Pirfenidone and post-Covid-19 pulmonary fibrosis: invoked again for realistic goals

Financiado para publicación en acceso aberto: Universidade de Vigo/CISUGPirfenidone (PFN) is an anti-fbrotic drug with signifcant anti-infammatory property used for treatment of fbrotic conditions such as idiopathic pulmonary fbrosis (IPF). In the coronavirus disease 2019 (Covid-19) era, severe acute respiratory syndrome 2 (SARS-CoV-2) could initially lead to acute lung injury (ALI) and in severe cases may cause acute respiratory distress syndrome (ARDS) which is usually resolved with normal lung function. However, some cases of ALI and ARDS are progressed to the more severe critical stage of pulmonary fbrosis commonly named post-Covid-19 pulmonary fbrosis which needs an urgent address and proper management. Therefore, the objective of the present study was to highlight the potential role of PFN in the management of post-Covid-19 pulmonary fbrosis. The precise mechanism of post-Covid-19 pulmonary fbrosis is related to the activation of transforming growth factor beta (TGF-β1), which activates the release of extracellular proteins, fbroblast proliferation, fbroblast migration and myofbroblast conversion. PFN inhibits accumulation and recruitment of infammatory cells, fbroblast proliferation, deposition of extracellular matrix in response to TGFβ1 and other pro-infammatory cytokines. In addition, PFN suppresses furin (TGFβ1 convertase activator) a protein efector involved in the entry of SARS-CoV-2 and activation of TGFβ1, and thus PFN reduces the pathogenesis of SARS-CoV-2. Besides, PFN modulates signaling pathways such as Wingless/Int (Wnt/β-catenin), Yes-Associated Protein (YAP)/Transcription CoActivator PDZ Binding Motif (TAZ) and Hippo Signaling Pathways that are involved in the pathogenesis of post-Covid-19 pulmonary fbrosis. In conclusion, the anti-infammatory and anti-fbrotic properties of PFN may attenuate post-Covid-19 pulmonary fbrosis

New insights into the potential cardioprotective effects of telmisartan and nanoformulated extract of Spirulina platensis via regulation of oxidative stress, apoptosis, and autophagy in an experimental model

BackgroundCardiotoxicity is one of the limiting side effects of the commonly used anticancer agent cyclophosphamide (Cyclo).Materials and methodsThe possible protective effects of telmisartan and nanoformulated Spirulina platensis (Sp) methanolic extract against Cyclo-induced cardiotoxicity were examined in this study. Experimental groups of rats were randomly divided into nine groups as control vehicle, control polymer, telmisartan (TEL, 10 mg/kg), free Sp extract (300 mg/kg), nano Sp extract (100 mg/kg), Cyclo (200 mg/kg), TEL + Cyclo, free Sp + Cyclo, and nano Sp + Cyclo. The groups with Cyclo combinations were treated in the same manner as their corresponding ones without Cyclo, with a single dose of Cyclo on day 18.ResultsThe results indicate that Cyclo causes significant cardiotoxicity, manifesting in the form of notable increases of 155.49%, 105.74%, 451.76%, and 826.07% in the serum levels of glutamic oxaloacetic transaminase (SGOT), lactate dehydrogenase (LDH), creatine kinase MB (CK-MB), and cardiac troponin I (cTnI) enzyme activities, respectively, as compared to the control. In addition, the cardiac glutathione (GSH) content and activity of glutathione peroxidase-1 (GPX-1) enzyme decreased by 65.94% and 73.85%, respectively. Treatment with nano Sp extract showed the most prominent restorations of the altered biochemical, histopathological, and immunohistochemical features as compared with those by TEL and free Sp; moreover, reductions of 30.64% and 43.02% in the p-AKT content as well as 60.43% and 75.30% of the endothelial nitric oxide synthase (eNOS) immunoreactivity were detected in the TEL and free Sp treatment groups, respectively. Interestingly, nano Sp boosted the autophagy signal via activation of beclin-1 (36.42% and 153.4%), activation of LC3II (69.13% and 195%), downregulation of p62 expressions (39.68% and 62.45%), and increased gene expressions of paraoxonase-1 (PON-1) (90.3% and 225.9%) compared to the TEL and free Sp treatment groups, respectively.ConclusionThe findings suggest the protective efficiency of telmisartan and nano Sp extract against cardiotoxicity via activations of the antioxidant, antiapoptotic, and autophagy signaling pathways

Fenofibrate and Diosmetin in a rat model of testicular toxicity: New insight on their protective mechanism through PPAR-α/NRF-2/HO-1 signaling pathway

One of the most significant chemotherapeutic side effects of cisplatin (Cis) that limits its use and efficacy is testicular toxicity. Thus, the objective of the present study was to investigate the possible ameliorative effect of Fenofibrate (Fen), Diosmetin (D), and their combination against cis-mediated testicular damage. Fifty-four adult male albino rats were randomly allocated into nine groups (6 rats each): Control group, Fen (100 mg/kg), D20 (20 mg/kg), D40 (40 mg/kg), Cis group (7 mg/kg), Cis +Fen group (7 mg/kg+100 mg/kg), Cis+D20 group (7 mg/kg+20 mg/kg), Cis+D40 group (7 mg/kg+40 mg/kg), Cis+Fen+D40 treated group (7 mg/kg+100 mg/kg+40 mg/kg). Relative testicular weight, epididymal sperm count and viability, serum testosterone level, testicular oxidative stress indices, mRNA expression of peroxisome proliferator-activated receptor alpha (PPAR-α), nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1), histopathological, and immunohistochemical alterations were assessed. Our results revealed that cis administration induced testicular oxidative and inflammatory damage as indicated by a substantial reduction in relative testicular weight, sperm parameters, serum testosterone levels, the antioxidant enzyme activity of catalase, and Johnson's histopathological score, PPAR-α/NRF-2/HO-1 and proliferating cell nuclear antigen (PCNA) immunoexpression with marked increment in malondialdehyde (MDA), Cosentino's score, nuclear factor kappa B (NF-κβ p65), interleukin (IL)− 1β and caspase 3 in testicular tissue. Interestingly, Fen and D diminished the harmful effects of cis on testes via upregulation of the antioxidant activities and downregulation of lipid peroxidation, apoptosis, and inflammation. Moreover, the combination therapy Fen/D40 also exhibited a more pronounced enhancement of previous markers than either treatment alone. In conclusion, because of their antioxidant, anti-inflammatory, and anti-apoptotic properties, cotreatment with Fen or D or their combination could be beneficial in reducing the harmful impacts of cis on testicular tissue, particularly in patients that receive cis chemotherapy

The potential role of scavenger receptor B type I (SR‐BI) in SARS‐CoV‐2 infection

Abstract Scavenger receptor type B I (SR‐BI), the major receptor for high‐density lipoprotein (HDL) mediates the delivery of cholesterol ester and cholesterol from HDL to the cell membrane. SR‐BI is implicated as a receptor for entry of severe acute respiratory syndrome coronavirus type 2 (SARS‐CoV‐2). SR‐BI is colocalized with the angiotensin‐converting enzyme 2 (ACE2) increasing the binding and affinity of SARS‐CoV‐2 to ACE2 with subsequent viral internalization. SR‐BI regulates lymphocyte proliferation and the release of pro‐inflammatory cytokines from activated macrophages and lymphocytes. SR‐BI is reduced during COVID‐19 due to consumption by SARS‐CoV‐2 infection. COVID‐19‐associated inflammatory changes and high angiotensin II (AngII) might be possible causes of repression of SR‐BI in SARS‐CoV‐2 infection. In conclusion, the downregulation of SR‐BI in COVID‐19 could be due to direct invasion by SARS‐CoV‐2 or through upregulation of pro‐inflammatory cytokines, inflammatory signaling pathways, and high circulating AngII. Reduction of SR‐BI in COVID‐19 look like ACE2 may provoke COVID‐19 severity through exaggeration of the immune response. Further studies are invoked to clarify the potential role of SR‐BI in the pathogenesis of COVID‐19 that could be protective rather than detrimental

Autophagy and autophagy signaling in Epilepsy: possible role of autophagy activator

Abstract Autophagy is an explicit cellular process to deliver dissimilar cytoplasmic misfolded proteins, lipids and damaged organelles to the lysosomes for degradation and elimination. The mechanistic target of rapamycin (mTOR) is the main negative regulator of autophagy. The mTOR pathway is involved in regulating neurogenesis, synaptic plasticity, neuronal development and excitability. Exaggerated mTOR activity is associated with the development of temporal lobe epilepsy, genetic and acquired epilepsy, and experimental epilepsy. In particular, mTOR complex 1 (mTORC1) is mainly involved in epileptogenesis. The investigation of autophagy’s involvement in epilepsy has recently been conducted, focusing on the critical role of rapamycin, an autophagy inducer, in reducing the severity of induced seizures in animal model studies. The induction of autophagy could be an innovative therapeutic strategy in managing epilepsy. Despite the protective role of autophagy against epileptogenesis and epilepsy, its role in status epilepticus (SE) is perplexing and might be beneficial or detrimental. Therefore, the present review aims to revise the possible role of autophagy in epilepsy

Isolation and Molecular Characterization of <i>Corynebacterium pseudotuberculosis</i>: Association with Proinflammatory Cytokines in Caseous Lymphadenitis Pyogranulomas

Corynebacterium pseudotuberculosis (C. pseudotuberculosis) is a causative agent of numerous chronic diseases, including caseous lymphadenitis (CLA) in sheep and goats, which has a zoonotic potential in humans in addition to a poor therapeutic response. In this study, out of 120 collected samples, only 12 (10%) were positive for C. pseudotuberculosis by PCR and by intraperitoneal injection of male Guinea pigs and then characterized for antimicrobial susceptibility and its genetic-relatedness by enterobacterial repetitive intergenic consensus polymerase chain reaction (ERIC-PCR), which showed 2–4 bands ranging from 100 to 3000 bp that can be clustered into four clusters (C1–C4). Despite the serotype biovar 1 only infecting sheep and goats, ERIC–PCR reveals intra-subtyping variation. Examination of affected LNs and organs revealed marked enlargement with either thick creamy green pus or multiple abscesses of variable sizes with a central caseated core surrounded by dense fibrous capsule. A histopathological examination revealed a central necrotic core surrounded by a peripheral mantle of mononuclear cells and a fibrous capsule. Positive immune expression of nuclear factor kappa B (NF-κB/p65) and interleukin-1β (IL-1β) and negative expression of tumor necrosis factor (TNF) in CLA is the first report to our knowledge. Conclusion: In CLA pyogranulomas, IL1β is a more crucial proinflammatory cytokine than TNF in the regulation of C. pseudotuberculosis infection, which is accompanied by marked NF-κB immunoexpression. Therefore, the NF-κB/p65 signaling pathway is involved in the activation of IL1β, and additional immunohistochemical studies are required to determine the various roles of NF-κB/p65 in the inflammatory response within CLA pyogranulomas to control this pathogen

Mixed storm in SARS‐CoV‐2 infection: A narrative review and new term in the Covid‐19 era

Abstract Coronavirus disease 2019 (Covid‐19) is caused by a novel severe acute respiratory syndrome coronavirus virus type 2 (SARS‐CoV‐2) leading to the global pandemic worldwide. Systemic complications in Covid‐19 are mainly related to the direct SARS‐CoV‐2 cytopathic effects, associated hyperinflammation, hypercytokinemia, and the development of cytokine storm (CS). As well, Covid‐19 complications are developed due to the propagation of oxidative and thrombotic events which may progress to a severe state called oxidative storm and thrombotic storm (TS), respectively. In addition, inflammatory and lipid storms are also developed in Covid‐19 due to the activation of inflammatory cells and the release of bioactive lipids correspondingly. Therefore, the present narrative review aimed to elucidate the interrelated relationship between different storm types in Covid‐19 and the development of the mixed storm (MS). In conclusion, SARS‐CoV‐2 infection induces various storm types including CS, inflammatory storm, lipid storm, TS and oxidative storm. These storms are not developing alone since there is a close relationship between them. Therefore, the MS seems to be more appropriate to be related to severe Covid‐19 than CS, since it develops in Covid‐19 due to the intricate interface between reactive oxygen species, proinflammatory cytokines, complement activation, coagulation disorders, and activated inflammatory signaling pathway

Vitamin D3 Prevents the Deleterious Effects of Testicular Torsion on Testis by Targeting miRNA-145 and ADAM17: In Silico and In Vivo Study

Testicular torsion (TT) is the most common urological emergency in children and young adults that can lead to infertility in many cases. The ischemia-reperfusion (IR) injury due to TT has been implicated in the pathogenesis of testicular damage. The main pathological mechanisms of contralateral injury after ipsilateral TT are not fully understood. In the presented study, we investigated the molecular and microscopic basis of ipsilateral and contralateral testicular injury following ipsilateral testicular torsion detorsion (T/D) and explored the possible protective role of vitamin D3. The biochemical analysis indicated that IR injury following T/D significantly decreased the activity of testicular glutathione peroxidase (GPx) enzyme, level of serum testosterone, serum inhibin B, and expression of testicular miRNA145, while increased the activity of testicular myeloperoxidase (MPO) enzyme, level of testicular malondialdehyde (MDA), level of serum antisperm-antibody (AsAb), and expression of ADAM-17. The histological and semen analysis revealed that torsion of the testis caused damages on different tissues in testis. Interestingly, administration of vitamin D3 prior to the IR injury reversed the deterioration effect of IR injury on the testicular tissues as indicated by biochemical and histological analysis which revealed normal appearance of the seminiferous tubules with an apparent decrease in collagen fiber deposition in both ipsilateral and contralateral testes. Our results revealed that the protective effect of vitamin D3 treatment could be attributed to target miRNA145 and ADAM17 protein. To further investigate these findings, we performed a detailed molecular modelling study in order to explore the binding affinity of vitamin D3 toward ADAM17 protein. Our results revealed that vitamin D3 has the ability to bind to the active site of ADAM17 protein via a set of hydrophobic and hydrophilic interactions with high docking score. In conclusion, this study highlights the protective pharmacological application of vitamin D3 to ameliorate the damages of testicular T/D on the testicular tissues via targeting miRNA145 and ADAM17 protein.Peer Reviewe

脑啡肽酶和脑啡肽酶抑制剂对葡萄糖稳态的影响:一个有争议的观点和有前景的领域

Abstract Neprilysin (NEP) is a transmembrane zinc‐dependent metalloproteinase that inactivates various peptide hormones including glucagon‐like peptide 1 (GLP‐1). NEP inhibitors may be effective in the management of type 2 diabetes mellitus (T2DM) by increasing the circulating level of GLP‐1. However, acute‐effect NEP inhibitors may lead to detrimental effects by increasing blood glucose independent of GLP‐1. These findings suggest a controversial point regarding the potential role of NEP inhibitors on glucose homeostasis in T2DM patients. Therefore, this perspective aimed to clarify the controversial points concerning the role of NEP inhibitors on glucose homeostasis in T2DM. NEP inhibitors may lead to beneficial effects by inhibition of NEP, which is involved in the impairment of glucose homeostasis through modulation of insulin resistance. NEP increases dipeptidyl peptidase‐4 (DPP4) activity and contributes to increasing active GLP‐1 proteolysis so NEP inhibitors may improve glycemic control through increasing endogenous GLP‐1 activity and reduction of DPP4 activity. Thus, NEP inhibitors could be effective alone or in combination with antidiabetic agents in treating T2DM patients. However, long‐term and short‐term effects of NEP inhibitors may lead to a detrimental effect on insulin sensitivity and glucose homeostasis through different mechanisms including augmentation of substrates and pancreatic amyloid deposition. These findings are confirmed in animal but not in humans. In conclusion, NEP inhibitors produce beneficial rather than detrimental effects on glucose homeostasis and insulin sensitivity in humans though most of the detrimental effects of NEP inhibitors are confirmed in animal studies