An abundance of data indicate there are sex differences in endogenous opioid peptides and opioid receptors, leading to functional differences in sensitivity to opioid-mediated behaviors between males and females. Many of these sex differences are mediated by the effects of gonadal hormones on the endogenous opioid system. Whereas much research has examined the role of ovarian hormones on opioid-mediated endpoints, comparatively less research has examined the role of androgens. This review describes what is currently known regarding the influence of androgens on opioid-mediated endpoints and how androgens may contribute to sex differences in opioid-mediated effects. The review also addresses the clinical implications of androgenic modulation of opioid-mediated behaviors and suggests future lines of research for preclinical and clinical investigators, We conclude that further investigation into androgenic modulation of opioid-mediated effects may lead to new options for addressing conditions such as chronic pain and substance use disorders.

Background and Purpose: Coronavirus disease (COVID-19) has resulted in high mortality worldwide. However, information regarding cardiac markers for precise risk-stratification is limited. We aimed to discover a sensitive and reliable early-warning biomarker for optimizing management and improving COVID-19 patients’ prognosis. Experiments Approach: This retrospectively single-center case series was conducted between February 4 and April 10, 2020. 3,046 consecutive COVID-19 patients who were receiving treatment at Wuhan Huoshenshan Hospital in China were included. Serum levels of cardiac markers and coronary artery disease (CAD) diagnosis were collected after admission. Single-cell RNA-sequencing was performed to analyze severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor expression. Key Results: Median patient age was 60 years; 1,461 (49.5%) were female, and 1,515 (51.3%) were in a severe/critical condition. Compared to mild/moderate patients, severe/critical patients showed significantly higher levels of cardiac markers within the first week after admission. Among severe/critical COVID-19 patients, those with abnormal serum levels of brain natriuretic peptide had a significantly higher mortality than patients with normal levels. Severe/critical COVID-19 patients with pre-existing CAD (165/1,515) had more cases of abnormal brain natriuretic peptide levels than those without CAD. Enhanced SARS-CoV-2 receptor expression was observed in patients with CAD. Regression analysis revealed patients with elevated brain natriuretic peptide were at a higher risk of death. Conclusion and Implications: Brain natriuretic peptide is an effective biomarker for early risk assessment in COVID-19 patients with or without pre-existing CAD. Monitoring BNP status will improve the risk-stratification management and prognosis of patients within one week after admission.

Metabolic stress and associated mitochondrial dysfunction are implicated in retinal degeneration irrespective of the underlying cause. We identified seven unique chemicals from a screen of the Chembridge DiverSET and tested their protection against calcium ionophore and IBMX-induced loss of mitochondrial capacity, as measured by viability and respirometry, in mouse retinal photoreceptor-derived 661W cells. Six of the agents (CB1, 2, 6, 10 11, 12) were protective. Cheminformatic analyses identified a unique pharmacophore with 6 physico-chemical features based on two of the compounds (CB11 and CB12). The protective efficacy of CB11 was further shown by a decrease in the loss of rod photoreceptor cells in retinal explants from two retinitis pigmentosa rodent models, the rd1 mouse and the S334ter-line-3 rat exposed to CB11 in the media. Using eye drops, CB11 biodistribution was confirmed in the retina of the pig eye. The same eye drops decreased photoreceptor cell loss in Balb/c mouse exposed to constant light, a model of age-related macular degeneration. Our studies have identified new chemicals that protect from mitochondrial damage and leads to improved mitochondrial function. Using ex vivo and in vivo models, CB11 decreased the loss of photoreceptor cells in murine models of retinal degeneration and may be effective in the treatment of a wide variety of retinal dystrophies.

BACKGROUND AND PURPOSE Chicken colibacillosis, caused by avian Escherichia coli (APEC), results in huge economic losses to the poultry industry. Baicalin exerts protective effects during the development of colibacillosis. In this study, we mainly explored the mechanism of this protective effects with regard to gut microbiota. EXPERIMENTAL APPROACH The chicken colibacillosis model was established by intratracheal instillation of APEC. The gut microbiota-depleted chicken model was established with broad-spectrum antibiotics. Viscera index measurement and Haematoxylin and eosin stain were applied to assess histological changes of tissues. ELISA were used to measure the cytokines and Quantitative-PCR were used to evaluate the gene expression. The gut microbiota and its metabolite were detected by 16srDNA and ultrahigh-performance liquid chromatography (LC-MS). KEY RESULTS Depletion of gut microbiota exacerbated the tissue damage and weakened the protective effects of baicalin during APEC-induced chicken colibacillosis while pretreatment of baicalin reduced these changes and inflammatory response induced by APEC. Moreover, APEC infection led to dysbiosis of gut microbiota and its metabolites. However, the pretreatment of baicalin remodeled the gut microbiota featured with increased abundance of Intestinimonas and its associated with beneficial metabolites. CONCLUSIONS Gut microbiota played a protective role in the prevention of chicken colibacillosis and the pharmacological action of baicalin. The altered specific gut bacterial and/or metabolites may be served as indicators to predict the occurrence and prognosis of chicken colibacillosis. Our findings may provide a paradigm for the mechanistic studies of compounds and aid the exploration of the mechanisms and pathways underlying the function of herbal medicines.

Endocrine disrupting effects have become a major issue in the field of environmental toxicology. Due to the testicular toxicity reported for acrylamide and confirmed in our study, and the double jeopardy with its well-documented carcinogenicity following leaching out from overcooked starchy foods, the current study was extended to address the possible protective effects of two nutraceuticals. The present study was designed to assess the possible reproductive toxicity of acrylamide in adult male Swiss albino rats. Also, the work was extended to investigate the potential protective effects of two nutraceuticals namely; thymoquinone (TQ) and capsaicin against acrylamide-induced reproductive toxicity. Sixty male albino rats were allotted into six groups. Group 1: Rats received free tap water and served as control group. Group 2: Rats received acrylamide in a daily dose and served as the model. Group 3: Rats were administered TQ twice weekly. Group 4: Rats were administered capsaicin once daily. Group 5: Rats challenged with acrylamide were administered TQ twice weekly. Group 6: Rats challenged with acrylamide were administered capsaicin once daily. A murine model of acrylamide testicular toxicity was reproduced and was characterized biochemically, morphologically and histologically. Acrylamide increased oxidative stress, expression of testicular NF-κB/p65, in addition down regulated the expression of occludin that may further account for its testicular toxicity. Both nutraceuticals; TQ and capsaicin have proven more or less efficacy in ameliorating all the toxic insults exerted by acrylamide in the current reproductive toxicity model. Key words: Testicular failure; Thymoquinone; Capsaicin; Acrylamide; NF-ΚB/P65; Occludin

Background and Purpose: Currently there are no licensed vaccines and limited antivirals for the treatment of COVID-19. Heparin (delivered systemically) is currently being used to treat anticoagulant anomalies in COVID-19 patients. In addition, in the UK, nebulised unfractionated heparin (UFH) is currently being trialled in COVID-19 patients as a potential treatment. A systematic comparison of the potential antiviral effect of various heparin preparations on live wild-type SARS-CoV-2, in vitro, is thus urgently needed. Experimental Approach: A range of heparin preparations both UFH (n=4) and low molecular weight heparins (LMWH) (n=3) of porcine or bovine origin were screened for antiviral activity against live SARS-CoV-2 (Victoria/01/2020) using a plaque reduction neutralisation assay and Vero E6 cells. ND50 values for each heparin were calculated using a mid-point probit analysis. Key Results: UFH had potent antiviral effects, with ND50 values of 12.5 and 23 μg/ml for two porcine mucosal UFH tested. Bovine mucosal UFH had similar antiviral effects although it was ~50% less active (ND50, 50-75 μg/ml). In contrast, LMWHs such as Clexane and Fragmin were markedly less active by ~100-fold (ND50 values of 2.6-6.8 mg/ml). Conclusions and Implications: This comparison of a panel of clinically relevant heparins, including the UFH preparation under trial in the UK, demonstrated that distinct products exhibit different degrees of antiviral activity against live SARS-CoV-2. Porcine mucosal UFH has the strongest antiviral activity followed by bovine mucosal UFH, whereas LMWHs had the lowest amount of antiviral activity (by 100-fold). Overall the data strongly support further clinical investigation of UFH as a potential treatment for patients with COVID-19.

Background and Purpose. Since the onset of COVID-19 many clinical trials of drugs and/or vaccines are continuing and new ones are introduce daily. Yet the international research process failed to develop a preventative vaccine or potent therapeutic drugs for relieving the severity of the disease. Therefore, at present the best recommendation to people to slow the spread of the disease is; please stay at home and maintain social distancing! Experimental approach. Many aspects of pharmacotherapeutic mechanism of action of some previously approved drugs with anti-inflammatory effects, such as colchicine, in various disorders is not fully understood. Therefore, many potential therapeutic uses for these drugs and its analogues can be imagined. In this hypothesis article, an attempt has been made to evaluate some potential therapeutic effects of colchicine that may be benefit against COVID-19. Key Results. Prophylactic therapy with colchicine regulates the innate inflammatory response by blocking intracellular signaling pathways. This can inhibit respiratory alveolar destruction following COVID-19 pneumonia, which is the main cause of ARDS and death in these patients. Conclusion and Implications Since the macrophage and granulocytes are the main pro-inflammatory mediators in the lung, it seems application of therapeutic doses of colchicine, before the onset of respiratory problems, will protect the lung against severe damages and respiratory failure in COVID-19 patients. Obviously, many clinical trials are required to prove the validity of this claim.

Updated, peer reviewed and published at Canadian Journal of Medicinehttps://cjm.cikd.ca/article_60573.htmlUntil recently, ibuprofen has been avoided in all COVID-19 protocols world-wide. The author has been trying since March, 2020 to publish a paper that disputes this unfortunate incident and he finally managed since May 2020 to publish two manuscripts that not only prove non-steroidal anti-inflammatory drugs not harmful for COVID-19, rather they were shown to possess a potential to cure the disease based on a unique new theory suggested to explain COVID-19 pathogenesis and he suggested NSAIDs to be added to unique protocol he suggested using nitazoxanide/azithromycin to manage early cases of COVID-19. In this manuscript, considered the fourth related to the subject, the author represents the first clinical results of using NSAIDs/Nitazoxanide/Azithromycin protocol, used partly or fully, that includes relatively cheap FDA approved drugs used in seventeen Egyptian patients, whether confirmed or suspected, including children, adults and two pregnant ladies whom have been mostly symptoms-free in five days. The manuscripts also presents a road-map to illustrate how to deal efficiently with early cases of COVID-19 according to the author’s clinical experience.

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Background and Purpose: SARS-coV-2 pandemic continues to cause an unprecedented global destabilization. There is an urgent need to develop vaccines or identify molecules to treat severe cases and repurposing of drugs is the best approach at this hour. Thalidomide, despite having an infamous history has been successfully repurposed and tested for various disease conditions including inflammatory diseases and tumor. Few reports emphasize the use of thalidomide with a SARS-coV-2 pneumonia patient being successfully treated with thalidomide. Experimental Approach: A meta-analysis comparing the transcriptomes of SARS-coV-2 infected tissues with thalidomide and lenalidomide-induced transcriptomic changes in transformed lung, endothelial and hematopoietic models was performed. Key Results: Thalidomide and lenalidomide exhibited pleiotropic effects affecting a range of biological processes including inflammation, immune response, angiogenesis, MAPK signaling, NOD-like receptor signaling, TLR signaling, leukocyte differentiation and innate immunity, the processes which are aberrantly regulated in severe COVID-19 patients. In addition, we show the similarities between the expression profiles of SARS-coV-2 infected lung and systemic lupus erythematous. Conclusion and Implications: The present study recommends thalidomide analogs as a “better fit” to treat severe cases of novel viral infections, healing the damaged network by compensating the impairment caused by the Coronavirus disease-2019 (COVID-19).

The novel coronavirus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has posed a serious threat to global public health. Respiratory failure followed by cardiovascular complications with wide-spread endothelial dysfunction and inflammation is rapidly emerging as a key threat in COVID-19. ACE-2 receptors are the cell-entry gate for SARS-CoV-2. Valproic Acid (VPA) is a proposed potential drug to treat COVID-19 but its mechanism of action is not well understood. We demonstrate that VPA-treatment significantly reduced ACE-2 expression in endothelial cells. VPA-treatment significantly reduced the expression of inflammatory cytokines IL-6 along with the endothelial activation marker ICAM-1. We provide evidence and discuss the plausible mechanism in detail for VPA use to prevent and treat COVID-19 in a personalized manner. Our study is expected to entice the scientific and clinical society to investigate VPA as a potential therapeutic option against COVID-19.

SARS-CoV-2 has claimed more than 300,000 lives while infecting 4 million individuals worldwide. There are no specific treatments for COVID-19. Symptoms vary from very mild/asymptomatic to severe, including admission to ICU. Strong sex-bias in COVID-19 have been noted with males showing more than double the odds of requiring ICU admission and higher mortality. Reproductive steroids, including estrogens, progesterone and its physiologically-active metabolite, allopregnanolone exert anti-inflammatory actions and influence the immune system. Intriguingly, pregnant women with COVID-19 appear to experience milder symptoms. In some pregnant women escalated symptoms severity is observed immediately postpartum in coincidence with the rapid hormonal drop associated with parturition. This finding suggests that reproductive steroids’ anti-inflammatory effects and their role in reshaping competence of immune cells may protect during pregnancy. The hypothesis that estradiol, progesterone may provide a treatment against COVID-19 in men and in postmenopausal women is discussed.

The global pandemic from Sars-cov-2 has down caused thousands of deaths worldwide, triggering a health crisis in the various countries involved, with few precedents in history. To date there are no vaccines for prophylaxis, and there are no antivirals directed against the virus. Among the therapeutic options that have shown effectiveness is passive immunization with immune plasma from convalescent patients cured of the infection. Plasma collected from patients cured of Sars-cov-2 infection is rich in antibodies that neutralized the pathogen. Plasma therapy has already demonstrated its efficacy in other epidemics, such as Sars-Cov and MERS. To date, there are limited data for its use in sars-Cov-2 infection, both for prophylaxis and treatment, but the few existing data bode well for the scientific world. Many questions are still unresolved, when to administer it? At what dosage? When is it most appropriate to take the plasma from the cured patient? Are there different answers depending on gender and age? Certainly in view of the high number of patients infected and cured by Sars-Cov-2, there could be a high amount of plasma from donor patients. In this article we want to give an overview on a current and important topic in the perspective of the battle against the new Sars-Cov-2, analysing the therapeutic successes in past epidemics, the clinical data currently available, the future prospect and an expert opinion.

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Background and Purpose. Drug resistance is a major problem in cancer treatment with traditional or targeted therapeutics. Gemcitabine, a traditional chemotherapeutics, is approved for several human cancers and the first line treatment for locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). However, gemcitabine resistance is frequently observed and a major problem in successful treatments of these cancers and the mechanism of gemcitabine resistance remains largely unknown. In this study, we aim to seek new and understand the molecule mechanisms of gemcitabine resistance in PDAC. Experimental Approach. Using whole genome Reduced Representation Bisulfite Sequencing analysis, we investigated a gemcitabine resistant PDAC cell line M3K compared with its parental MiaPaCa-2 cells and the resistance revertant cell line Rev followed by detailed analyses of PDGFD in gemcitabine resistance using MTT survival assay, bisulfite sequencing, Western blot, siRNA knockdown and over-expression. Key Results. We found that 65 genes had reversible methylation changes in their promoters in gemcitabine resistant PDAC cells. One of these genes, PDGFD, was further studied in detail for the reversible methylation change in its promoter and shown to reversibly up-regulate in expression, contribute to gemcitabine resistance in vitro and in vivo via activating STAT3 signaling in both autocrine and paracrine manners. Its expression also positively associates with poor outcome of PDAC patients. Conclusion and Implications. Reversible epigenetic regulation may play an important role in gemcitabine resistance and targeting PDGFD signaling may alleviate gemcitabine resistance for PDAC treatment.

Background & Purpose: The constitutive androstane receptor (CAR) belongs to nuclear receptor superfamily. The administration of CAR agonist TCPOBOP to mice leads to hepatomegaly but the mechanism is unclear. Yes-associated protein (YAP) is a downstream factor of Hippo signaling pathway, which is a potent regulator of organ size and tissue homeostasis. This study examined the role of YAP in CAR-promoted hepatomegaly and liver regeneration. Experimental Approach: The effect of CAR on liver enlargement and liver regeneration was evaluated in wild-type (WT) mice, liver-specific YAP-deficient mice, and partial hepatectomy (PHx) mice. KI67 and CTNNB1 staining were performed to evaluate the proliferation response and hepatocytes size. The protein levels of YAP and its downstream targets were measured and Co-IP was conducted to explore the protein-protein interaction between CAR and YAP. Key Results: The results suggested TCPOBOP increases the liver/body weight ratio in WT mice and PHx mice. Hepatocytes enlargement occurred around the central vein area, while the number of KI67+ cells increased around portal vein area. The translocation of YAP was induced and its downstream targets were upregulated after CAR activation via TCPOBOP. Co-IP results revealed a potential protein-protein interaction between CAR and YAP. However, CAR-induced hepatomegaly was still observed in Yap-/- mice. Conclusion and Implications: CAR activation promotes hepatomegaly and liver regeneration in part by inducing nuclear translocation of YAP and interaction with YAP pathway, which provides new insights for understanding the physiological functions of CAR, and suggests the potential for manipulation of liver size.

BACKGROUND AND PURPOSE Neutrophil overactivation is crucial in the pathogenesis of acute lung injury (ALI). Bletinib (3,3′-dihydroxy-2′,6′-bis(p-hydroxybenzyl)-5-methoxybibenzyl), a natural bibenzyl first extracted from Bletilla striata in 1983, has anti-inflammatory, antibacterial, and antimitotic potential. In this study, we evaluated the therapeutic effects of Bletinib in human neutrophilic inflammation and lipopolysaccharide (LPS)-mediated ALI. EXPERIMENTAL APPROACH We assessed integrin expression, superoxide anion production, degranulation, neutrophil extracellular trap (NET) formation, and adhesion in activated human neutrophils through flow cytometry, spectrophotometry, and immunofluorescence microscopy. Moreover, phosphorylation of Src family kinases (SFKs) and downstream proteins was evaluated through immunoblotting. Finally, a murine LPS-induced ALI model was used to investigate the potential therapeutic effects of Bletinib treatment. KEY RESULTS In activated human neutrophils, Bletinib reduced degranulation, respiratory burst, NET formation, adhesion, migration, and integrin expression; suppressed the enzymatic activity of SFKs, including Src, Lyn, Fgr, and Hck; and inhibited the phosphorylation of SFKs as well as Vav and Bruton’s tyrosine kinase (Btk). In our mice with ALI, the pulmonary sections demonstrated considerable amelioration of prominent inflammatory changes, such as haemorrhage, pulmonary oedema, and neutrophil infiltration, after Bletinib treatment. CONCLUSION AND IMPLICATIONS This is the first study to provide evidence that Bletinib regulates neutrophilic inflammation by inhibiting the SFKs–Btk–Vav pathway and that Bletinib ameliorates LPS-induced ALI in mice. Further biochemical optimisation of Bletinib may be a promising strategy for the development of novel therapeutics for inflammatory diseases.

Background The covid 19 positive patient who is subject to a hyperinflammatory condition associated with lung injury with the development of pneumonia is hospitalized in the intensive care unit. Before resolving and overcoming the “cytokine storm”, with overexpression of pro-inflammatory interleukins (IL-, Il-6), this patient will be intubated for more than 48 hours and therefore needs adequate nutrition. Experimental approach Malnutrition can lead to sarcopenia with a decrease in lean body mass and worsening of the inflammatory state underway. In addition, severe debilitation, if not corrected with adequate nutrition, can greatly lengthen rehabilitation times with prolonged hospitalization, increased costs and reduced turn over already in crisis due to the health emergency caused by coronavirus. Key Results The aim of this study is to focus attention on the nutritional importance that must be provided in case of covid 19 together with pharmacological treatments to lower the number of circulating proinflammatory cytokines. Conclusions Oral, enteral and parenteral nutrition should always be carried out according to the patient’s condition and, in the case of a hyperinflammatory patient, such as the one affected by covid 19, it has been shown that the supplementation of amino acids helps to lower the inflammatory state and promotes normal recovery physiological. Keywords: amino acids, nutrition, covid, glutamine, hyperinflammatory, sarcopenia, cytokine.