Pharmaceutical Development of Intraperitoneal Arachis hypogaea as a Renal Protective Agent.

BACKGROUND: Kidneys are among the vital organs of the human body; therefore, damage from any exogenous/endogenous agent may put human life at risk. Arachis hypogaea (AH) contains different free radical scavenging flavonoids, stilbenes, and tannins. This research aimed to elucidate the possible nephroprotective mechanism of AH methanolic crude extract (AHcr) and n-hexane oil fraction (AHO) against gentamycin-induced nephrotoxicity. METHODS: After the extraction of the crude oil of the plant, they were tested against a Gentamycin (GM)-treated group of Swiss Albino mice for their nephroprotective action. Animals were divided into six (6) equal groups with five (5) animals in each group. These groups were: control group (0.5 mL normal saline via intraperitoneal -i.p), gentamycin group (gentamycin 100 mg/kg i.p), Silymarin + gentamycin group (Silymarin 50 mg/kg and gentamycin 100 mg/kg i.p), plant extract (AHcr1) and gentamycin group (AHcr1 250 mg/kg and gentamycin 100 mg/kg i.p), AHcr2 + gentamycin group (AHcr2; 500 mg/kg and gentamycin 100 mg/kg i.p) and the hexane oil fraction (AHO) + gentamycin (AHO 1 mL/kg and GM 100 mg/kg i.p). After completion of doses, animals were sacrificed for the collection of blood to further investigate biochemical changes and histopathological changes in kidney tissues. RESULTS: Serum creatinine, urea, and blood urea nitrogen significantly increased (p < 0.001) in the gentamycin-treated group as compared to the control group. The elevated level of serum creatinine, urea, and blood urea nitrogen was decreased significantly (p < 0.001) in groups treated with AHcr and AHO compared to the gentamycin group. Similarly, the histopathological study of kidney tissues from the gentamycin group showed tubular necrosis, vacuolation, and fibrosis. CONCLUSIONS: The effect of crude extract and hexane soluble fraction of AH caused a significant reversal of gentamycin-induced nephrotoxicity.

New C8-substituted caffeine derivatives as promising antioxidants and cytoprotective agents in human erythrocytes.

New structurally diverse groups of C8-substituted caffeine derivatives were synthesized and evaluated for their chemical and biological properties. Mass spectrometry, FT-IR, and NMR characterizations of these derivatives were performed. The cytotoxic activity of the derivatives was estimated in vitro using human red blood cells (RBC) and in silico pharmacokinetic studies. The antioxidant capacity of the compounds was analyzed using a ferrous ion chelating activity assay. The ability of the derivatives to protect RBC from oxidative damage, including the oxidation of hemoglobin to methemoglobin, was assessed using a water-soluble 2,2'-azobis(2-methyl-propionamidine) dihydrochloride (AAPH) as a standard inducer of peroxyl radicals. The level of intracellular oxidative stress was assessed using the fluorescent redox probe 2',7'-dichlorodihydrofluorescein diacetate (DCF-DA). The results indicate that all derivatives are biocompatible compounds with significant antioxidant and cytoprotective potential dependent on their chemical structure. In order to explain the antioxidant and cytoprotective activity of the derivatives, a mechanism of hydrogen atom transfer (HAT), radical adduct formation (RAF), or single electron transfer (SET), as well as the specific interactions of the derivatives with the lipid bilayer of RBC membrane, have been proposed. The results show that selected modifications of the caffeine molecule enhance its antioxidant properties, which expands our knowledge of the structure-activity relationship of caffeine-based cytoprotective compounds.

Amino Derivatives of Diaryl Pyrimidines and Azolopyrimidines as Protective Agents against LPS-Induced Acute Lung Injury.

The problem of lung damage originating from excessive inflammation and cytokine release during various types of infections remains relevant and stimulates the search for highly effective and safe drugs. The biological activity of the latter may be associated with the regulation of hyperactivation of certain immune cells and enzymes. Here, we propose the design and synthesis of amino derivatives of 4,6- and 5,7-diaryl substituted pyrimidines and [1,2,4]triazolo[1,5-a]pyrimidines as promising double-acting pharmacophores inhibiting IL-6 and NO. The anti-inflammatory activity of 14 target compounds was studied on isolated primary murine macrophages after LPS stimulation. Seven compounds were identified to inhibit the synthesis of nitric oxide and interleukin 6 at a concentration of 100 µM. The most active compounds are micromolar inhibitors of IL-6 secretion and NO synthesis, showing a minimal impact on innate immunity, unlike the reference drug dexamethasone, along with acceptable cytotoxicity. Evaluation in an animal model of acute lung injury proved the protective activity of compound 6e, which was supported by biochemical, cytological and morphological markers.

Natural Reno-Protective Agents against Cyclosporine A-Induced Nephrotoxicity: An Overview.

CA (cyclosporine A) is a powerful immunosuppressing agent that is commonly utilized for treating various autoimmune illnesses and in transplantation surgery. However, its usage has been significantly restricted because of its unwanted effects, including nephrotoxicity. The pathophysiology of CA-induced kidney injury involves inflammation, apoptosis, tubular injury, oxidative stress, and vascular injury. Despite the fact that exact mechanism accountable for CA's effects is inadequately understood, ROS (reactive oxygen species) involvement has been widely proposed. At present, there are no efficient methods or drugs for treating CA-caused kidney damage. It is noteworthy that diverse natural products have been investigated both in vivo and in-vitro for their possible preventive potential in CA-produced nephrotoxicity. Various extracts and natural metabolites have been found to possess a remarkable potential for restoring CA-produced renal damage and oxidative stress alterations via their anti-apoptosis, anti-inflammatory, and antioxidative potentials. The present article reviews the reported studies that assess the protective capacity of natural products, as well as dietary regimens, in relation to CA-induced nephrotoxicity. Thus, the present study presents novel ideas for designing and developing more efficient prophylactic or remedial strategies versus CA passive influences.

Evaluation of the hepatoprotective effect of naringenin loaded nanoparticles against acetaminophen overdose toxicity.

Acute liver injury is a common clinical disease, which easily leads to liver failure and endangers life, seriously threatening human health. Naringenin is a natural flavonoid that holds therapeutic potential against various liver injuries; however it has poor water solubility and bioavailability. In this study, we aimed to develop naringenin-loaded bovine serum albumin nanoparticles (NGNPs) and to evaluate their hepatoprotective effect and underlying mechanisms against acetaminophen overdose toxicity. In vitro data indicated that NGNPs significantly increased the drug solubility and also more effectively protected the hepatocyte cells from oxidative damage during hydrogen peroxide exposure or lipopolysaccharide (LPS) stimulation. In vivo results confirmed that NGNPs showed an enhanced accumulation in the liver tissue. In the murine model of acetaminophen-induced hepatotoxicity, NGNPs could effectively alleviate the progression of acute liver injury by reducing drug overdose-induced levels of oxidative stress, inflammation and apoptosis in hepatocytes. In conclusion, NGNPs has strong hepatoprotective effects against acetaminophen induced acute liver injury.

Research Progress on the Role of Pyroptosis in Myocardial Ischemia-Reperfusion Injury.

Myocardial ischemia-reperfusion injury (MIRI) results in the aggravation of myocardial injury caused by rapid recanalization of the ischemic myocardium. In the past few years, there is a growing interest in investigating the complex pathophysiological mechanism of MIRI for the identification of effective targets and drugs to alleviate MIRI. Currently, pyroptosis, a type of inflammatory programmed death, has received greater attention. It is involved in the MIRI development in combination with other mechanisms of MIRI, such as oxidative stress, calcium overload, necroptosis, and apoptosis, thereby forming an intertwined association between different pathways that affect MIRI by regulating common pathway molecules. This review describes the pyroptosis mechanism in MIRI and its relationship with other mechanisms, and also highlights non-coding RNAs and non-cardiomyocytes as regulators of cardiomyocyte pyroptosis by mediating associated pathways or proteins to participate in the initiation and development of MIRI. The research progress on novel small molecule drugs, clinical drugs, traditional Chinese medicine, etc. for regulating pyroptosis can play a crucial role in effective MIRI alleviation. When compared to research on other mature mechanisms, the research studies on pyroptosis in MIRI are inadequate. Although many related protective drugs have been identified, these drugs generally lack clinical applications. It is necessary to further explore and verify these drugs to expand their applications in clinical setting. Early inhibition of MIRI by targeted regulation of pyroptosis is a key concern that needs to be addressed in future studies.

Lycopene protects against Bisphenol A induced toxicity on the submandibular salivary glands via the upregulation of PPAR-γ and modulation of Wnt/ß-catenin signaling.

BACKGROUND AND AIM: The submandibular salivary glands (SMG) represent a suitable model for studying epithelial cell growth and differentiation. Bisphenol A (BPA) is a xenoestrogen, synthesized to produce polymers such as polycarbonates and epoxy resins. There are concerns about the occurrence of BPA in food, water as well as its appearance in human tissues and body fluids. Lycopene (LYC) is a carotenoid compound that exerts antioxidant and anti-inflammatory properties. This work was performed to study possible protective effect of LYC against BPA toxicity in SMG. MATERIAL AND METHODS: 40 albino rats were divided into 4 groups; Group I: served as controls. Group II: rats received LYC (4 mg/kg, p.o), Group III: rats received BPA (10 mg/kg, p.o) and Group IV: rats received LYC (4 mg/kg, p.o) and BPA (10 mg/kg, p.o). All drugs were administered for 45 days then under anesthesia, rats were sacrificed. The SMG specimens were taken for histological and biochemical studies. RESULTS: BPA resulted in a significant rise of malondialdehyde, tumor necrosis factor-α and interleukine-1ß. In contrast, the tissue levels of glutathione and PPAR-γ were significantly decreased. BPA activated Wnt/ß-catenin pathway evidenced by upregulating WNT3a, ß-catenin and c-myc expression. Moreover, SMG of BPA showed degenerative changes that affected the parenchymal and stromal elements of the glands. The immunohistochemical localization of cytokeratin 5,6 and 18 of BPA rats revealed weak immunostaining of the serous secretory cells, myoepithelial cells and ductal cells. Upon treatment with LYC, glutathione and PPAR-γ were restored. CONCLUSION: LYC acted as a protective agent against BPA-induced pathological changes in SMG.

KLF11 Is a Novel Endogenous Protectant against Renal Ischemia-Reperfusion Injury.

Discovering new nephroprotectants may provide therapeutic strategies in AKI.This study provides the first evidence that KLF11, a member of the Krüppel-like factor (KLF) family of proteins, protects against AKI.In the absence of KLF11, exaggerated induction of endothelin-1 and IL-6 occurs after ischemic renal injury and may contribute to worse AKI.

Development of protective agents against ovarian injury caused by chemotherapeutic drugs.

BACKGROUND: Chemotherapy is one of the causes of ovarian injury and infertility. Although assisted reproductive technology helps young female patients with cancer become pregnant, preventing chemotherapy-induced ovarian injury will often possess even more significant benefits. OBJECTIVE: We aimed at demonstrating the hazardous effects and mechanisms of ovarian injury by chemotherapeutic agents, as well as demonstrating agents that protect the ovary from chemotherapy-induced injury. RESULTS: Chemotherapeutic agents cause death or accelerate activation of follicles and damage to the blood vessels in the ovary, resulting in inflammation. These often require drug development to protect the ovaries from injury. CONCLUSIONS: Our findings provide a basis for the development of drugs to protect the ovaries from injury. Although there are many preclinical studies on potential protective drugs, there is still an urgent need for a large number of clinical experiments to verify their potential use.

Hawk Tea Flavonoids as Natural Hepatoprotective Agents Alleviate Acute Liver Damage by Reshaping the Intestinal Microbiota and Modulating the Nrf2 and NF-κB Signaling Pathways.

Hawk tea (Litsea coreana Levl. var. lanuginosa) is a traditional herbal tea in southwestern China, and was found to possess hepatoprotective effects in our previous study. However, it is unclear whether hawk tea flavonoids (HTF) can alleviate alcoholic liver damage (ALD). Firstly, we extracted and identified the presence of 191 molecules categorized as HTFs, with reynoutrin, avicularin, guaijaverin, cynaroside, and kaempferol-7-O-glucoside being the most prevalent. After taking bioavailability into consideration and conducting comprehensive sorting, the contribution of guaijaverin was the highest (0.016 mg/mice). Then, by daily intragastric administration of HTF (100 mg/kg/day) to the ALD mice, we found that HTF alleviated liver lipid deposition (inhibition of TG, TC, LDL-C) by reducing liver oxidative-stress-mediated inflammation (up-regulation NRF2/HO-1 and down-regulation TLR4/MyD88/NF-κB pathway) and reshaping the gut microbiota (Lactobacillus, Bifidobacterium, Bacillus increased). Overall, we found HTF could be a potential protective natural compound for treating ALD via the gut-liver axis and guaijaverin might be the key substance involved.

Beetroot Nanoencapsulation in Flavored Beverage and its Effect as Hepatoprotective Agent in Rats.

<b>Background and Objective:</b> Beetroot juice is a biological antioxidant and acts as health-promoting minerals as well as soluble fibres and vitamins. This study aimed to encapsulate the Beetroot Juice Powder (BJP) by the conjugate sodium caseinate (NaCas) and Maltodextrin (MD) to protect it from environmental conditions. Produced flavoured acid beverage using BJP encapsulated using conjugates. <b>Materials and Methods:</b> Nano-encapsulation of BJP (20, 30, 40 mg g¹) and determine the encapsulation efficiency, size and zeta potential. Rats were divided into 4 groups as follows, negative control, positive control and 2 test groups that received free BJP or encapsulated BJP. All rats except the negative control group were injected with CCl₄ twice a week. <b>Results:</b> The NaCas-MD conjugate has the advantage over the NaCas-MD complex of higher stability and BJP binding, also showing high encapsulation efficiency (>93.75%) of different levels of BJP. The flavoured beverage from the addition of BJP encapsulated by conjugate has better sensory and technological properties than fortified with BJP in the complex. Injection with CCl₄ leads to a decrease in body weight, serum parameters including, protein, albumin, GSH, CAT and SOD, also increase ALT, AST, ALP and liver weight. Moreover, a variable pathological alteration in liver tissue was found. At the end of the experiment receiving encapsulated beetroot juice led to improvement in all above body and liver weight, all biochemical parameters and histopathological elevation. <b>Conclusion:</b> Thus, it could be concluded that flavoured beverage containing BJP encapsulated by conjugate is of acceptable quality and high antioxidant activity. Also, it has a remarkable protective effect against acute hepatotoxicity.

Nanocurcumin, Promising Potential Protective Agent Against Histopathological Damage in the Cerebral Cortex of Mice Induced by Aluminum Chloride.

<b>Background and Objective:</b> Aluminum (Al) is widely used in many aspects of daily life, such as food packaging, cooking utensil components, food additives, cosmetics and water distillation. This study aimed to evaluate the protective role of nanocurcumin on the cerebral cortex of one and two-month-old mice exposed to 200 mg kg¹ b.wt., aluminium. <b>Materials and Methods:</b> The Swiss Webster mice were used in this study. The control group only received sterile distilled water, the Al group was administered 200 mg kg¹ b.wt., of AlCl₃ solution and the Al+Na Cur group was administered 200 mg kg¹ b.wt., AlCl₃+200 mg kg¹ nanocurcumin by intraperitoneal injection. The nanocurcumin was administered one hour after AlCl₃exposure and then on days 0, 3, 6, 9, 12, 15, 18, 21, 24, 27 and 30. All the mice were anaesthetized and their brains were collected and fixed in a neutral formalin buffer solution for histological analysis. The paraffin method was used in this study. <b>Results:</b> The death of granular neuron cells and karyolysis cells and the vacuolation of the pyramid cell layer of the cerebral cortex could be prevented by the intraperitoneal administration of nanocurcumin. The effect of nanocurcumin administration on the Al group at two months of age was more effective than on the Al group at one month of age. <b>Conclusion:</b> Nanocurcumin can be a promising candidate protective agent against cerebral cortex changes after aluminium administration.

Glycine protects the male reproductive system against lead toxicity via alleviating oxidative stress, preventing sperm mitochondrial impairment, improving kinematics of sperm, and blunting the downregulation of enzymes involved in the steroidogenesis.

Lead (Pb) is a highly toxic heavy metal widely dispersed in the environment because of human industrial activities. Many studies revealed that Pb could adversely affect several organs, including the male reproductive system. Pb-induced reproductive toxicity could lead to infertility. Thus, finding safe and clinically applicable protective agents against this complication is important. It has been found that oxidative stress plays a fundamental role in the pathogenesis of Pb-induced reprotoxicity. Glycine is the simplest amino acid with a wide range of pharmacological activities. It has been found that glycine could attenuate oxidative stress and mitochondrial impairment in various experimental models. The current study was designed to evaluate the role of glycine in Pb-induced reproductive toxicity in male mice. Male BALB/c mice received Pb (20 mg/kg/day; gavage; 35 consecutive days) and treated with glycine (250 and 500 mg/kg/day; gavage; 35 consecutive days). Then, reproductive system weight indices, biomarkers of oxidative stress in the testis and isolated sperm, sperm kinetic, sperm mitochondrial indices, and testis histopathological alterations were monitored. A significant change in testis, epididymis, and Vas deferens weight was evident in Pb-treated animals. Markers of oxidative stress were also significantly increased in the testis and isolated sperm of the Pb-treated group. A significant disruption in sperm kinetic was also evident when mice received Pb. Moreover, Pb exposure caused significant deterioration in sperm mitochondrial indices. Tubular injury, tubular desquamation, and decreased spermatogenic index were histopathological alterations detected in Pb-treated mice. It was found that glycine significantly blunted oxidative stress markers in testis and sperm, improved sperm mitochondrial parameters, causing considerable higher velocity-related indices (VSL, VCL, and VAP) and percentages of progressively motile sperm, and decreased testis histopathological changes in Pb-exposed animals. These data suggest glycine as a potential protective agent against Pb-induced reproductive toxicity. The effects of glycine on oxidative stress markers and mitochondrial function play a key role in its protective mechanism.

In-vitro alleviation of ochratoxin a mediated cytotoxicity using N-acetyl-L-tryptophan glucoside pretreatment.

AIMS: Ochratoxin A (OTA) has been reported to exhibit nephrotoxicity through induction of cell redox homeostasis perturbation, mitochondrial hyperpolarization and depolarization, protein synthesis inhibition, apoptosis, etc. In the present examination, the protective efficiency of novel synthesized molecule, N-acetyl-L-Tryptophan glucoside (NATG) towards OTA prompted toxicity was evaluated using Human Embryonic Kidney (HEK-293) cells. MAIN METHODS & KEY FINDINGS: The cells were treated with NATG (0-200 µg/ml) before OTA treatment (0-20 µg/ml) the and protection efficiency of NATG was evaluated using MTT and SRB assay. OTA-induced intracellular ROS and its inhibition via NATG (10 µg/ml) pre-treatment was evaluated using the 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) probe. Protective effects of NATG pre-treatment on OTA treated cells had been evaluated in terms of oxidative stress, cell cycle perturbations, mitochondrial membrane disturbance and apoptotic modulation through flowcytometry. Results of the study demonstrated that NATG provides significant protection to HEK -293 cells against OTA induced toxicity primarily by reducing oxidative stress, maintaining mitochondrial membrane homeostasis and inhibiting apoptosis. Furthermore, molecular docking study demonstrated that NATG may efficiently bind with OTA binding pocket on phenylalanyl t-RNA synthetase, resulting in inhibiting OTA incorporation within the newly synthesized peptides and therefore may ameliorate OTA mediated protein synthesis inhibition. SIGNIFICANCE: Present study demonstrated a significant protective efficacy of N acetyl-L- tryptophan glucoside (NATG) against OTA induced toxicity in HEK -293 cells. In future, NATG can be developed as a potential protective agent against OTA induced toxicity in humans.

Malvidin protects against lipopolysaccharide-induced acute liver injury in mice via regulating Nrf2 and NLRP3 pathways and suppressing apoptosis and autophagy.

Sepsis-related acute liver injury (ALI) is a fatal disease associated with many complications. Recent studies indicate that malvidin, an active flavonoid, has multiple bioactivities including anti-oxidant and anti-inflammation. However, the protective roles of malvidin against LPS-induced ALI are unknown. The purpose of this research is to explore whether malvidin has biological activities on LPS-induced ALI in mice and the underlying mechanisms. Male C57 mice were injected intraperitoneally with malvidin for five days and the mice were euthanized 6 h after LPS (10 mg/kg body weight) intraperitoneal injection. Multiple methods of H&E staining, biochemical kits, qRT-PCR assay, western blotting analysis, TUNEL and transmission electron microscope (TEM) were used. Results showed that decreased ALT, AST levels and alleviated histopathological damage of liver tissue were observed in malvidin pretreatment group in mice. Then, malvidin prevented LPS-induced reduction of antioxidant enzyme activities such as superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) and catalase (CAT) via up-regulating nuclear factor E2-related factor2 (Nrf2) pathway. In addition, in malvidin pretreatment groups, mRNA levels of pro-inflammatory cytokines (TNF-α，IL-1ß, IL-6) and protein levels of NOD-like receptor protein 3 (NLRP3) inflammasome in the liver were significantly down-regulated. We also found that the malvidin could reduce the expression of apoptosis key protein and TUNEL-labeled apoptotic hepatocytes. Furthermore, malvidin inhibited the protein expression of ATG5, p62 and the ratio of LC3-II/LC3-I. In conclusion, our study firstly suggests that malvidin is a potentially protective agent against LPS-induced ALI through up-regulating Nrf2 signaling pathway, suppressing NLRP3 inflammasome and inhibiting apoptosis and autophagy.

Metabolic heterogeneity caused by HLA-DRB1*04:05 and protective effect of inosine on autoimmune hepatitis.

Autoimmune hepatitis (AIH) is an autoimmune disease caused by disruption of liver immune homeostasis. Genetic studies have revealed the predisposition of AIH with the human leukocyte antigen (HLA) region. Recently, metabolomics integrated with genomics has identified many genetic loci of biomedical interest. However, there is no related report in AIH. In the present study, we found that HLA-DRB1*04:05 was linked to the clinical features and prognosis of AIH in Chinese patients. Furthermore, our patients were divided into DRB1*04:05 positive and DRB1*04:05 negative groups and the metabolic profiling was done by HPLC/MS. We chose inosine, one of the highly altered metabolites, to explore the effect on an acute severe hepatitis murine model. The results showed that inosine treatment attenuated hepatocyte apoptosis, enhanced antioxidant ability and inhibited the activation and glycolysis of CD4+ T cell. We propose that inosine participates in the regulation of AIH through its protective effect on hepatocytes and inhibition of overactivated immune cells, which might provide a potential novel approach in treating acute form of AIH.

Protective effects and mechanism of amino acids as chokeberry cyanidin and its glycoside protectant under the condition of vitamin C coexistence.

In the presence of vitamin C, cyanidin and cyanidin glycosides are degraded during the processing and storage of food products. To solve this issue, we investigated the protective effects and mechanism of action of five amino acids on the stability of cyanidin and its glycosides from chokeberry. The results showed that 0.3% tryptophan most effectively inhibited the degradation of cyanidin and its glycosides in the presence of vitamin C, under ultraviolet, dark, and sucrose-rich conditions. Fluorescence spectrum analysis showed that tryptophan could form noncovalent binding complexes with cyanidin-3-O-galactoside and cyanidin through hydrophobic and electrostatic forces and hydrogen bonds. Molecular docking results showed that the indole structure of tryptophan could form hydrophobic interactions with cyanidin-3-O-galactoside and cyanidin via hydrogen bonding, resulting in greater protection. Therefore, tryptophan could effectively protect cyanidin and its glycosides in cyanidin- and cyanidin glycoside-rich food products.

The role of Bax/Bcl-2 and Nrf2-Keap-1 signaling pathways in mediating the protective effect of boric acid on acrylamide-induced acute liver injury in rats.

INTRODUCTION: This study aims to investigate whether boric acid (BA) can protect rats from acrylamide (AA)-induced acute liver injury. MATERIALS AND METHODS: AA was used to induce acute liver injury. Thirty rats were divided into five group including Group 1 (saline), Group 2 (AA), Group 3 (20 mg/kg BA), Group 4 (10 mg/kg BA+AA) and Group 5 (20 mg/kg BA+AA). Their blood and liver were harvested to be kept for analysis. Liver function enzyme activities were performed by spectrophotometric method. Catalase (CAT), superoxide dismutase (SOD) activity, and malondialdehyde levels were determined by colorimetric method. The in-silico studies were performed using the "blind docking" method. RESULTS: Administration AA to rats, biochemical parameters, liver histology, and expression levels of apoptotic markers were negatively affected. However, after the administration of BA, the altered biochemical parameters, liver histology, and expression levels of apoptotic markers were reversed. Moreover, the mechanisms of AA-induced deterioration in the levels of SOD, CAT, and Nrf2-Keap-1 and the mechanisms of the protective effect of BA against these deteriorations were explained by in silico studies. CONCLUSION: Thus, the present study could explain the interactions between AA and thiol-containing amino acid residues of Keap-1, the effect of BA on these interactions, and the biochemical toxicity caused by the AA. In this sense, this work is the first of its kind in the literature. Based on the biochemical, histopathological, and in silico results, it can be suggested that BA has the potential to be used as a protective agent against AA-induced liver injury.

Hunting for protective drugs at the break of a pandemic: Causal inference from hospital data.

At the break of a pandemic, the protective efficacy of therapeutic interventions needs rapid evaluation. An experimental approach to the problem will not always be appropriate. An alternative route are observational studies, whether based on regional health service data or hospital records. In this paper, we discuss the use of methods of causal inference for the analysis of such data, with special reference to causal questions that may arise in a pandemic. We apply the methods by using the aid of a directed acyclic graph (DAG) representation of the problem, to encode our causal assumptions and to logically connect the scientific questions. We illustrate the usefulness of DAGs in the context of a controversy over the effects of renin aldosterone system inhibitors (RASIs) in hypertensive individuals at risk of (or affected by) severe acute respiratory syndrome coronavirus 2 disease. We consider questions concerning the existence and the directions of those effects, their underlying mechanisms, and the possible dependence of the effects on context variables. This paper describes the cognitive steps that led to a DAG representation of the problem, based on background knowledge and evidence from past studies, and the use of the DAG to analyze our hospital data and assess the interpretive limits of the results. Our study contributed to subverting early opinions about RASIs, by suggesting that these drugs may indeed protect the older hypertensive Covid-19 patients from the consequences of the disease. Mechanistic interaction methods revealed that the benefit may be greater (in a sense to be made clear) in the older stratum of the population.

Melatonin attenuates polystyrene microplastics induced motor neurodevelopmental defect in zebrafish (Danio rerio) by activating nrf2 - isl2a Axis.

Microplastics, a new type of ecological pollutant, have now become a major environmental concern worldwide. Polystyrene microplastics (PS), one of the most abundant form of microplastics, cause deleterious effects across species. Melatonin (MT), which is secreted by pineal gland, exhibits protective role against pollutant-induced damage. However, whether MT could ameliorate PS-induced neurodevelopmental toxicity remain unclear. In our study, zebrafish embryos were treated with PS (0.5, 25 mg/L) in the presence or absence of MT (1 µM) from 4 h post-fertilization (hpf) to 144 hpf. Locomotion behavior, oxidative stress, apoptosis, proliferation and development of caudal primary (Cap) motoneuron axon were analyzed. Gene expression was determined by qRT-PCR or whole-mount in situ hybridization. Results showed that PS exposure significantly reduced swimming speed of zebrafish larvae and induced excessive reactive oxygen species (ROS), apoptosis and aberrant proliferation. In addition, PS treatment markedly shortened the length of Cap motoneuron axons and decreased expression of neurodevelopment related genes. While, MT administration considerably rescued the neurodevelopmental toxicity of PS. Mechanistically, MT activated nrf2 (nuclear factor-E2-related factor 2) - isl2a (ISL LIM homeobox 2a) axis to antagonize the side effects of PS. In all, our findings suggest that PS exposure during early life lead to aberrant neurodevelopment of zebrafish, and MT might be a therapeutic option for protecting such disorder.