicity induced by xenobiotics. On the other hand, it has been found that several endogenously-found amino acids have hepatoprotective properties. The current study was designed to evaluate the effect of taurine, glycine, and histidine on the liver function in an ex vivo model of prolonged organ perfusion. Methods: Rat liver was isolated and perfused with a hemoglobin- and albumin-free Krebs-Henseleit buffer (KBH). Liver injury biomarkers were monitored at scheduled time intervals. Results: The perfusate level of lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and the potassium ion (K+) were gradually increased in control (Only KBH) group. The histopathological evaluation also revealed significant necrosis, sinusoidal dilation, and pyknosis in control liver. Moreover, significant increase in lipid peroxidation and depletion of hepatic glutathione stores were detected in the control group. It was found that taurine (5, 10 and 20 mM) and glycine (5, 10 and 20 mM)-containing KBH buffer significantly decreased the perfusate level of liver injury biomarkers. Furthermore, lower liver tissue pathological changes, decreased lipid peroxidation, and higher glutathione content was detected in amino acid-treated groups. Histidine administration showed no significant protective effect on liver injury in the current study. On the other hand, combination amino acid administration (glycine and taurine) showed a better hepatoprotective profile. Conclusion: The data obtained from the current study might help to provide safe hepatoprotective agents against xenobiotics-induced hepatotoxicity or preserve liver functionality outside the body

Boldine Supplementation Regulates Mitochondrial Function and Oxidative Stress in a Rat Model of Hepatotoxicity

Background: The xenobiotics-induced liver injury is a clinical complication. Hence, finding new hepatoprotective strategies has clinical value. Oxidative stress and its subsequent complications are major mechanisms involved in xenobiotics-induced hepatotoxicity. Boldine is one of the most potent antioxidant molecules widely investigated for its protective properties in different experimental models. In the current study, the hepatoprotective properties of boldine and its potential mechanisms of hepatoprotection have been investigated. Methods: Rats received thioacetamide (TAA; 200 mg/kg, i.p) as a model of acute liver injury. Boldine (5, 10, 1nd 20 mg/kg; 24 hours intervals; oral) was administered as the hepatoprotective agent. Results: Liver injury was evident in TAA-treated animals (48 hours after TAA exposure) as a severe increase in serum level of liver injury biomarkers and histopathological alterations. Moreover, markers of oxidative stress were increased in liver tissue of TAA-treated rats. Assessment of mitochondrial indices of functionality revealed a significant decrease in mitochondrial dehydrogenases activity, the collapse of mitochondrial membrane potential, mitochondrial swelling and depletion of ATP content. It was found that boldine supplementation mitigated liver tissue markers of oxidative stress and improved mitochondrial indices of functionality in TAA-treated animals. Conclusion: The hepatoprotective properties of boldine might primarily rely on antioxidant and mitochondria protecting effects of this alkaloid

Pandemic COVID-19 and Endemic Neglected Tropical Diseases: Friends or Foes?

The COVID-19 pandemic, caused by the SARS-CoV-2, is the most serious global health calamity since the 2 nd World War. The COVID-19 pandemic threatens public health systems worldwide, both in developed and developing countries. In the present report we discuss various effects of the pandemic on the status of neglected tropical diseases (NTDs). COVID-19 will be a public health issue for an extended period. COVID-19 presented several challenges and opportunities for NTD prevention and control. Significant alterations include impact of the pandemic on preventive/control measures and poverty-related plans, service failures and injury to health workers, delayed treatment of NTDs, health service funding, and worsening poverty in marginalized societies. Additionally, the COVID-19 pandemic necessitated school and university closures on public education and research institutes. Furthermore, the COVID-19 pandemic has also provided opportunities, such as improving health literacy, changing approaches to NTD treatments, restructuring the health system and emergency responses, and enhancing science communication

Sildenafil Blunts Lung Inflammation and Oxidative Stress in a Rat Model of Cholestasis

Background: Cholestasis is a multifaceted disease that influences not only the function of the liver but also affects many other organs. In this context, cholestasis-induced lung injury is a significant clinical complication. Unfortunately, there is no precise therapeutic option against cholestasis-associated lung injury. It has been revealed that oxidative stress and inflammatory response play a role in cholestasis-induced pulmonary damage. Sildenafil is a phosphodiesterase enzyme inhibitor used in the management of erectile dysfunction. Meanwhile, several experiments revealed the effects of sildenafil on oxidative stress and inflammation. This study aimed to evaluate the effect of sildenafil on cholestasis-induced oxidative stress and inflammation in cholestasis-induced lung injury. Methods: Rats underwent bile duct ligation (BDL) to induce cholestasis. Bronchoalveolar lavage fluid (BALF) levels of inflammatory cells, cytokine, and immunoglobulin were monitored at (3, 7, and 14 days after BDL surgery). Moreover, lung tissue histopathological alterations and biomarkers of oxidative stress were evaluated. Results: A significant increase in BALF inflammatory cells, TNF-α, and immunoglobulin G (IgG) was evident in BDL animals. Moreover, the infiltration of inflammatory cells, vascular congestion, and hemorrhage were detected in the lung of BDL rats. Increased markers of oxidative stress were also evident in the lung of BDL animals. Sildenafil (10 and 20 mg/kg) significantly blunted inflammatory response, oxidative stress, and histopathological alterations in the lung of cholestatic animals. Conclusion: The effects of sildenafil on inflammatory response and oxidative stress biomarkers seems to play a crucial role in its protective properties in the lung of cholestatic animals

The Hepatoprotection Provided by Taurine and Glycine against Antineoplastic Drugs Induced Liver Injury in an Ex Vivo Model of Normothermic Recirculating Isolated Perfused Rat Liver

Taurine (2-aminoethane sulfonic acid) is a non-protein amino acid found in high concentration in different tissues. Glycine (Amino acetic acid) is the simplest amino acid incorporated in the structure of proteins. Several investigations indicate the hepatoprotective properties of these amino acids. On the other hand, antineoplastic agents-induced serum transaminase elevation and liver injury is a clinical complication. The current investigation was designed to screen the possible hepatoprotective properties of taurine and glycine against antineoplastic drugs-induced hepatic injury in an ex vivo model of isolated perfused rat liver. Rat liver was perfused with different concentration (10 µM, 100 µM and 1000 µM) of antineoplastic drugs (Mitoxantrone, Cyclophosphamide, Cisplatin, 5‑Fluorouracil, Doxorubicin and Dacarbazine) via portal vein. Taurine and glycine were administered to drug-treated livers and liver perfusate samples were collected for biochemical measurements (ALT, LDH, AST, and K+). Markers of oxidative stress (reactive oxygen species formation, lipid peroxidation, total antioxidant capacity and glutathione) were also assessed in liver tissue. Antineoplastic drugs caused significant pathological changes in perfusate biochemistry. Furthermore, markers of oxidative stress were significantly elevated in drug‑treated livers. It was found that taurine (5 and 10 mM) and glycine (5 and 10 mM) administration significantly mitigated the biomarkers of liver injury and attenuated drug‑induced oxidative stress. Our data indicate that taurine and glycine supplementation might help as potential therapeutic options to encounter anticancer drugs-induced liver injury.</p

Dexamethasone Blunts Lung Inflammation in Cholestatic Mice

Cholestasis/cirrhosis is a multifaceted clinical complication that influences many organs, including the liver, kidney, heart, skeletal muscle, and lung. Cirrhosis-associated lung injury could lead to severe and lethal consequences, including acute respiratory syndrome and patient dearth. Unfortunately, there is no specific pharmacological intervention to manage cholestasis-induced lung injury. It has been revealed that severe inflammation and its associated complications, such as oxidative stress, are involved in the pathogenesis of cholestasis-associated pulmonary damage. The current study was designed to evaluate the role of dexamethasone (DXM) on lung inflammation in cholestatic mice. For this purpose, bile duct ligated (BDL) mice received DXM (1 and 2.5 mg/kg, i.p, 2 times/week) for 14 days. On day 15, the bronchoalveolar lavage fluid (BALF) was prepared. Several markers, including inflammatory cell infiltration, TNF-α, and IgG, were assessed in the BALF of BDL animals. Significant infiltration of inflammatory cells along with increased TNF-α and IgG were detected in the BALF of BDL mice (14 days after surgery). Moreover, significant ROS formation, glutathione depletion, lipid peroxidation, and protein carbonylation were evident in the lung tissue of the BDL group. It was found that DXM (1 and 2.5 mg/kg) significantly blunted inflammation and oxidative stress in the lung of cholestatic mice. Moreover, lung tissue histopathological changes, including inflammatory cell infiltration, were significantly mitigated in DXM-treated mice. These data offer the potential therapeutic effects of DXM against cholestasis-related complications. Therefore, patients with cholestasis-induced lung injury might benefit from repurposing DXM in clinical settings

Thiol-reducing agents abate cholestasis-induced lung inflammation, oxidative stress, and histopathological alterations

Cholestasis is not only influences the hepatic function but also damages many other organs. Lung injury is a critical secondary organ damage associated with cholestasis/cirrhosis. Pulmonary histopathological alterations, respiratory distress, and hypoxia are related to cholestasis/cirrhosis-induced lung injury. It has been found that oxidative stress plays a crucial role in this complication. The current study was designed to investigate the effect of N-acetyl cysteine (NAC) and dithiothreitol (DTT) as thiol-reducing and antioxidant agents against cholestasis-induced lung injury. Bile duct ligated (BDL) rats were monitored for the presence of inflammatory cells, TNF-α, and IgG levels in their broncho-alveolar fluid (BALF) at scheduled time intervals (3, 7, 14, and 28 days post-BDL surgery). These markers reached their highest level in the BALF of BDL rats on day 28 after the surgery. Therefore, in another set of experiments, the BDL animals were treated with NAC (100 and 300 mg/kg/day, i.p, for 28 consecutive days) and DTT (10 and 20 mg/kg/day, i.p, for 28 consecutive days). Meanwhile, a significant increase in the levels of TNF-α and IgG was detected in the BALF of BDL rats. The BALF level of neutrophils, monocytes, and lymphocytes was also significantly increased in cholestatic animals. A significant increase in lung tissue biomarkers of oxidative stress was detected in the BDL rats. It was found that NAC and DTT could significantly blunt pulmonary damage induced by cholestasis. The effects of these agents on oxidative stress biomarkers and inflammatory response seem to play a pivotal role in their mechanisms of protective properties

Protective Role of Probiotic Supplements in Hepatic Steatosis: A Rat Model Study

Background. Treating nonalcoholic fatty liver disease (NAFLD) is considered one of the public health priorities in the past decade. So far, probiotics have represented promising results in controlling the signs and symptoms of NAFLD. However, attempts to find the ideal probiotic strain are still ongoing. The present study is designed to find the best strain amongst suitable probiotic strains according to their ability to ameliorate histopathological and oxidative stress biomarkers in hepatic steatosis-induced rats. Methods. Initially, four probiotics species, including Lactobacillus (L.) acidophilus, L. casei, L. reuteri, and Bacillus coagulans, were cultured and prepared as a lyophilized powder for animals. The experiment lasted for fifty days. Initially, hepatic steatosis was induced by excessive ingestion of D-fructose in rats for eight weeks, followed by eight weeks of administering probiotics and D-fructose concurrently. Forty-two six-week-old male rats were alienated to different groups and were supplemented with different probiotics (1∗109 CFU in 500 mL drinking water). After eight weeks, blood and liver samples were taken for further evaluation, and plasma and oxidative stress markers corresponding to liver injuries were examined. Results. Administration of probiotics over eight weeks reversed hepatic and blood triglyceride concentration and blood glucose levels. Also, probiotics significantly suppressed markers of oxidative stress in the liver tissue. Conclusions. Although some of the single probiotic formulations were able to mitigate oxidative stress markers, mixtures of probiotics significantly ameliorated more symptoms in the NAFLD animals. This enhanced effect might be due to probiotics’ cumulative potential to maintain oxidative stress and deliver improved lipid profiles, liver function markers, and inflammatory markers

The Hepatoprotection Provided by Taurine and Glycine against Antineoplastic Drugs Induced Liver Injury in an Ex Vivo Model of Normothermic Recirculating Isolated Perfused Rat Liver

Taurine (2-aminoethane sulfonic acid) is a non-protein amino acid found in high concentration in different tissues. Glycine (Amino acetic acid) is the simplest amino acid incorporated in the structure of proteins. Several investigations indicate the hepatoprotective properties of these amino acids. On the other hand, antineoplastic agents-induced serum transaminase elevation and liver injury is a clinical complication. The current investigation was designed to screen the possible hepatoprotective properties of taurine and glycine against antineoplastic drugs-induced hepatic injury in an ex vivo model of isolated perfused rat liver. Rat liver was perfused with different concentration (10 μM, 100 μM and 1000 μM) of antineoplastic drugs (Mitoxantrone, Cyclophosphamide, Cisplatin, 5 Fluorouracil, Doxorubicin and Dacarbazine) via portal vein. Taurine and glycine were administered to drug-treated livers and liver perfusate samples were collected for biochemical measurements (ALT, LDH, AST, and K+). Markers of oxidative stress (reactive oxygen species formation, lipid peroxidation, total antioxidant capacity and glutathione) were also assessed in liver tissue. Antineoplastic drugs caused significant pathological changes in perfusate biochemistry. Furthermore, markers of oxidative stress were significantly elevated in drug treated livers. It was found that taurine (5 and 10 mM) and glycine (5 and 10 mM) administration significantly mitigated the biomarkers of liver injury and attenuated drug induced oxidative stress. Our data indicate that taurine and glycine supplementation might help as potential therapeutic options to encounter anticancer drugs-induced liver injury