HDAC6 Degrades nsp8 of Porcine Deltacoronavirus through Deacetylation and Ubiquitination to Inhibit Viral Replication.

Porcine deltacoronavirus (PDCoV) is an emerging swine enteropathogenic coronavirus that has the potential to infect humans. Histone deacetylase 6 (HDAC6) is a unique type IIb cytoplasmic deacetylase with both deacetylase activity and ubiquitin E3 ligase activity, which mediates a variety of cellular processes by deacetylating histone and nonhistone substrates. In this study, we found that ectopic expression of HDAC6 significantly inhibited PDCoV replication, while the reverse effects could be observed after treatment with an HDAC6-specific inhibitor (tubacin) or knockdown of HDAC6 expression by specific small interfering RNA. Furthermore, we demonstrated that HDAC6 interacted with viral nonstructural protein 8 (nsp8) in the context of PDCoV infection, resulting in its proteasomal degradation, which was dependent on the deacetylation activity of HDAC6. We further identified the key amino acid residues lysine 46 (K46) and K58 of nsp8 as acetylation and ubiquitination sites, respectively, which were required for HDAC6-mediated degradation. Through a PDCoV reverse genetics system, we confirmed that recombinant PDCoV with a mutation at either K46 or K58 exhibited resistance to the antiviral activity of HDAC6, thereby exhibiting higher replication compared with wild-type PDCoV. Collectively, these findings contribute to a better understanding of the function of HDAC6 in regulating PDCoV infection and provide new strategies for the development of anti-PDCoV drugs. IMPORTANCE As an emerging enteropathogenic coronavirus with zoonotic potential, porcine deltacoronavirus (PDCoV) has sparked tremendous attention. Histone deacetylase 6 (HDAC6) is a critical deacetylase with both deacetylase activity and ubiquitin E3 ligase activity and is extensively involved in many important physiological processes. However, little is known about the role of HDAC6 in the infection and pathogenesis of coronaviruses. Our present study demonstrates that HDAC6 targets PDCoV-encoded nonstructural protein 8 (nsp8) for proteasomal degradation through the deacetylation at the lysine 46 (K46) and the ubiquitination at K58, suppressing viral replication. Recombinant PDCoV with a mutation at K46 and/or K58 of nsp8 displayed resistance to the antiviral activity of HDAC6. Our work provides significant insights into the role of HDAC6 in regulating PDCoV infection, opening avenues for the development of novel anti-PDCoV drugs.

SARS-CoV-2 infection and smoking: What is the association? A brief review.

Susceptibility to severe illness from COVID-19 is anticipated to be associated with cigarette smoking as it aggravates the risk of cardiovascular and respiratory illness, including infections. This is particularly important with the advent of a new strain of coronaviruses, the severe acute respiratory syndrome coronavirus (SARS-CoV-2) that has led to the present pandemic, coronavirus disease 2019 (COVID-19). Although, the effects of smoking on COVID-19 are less described and controversial, we presume a link between smoking and COVID-19. Smoking has been shown to enhance the expression of the angiotensin-converting enzyme-2 (ACE-2) and transmembrane serine protease 2 (TMPRSS2) key entry genes utilized by SARS-CoV-2 to infect cells and induce a 'cytokine storm', which further increases the severity of COVID-19 clinical course. Nevertheless, the impact of smoking on ACE-2 and TMPRSS2 receptors expression remains paradoxical. Thus, further research is necessary to unravel the association between smoking and COVID-19 and to pursue the development of potential novel therapies that are able to constrain the morbidity and mortality provoked by this infectious disease. Herein we present a brief overview of the current knowledge on the correlation between smoking and the expression of SARS-CoV-2 key entry genes, clinical manifestations, and disease progression.

Mechanism-based approaches of 1,3,4 thiadiazole scaffolds as potent enzyme inhibitors for cytotoxicity and antiviral activity

Significant progress in understanding cancer pathogenesis, it remains one of the leading causes of death after cardiovascular diseases. Similarly viral infections have emerged from wildlife or re-emerged, generating serious threats to the global health. As a result, there is an urgent need for the development of novel, more effective anticancer and antiviral therapeutics. Scientists, medicinal chemists and researchers are continuously finding novel targets, mechanisms and molecules against theses severe and dangerous infections. Therefore, ongoing extensively study and research emphasizes 1,3,4 thiadiazole pharmacophore have versatile pharmacological actions. Due to mesoionic behaviour of 1,3,4 thiadiazole pharmacophore allows to enter and easily cross biological membrane which allow to interact various biological proteins. In this review study an attempt has been made of various mechanisms involved in cancer and viral prevalence with updated studies done so far. This review study also findings the role of 1,3,4 thiadiazole motif in the management of various cancers and viral infection. This study also highlighting research statics on clinical trials and various patents containing 1,3,4 thiadiazole derivatives. © 2022 The Author(s)

Interaction of HDAC2 with SARS-CoV-2 NSP5 and IRF3 Is Not Required for NSP5-Mediated Inhibition of Type I Interferon Signaling Pathway.

Over the last 2 years, several global virus-host interactome studies have been published with SARS-CoV-2 proteins with the purpose of better understanding how specific viral proteins can subvert or utilize different cellular processes to promote viral infection and pathogenesis. However, most of the virus-host protein interactions have not yet been confirmed experimentally, and their biological significance is largely unknown. The goal of this study was to verify the interaction of NSP5, the main protease of SARS-CoV-2, with the host epigenetic factor histone deacetylase 2 (HDAC2) and test if HDAC2 is required for NSP5-mediated inhibition of the type I interferon signaling pathway. Our results show that NSP5 can significantly reduce the expression of a subset of immune response genes such as IL-6, IL-1ß, and IFNß, which requires NSP5's protease activity. We also found that NSP5 can inhibit Sendai virus-, RNA sensor-, and DNA sensor-mediated induction of IFNß promoter, block the IFN response pathway, and reduce the expression of IFN-stimulated genes. We also provide evidence for HDAC2 interacting with IRF3, and NSP5 can abrogate their interaction by binding to both IRF3 and HDAC2. In addition, we found that HDAC2 plays an inhibitory role in the regulation of IFNß and IFN-induced promoters, but our results indicate that HDAC2 is not involved in NSP5-mediated inhibition of IFNß gene expression. Taken together, our data show that NSP5 interacts with HDAC2 but NSP5 inhibits the IFNß gene expression and interferon-signaling pathway in an HDAC2-independent manner. IMPORTANCE SARS-CoV-2 has developed multiple strategies to antagonize the host antiviral response, such as blocking the IFN signaling pathway, which favors the replication and spreading of the virus. A recent SARS-CoV-2 protein interaction mapping revealed that the main viral protease NSP5 interacts with the host epigenetic factor HDAC2, but the interaction was not confirmed experimentally and its biological importance remains unclear. Here, we not only verified the interaction of HDAC2 with NSP5, but we also found that HDAC2 also binds to IRF3, and NSP5 can disrupt the IRF3-HDAC2 complex. Furthermore, our results show that NSP5 can efficiently repress the IFN signaling pathway regardless of whether viral infections, RNA, or DNA sensors activated it. However, our data indicate that HDAC2 is not involved in NSP5-mediated inhibition of IFNß promoter induction and IFNß gene expression.

Phase II study of sodium valproate in combination with oral etoposide in platinum-resistant ovarian cancer.

Patients with platinum-resistant ovarian cancer (PROC) have limited therapeutic options and poor survival. There is a need for the development of newer therapies. Sodium valproic acid (VPA) is a short-chain fatty acid histone deacetylase (HDAC) inhibitor with antitumor activity in preclinical models of PROC. Synergism with conventional cytotoxic agents like etoposide has been demonstrated. In this prospective, single-arm, open-label, phase 2 study, we included patients ≥ 18 years with histologically or cytologically confirmed PROC and Eastern Cooperative Oncology Group performance status (ECOG-PS) 0-3. Patients received oral VPA 60 mg/kg/day in three divided doses for 3 days (D1-D3), followed by oral etoposide 50 mg once daily for two consecutive weeks (D4-D17). Serum samples were collected to assess peak VPA drug levels. The primary endpoint was the overall response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. We sought to show an improvement in response rate from 25% (historically with oral etoposide) to 40% with the addition of VPA. 27 patients were enrolled in the study, and 18 [median age: 52 (45-59) years; serous histology:17 (94%); ECOG-PS 2 or 3: 14 (78%)] were evaluable for the response after 4 months. Nine patients were lost from follow-up before achieving the primary endpoint (mainly due to Covid-related lockdown issues). The median number of prior lines of treatment was 2 (1-3). ORR was 0% according to GCIG criteria. The disease was stable in two patients [clinical benefit rate (CBR) of 11%]. The median OS and PFS were 7 months and 2 months, respectively. Grade ≥ 3 adverse events were reported in 6 (33%) patients. The addition of valproic acid to oral etoposide in patients with PROC and poor general condition was not helpful and failed to improve responses compared to those historically achieved with single-agent etoposide. However, further phase 2 randomized controlled trials with larger sample size can be done to confirm the findings.

Porcine Deltacoronavirus Infection Cleaves HDAC2 to Attenuate Its Antiviral Activity.

Protein acetylation plays an important role during virus infection. Thus, it is not surprising that viruses always evolve elaborate mechanisms to regulate the functions of histone deacetylases (HDACs), the essential transcriptional and epigenetic regulators for deacetylation. Porcine deltacoronavirus (PDCoV), an emerging enteropathogenic coronavirus, causes severe diarrhea in suckling piglets and has the potential to infect humans. In this study, we found that PDCoV infection inhibited cellular HDAC activity. By screening the expressions of different HDAC subfamilies after PDCoV infection, we unexpectedly found that HDAC2 was cleaved. Ectopic expression of HDAC2 significantly inhibited PDCoV replication, while the reverse effects could be observed after treatment with an HDAC2 inhibitor (CAY10683) or the knockdown of HDAC2 expression by specific siRNA. Furthermore, we demonstrated that PDCoV-encoded nonstructural protein 5 (nsp5), a 3C-like protease, was responsible for HDAC2 cleavage through its protease activity. Detailed analyses showed that PDCoV nsp5 cleaved HDAC2 at glutamine 261 (Q261), and the cleaved fragments (amino acids 1 to 261 and 262 to 488) lost the ability to inhibit PDCoV replication. Interestingly, the Q261 cleavage site is highly conserved in HDAC2 homologs from other mammalian species, and the nsp5s encoded by seven tested mammalian coronaviruses also cleaved HDAC2, suggesting that cleaving HDAC2 may be a common strategy used by different mammalian coronaviruses to antagonize the antiviral role of HDAC2. IMPORTANCE As an emerging porcine enteropathogenic coronavirus that possesses the potential to infect humans, porcine deltacoronavirus (PDCoV) is receiving increasing attention. In this work, we found that PDCoV infection downregulated cellular histone deacetylase (HDAC) activity. Of particular interest, the viral 3C-like protease, encoded by the PDCoV nonstructural protein 5 (nsp5), cleaved HDAC2, and this cleavage could be observed in the context of PDCoV infection. Furthermore, the cleavage of HDAC2 appears to be a common strategy among mammalian coronaviruses, including the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), to antagonize the antiviral role of HDAC2. To our knowledge, PDCoV nsp5 is the first identified viral protein that can cleave cellular HDAC2. Results from our study provide new targets to develop drugs combating coronavirus infection.

Targeting Histone Deacetylases in Idiopathic Pulmonary Fibrosis: A Future Therapeutic Option.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited therapeutic options, and there is a huge unmet need for new therapies. A growing body of evidence suggests that the histone deacetylase (HDAC) family of transcriptional corepressors has emerged as crucial mediators of IPF pathogenesis. HDACs deacetylate histones and result in chromatin condensation and epigenetic repression of gene transcription. HDACs also catalyse the deacetylation of many non-histone proteins, including transcription factors, thus also leading to changes in the transcriptome and cellular signalling. Increased HDAC expression is associated with cell proliferation, cell growth and anti-apoptosis and is, thus, a salient feature of many cancers. In IPF, induction and abnormal upregulation of Class I and Class II HDAC enzymes in myofibroblast foci, as well as aberrant bronchiolar epithelium, is an eminent observation, whereas type-II alveolar epithelial cells (AECII) of IPF lungs indicate a significant depletion of many HDACs. We thus suggest that the significant imbalance of HDAC activity in IPF lungs, with a "cancer-like" increase in fibroblastic and bronchial cells versus a lack in AECII, promotes and perpetuates fibrosis. This review focuses on the mechanisms by which Class I and Class II HDACs mediate fibrogenesis and on the mechanisms by which various HDAC inhibitors reverse the deregulated epigenetic responses in IPF, supporting HDAC inhibition as promising IPF therapy.

miRNA expression in COVID-19.

Coronavirus disease 2019 (COVID-19) is regarded as a challenge in health system. Several studies have assessed the immune-related aspect of this disorder to identify the host-related factors that affect the course of COVID-19. microRNAs (miRNAs) as potent regulators of immune responses have gained much attention in this regard. Recent studies have shown aberrant expression of miRNAs in COVID-19 in association with disease course. Differentially expressed miRNAs have been enriched in pathways related with inflammation and antiviral immune response. miRNAs have also been regarded as potential therapeutic targets in COVID-19, particularly for management of pathological consequences of COVID-19. In the current review, we summarize the data about dysregulation of miRNAs in COVID-19.

Microtubule depolymerization limits porcine betacoronavirus PHEV replication.

Porcine hemagglutinating encephalomyelitis virus (PHEV) is a typical neurotropic betacoronavirus causing digestive disease and/or neurological dysfunction in neonatal pigs. Actin filaments have been identified to implicate in PHEV invasion, but the effects of viral infection on microtubules (MTs) cytoskeleton are unknown. Here, we observed that PHEV infection induced MT depolymerization and was accompanied by the disappearance of microtubule organizing centers. Depolymerization of MTs induced by nocodazole significantly inhibited viral RNA replication, but over-polymerization of MTs induced by paclitaxel did not substantially affect PHEV infection. The expression of histone deacetylase 6 (HDAC6), an important regulator of MT acetylation, progressively increased during PHEV infection. Tramstatin A could alter HDAC6 deacetylase activity to enhance the acetylation of the substrate α-tubulin and MT polymerization, but does not increase PHEV proliferation. These findings suggest that PHEV could subvert host MT cytoskeleton to facilitate infection, and that MT depolymerization negatively affects viral replication independently of HDAC6 activity.

HDAC Inhibition as Neuroprotection in COVID-19 Infection.

The SARS-CoV-2 virus is responsible for COVID-19 affecting millions of humans around the world. COVID-19 shows various clinical symptoms (fever, cough, fatigue, diarrhea, body aches, headaches, anosmia, and hyposmia). Approximately 30% of patients with COVID-19 showed neurological symptoms, from mild to severe manifestations including headache, dizziness, impaired consciousness, encephalopathy, anosmia, hypogeusia, and hyposmia, among others. The neurotropism of the SARS-CoV-2 virus explains its neuroinvasion provoking neurological damage such as acute demyelination, neuroinflammation, etc. At the molecular level, the COVID-19 patients had higher levels of cytokines and chemokines known as cytokines storms which disrupt the blood-brain barrier allowing the entrance of monocytes and lymphocytes, causing neuroinflammation, neurodegeneration, and demyelination. In addition, the proinflammatory cytokines have been observed in ischemic, hemorrhagic strokes, seizures, and encephalopathy. In this sense, early neuroprotective management should be adopted to avoid or decrease neurological damage due to SARS-CoV-2 infection. Several approaches can be used; one of them includes using HDAC inhibitors (HDACi) due to their neuroprotective effects. Also, the HDACi down-regulates the proinflammatory cytokines (IL-6 and TNF-α) decreasing the neurotoxicity. HDACi can also avoid and prevent the entrance of the virus into the central nervous System (CNS) and decrease the virus replication by downregulating the virus receptors. Here we review the mechanisms that could explain how the SARS-CoV-2 virus could reach the CNS, induce neurological damage and symptoms, and the possibility to use HDACi as neuroprotective therapy.

Epigenetic targeting of the ACE2 and NRP1 viral receptors limits SARS-CoV-2 infectivity.

BACKGROUND: SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1) receptors for entry into cells, and the serine protease TMPRSS2 for S protein priming. Inhibition of protease activity or the engagement with ACE2 and NRP1 receptors has been shown to be an effective strategy for blocking infectivity and viral spreading. Valproic acid (VPA; 2-propylpentanoic acid) is an epigenetic drug approved for clinical use. It produces potent antiviral and anti-inflammatory effects through its function as a histone deacetylase (HDAC) inhibitor. Here, we propose VPA as a potential candidate to tackle COVID-19, in which rapid viral spread and replication, and hyperinflammation are crucial elements. RESULTS: We used diverse cell lines (HK-2, Huh-7, HUVEC, Caco-2, and BEAS-2B) to analyze the effect of VPA and other HDAC inhibitors on the expression of the ACE-2 and NRP-1 receptors and their ability to inhibit infectivity, viral production, and the inflammatory response. Treatment with VPA significantly reduced expression of the ACE2 and NRP1 host proteins in all cell lines through a mechanism mediated by its HDAC inhibitory activity. The effect is maintained after SARS-CoV-2 infection. Consequently, the treatment of cells with VPA before infection impairs production of SARS-CoV-2 infectious viruses, but not that of other ACE2- and NRP1-independent viruses (VSV and HCoV-229E). Moreover, the addition of VPA 1 h post-infection with SARS-CoV-2 reduces the production of infectious viruses in a dose-dependent manner without significantly modifying the genomic and subgenomic messenger RNAs (gRNA and sg mRNAs) or protein levels of N protein. The production of inflammatory cytokines (TNF-α and IL-6) induced by TNF-α and SARS-CoV-2 infection is diminished in the presence of VPA. CONCLUSIONS: Our data showed that VPA blocks three essential processes determining the severity of COVID-19. It downregulates the expression of ACE2 and NRP1, reducing the infectivity of SARS-CoV-2; it decreases viral yields, probably because it affects virus budding or virions stability; and it dampens the triggered inflammatory response. Thus, administering VPA could be considered a safe treatment for COVID-19 patients until vaccines have been rolled out across the world.

MicroRNAs based regulation of cytokine regulating immune expressed genes and their transcription factors in COVID-19.

BACKGROUND: Coronavirus disease 2019 is characterized by the elevation of a broad spectrum of inflammatory mediators associated with poor disease outcomes. We aimed at an in-silico analysis of regulatory microRNA and their transcription factors (TF) for these inflammatory genes that may help to devise potential therapeutic strategies in the future. METHODS: The cytokine regulating immune-expressed genes (CRIEG) were sorted from literature and the GEO microarray dataset. Their co-differentially expressed miRNA and transcription factors were predicted from publicly available databases. Enrichment analysis was done through mienturnet, MiEAA, Gene Ontology, and pathways predicted by KEGG and Reactome pathways. Finally, the functional and regulatory features were analyzed and visualized through Cytoscape. RESULTS: Sixteen CRIEG were observed to have a significant protein-protein interaction network. The ontological analysis revealed significantly enriched pathways for biological processes, molecular functions, and cellular components. The search performed in the miRNA database yielded ten miRNAs that are significantly involved in regulating these genes and their transcription factors. CONCLUSION: An in-silico representation of a network involving miRNAs, CRIEGs, and TF, which take part in the inflammatory response in COVID-19, has been elucidated. Thus, these regulatory factors may have potentially critical roles in the inflammatory response in COVID-19 and may be explored further to develop targeted therapeutic strategies and mechanistic validation.

How Influenza Virus Uses Host Cell Pathways during Uncoating.

Influenza is a zoonotic respiratory disease of major public health interest due to its pandemic potential, and a threat to animals and the human population. The influenza A virus genome consists of eight single-stranded RNA segments sequestered within a protein capsid and a lipid bilayer envelope. During host cell entry, cellular cues contribute to viral conformational changes that promote critical events such as fusion with late endosomes, capsid uncoating and viral genome release into the cytosol. In this focused review, we concisely describe the virus infection cycle and highlight the recent findings of host cell pathways and cytosolic proteins that assist influenza uncoating during host cell entry.

Recent Advances in Pathology: the 2021 Annual Review Issue of The Journal of Pathology.

The 2021 Annual Review Issue of The Journal of Pathology contains 14 invited reviews on current research areas of particular importance in pathology. The subjects included here reflect the broad range of interests covered by the journal, including both basic and applied research fields but always with the aim of improving our understanding of human disease. This year, our reviews encompass the huge impact of the COVID-19 pandemic, the development and application of biomarkers for immune checkpoint inhibitors, recent advances in multiplexing antigen/nucleic acid detection in situ, the use of genomics to aid drug discovery, organoid methodologies in research, the microbiome in cancer, the role of macrophage-stroma interactions in fibrosis, and TGF-ß as a driver of fibrosis in multiple pathologies. Other reviews revisit the p53 field and its lack of clinical impact to date, dissect the genetics of mitochondrial diseases, summarise the cells of origin and genetics of sarcomagenesis, provide new data on the role of TRIM28 in tumour predisposition, review our current understanding of cancer stem cell niches, and the function and regulation of p63. The reviews are authored by experts in their field from academia and industry, and provide comprehensive updates of the chosen areas, in which there has been considerable recent progress. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Computationally predicted SARS-COV-2 encoded microRNAs target NFKB, JAK/STAT and TGFB signaling pathways.

Recently an outbreak that emerged in Wuhan, China in December 2019, spread to the whole world in a short time and killed >1,410,000 people. It was determined that a new type of beta coronavirus called severe acute respiratory disease coronavirus type 2 (SARS-CoV-2) was causative agent of this outbreak and the disease caused by the virus was named as coronavirus disease 19 (COVID19). Despite the information obtained from the viral genome structure, many aspects of the virus-host interactions during infection is still unknown. In this study we aimed to identify SARS-CoV-2 encoded microRNAs and their cellular targets. We applied a computational method to predict miRNAs encoded by SARS-CoV-2 along with their putative targets in humans. Targets of predicted miRNAs were clustered into groups based on their biological processes, molecular function, and cellular compartments using GO and PANTHER. By using KEGG pathway enrichment analysis top pathways were identified. Finally, we have constructed an integrative pathway network analysis with target genes. We identified 40 SARS-CoV-2 miRNAs and their regulated targets. Our analysis showed that targeted genes including NFKB1, NFKBIE, JAK1-2, STAT3-4, STAT5B, STAT6, SOCS1-6, IL2, IL8, IL10, IL17, TGFBR1-2, SMAD2-4, HDAC1-6 and JARID1A-C, JARID2 play important roles in NFKB, JAK/STAT and TGFB signaling pathways as well as cells' epigenetic regulation pathways. Our results may help to understand virus-host interaction and the role of viral miRNAs during SARS-CoV-2 infection. As there is no current drug and effective treatment available for COVID19, it may also help to develop new treatment strategies.

MicroRNAs Bioinformatics Analyses Identifying HDAC Pathway as a Putative Target for Existing Anti-COVID-19 Therapeutics.

Over 313,000 SARS-CoV-2 positive cases have been confirmed in Italy as of 30 September 2020, and the number of deaths exceeding thirty-five thousand makes Italy among the list of most significantly affected countries in the world. Such an enormous occurrence of infections and death raises the urgent demand for effective available treatments. Discovering the cellular/molecular mechanisms of SARS-CoV-2 pathogenicity is of paramount importance to understand how the infection becomes a disease and how to plan any therapeutic approach. In this regard, we performed an in silico analysis to predict the putative virus targets and evidence the already available therapeutics. Literature experimental results identified angiotensin-converting enzyme ACE and Spike proteins particularly involved in COVID-19. Consequently, we investigated the signalling pathways modulated by the two proteins through query miRNet, the platform linking miRNAs, targets, and functions. Our bioinformatics analysis predicted microRNAs (miRs), miR-335-5p and miR-26b-5p, as being modulated by Spike and ACE together with histone deacetylate (HDAC) pathway. Notably, our results identified ACE/ACE2-ATR1-Cholesterol-HDAC axis signals that also matched with some available clinical data. We hypothesize that the current and EMA-approved, SARS-CoV-2 off-label HDAC inhibitors (HDACis) drugs may be repurposed to limit or block host-virus interactions. Moreover, a ranked list of compounds is provided for further evaluation for safety, efficacy, and effectiveness.

Repurposing of histone deacetylase inhibitors: A promising strategy to combat pulmonary fibrosis promoted by TGF-ß signalling in COVID-19 survivors.

Coronavirus disease 2019 (COVID-19) has rapidly spread around the world causing global public health emergency. In the last twenty years, we have witnessed several viral epidemics such as severe acute respiratory syndrome coronavirus (SARS-CoV), Influenza A virus subtype H1N1 and most recently Middle East respiratory syndrome coronavirus (MERS-CoV). There were tremendous efforts endeavoured globally by scientists to combat these viral diseases and now for SARS-CoV-2. Several drugs such as chloroquine, arbidol, remdesivir, favipiravir and dexamethasone are adopted for use against COVID-19 and currently clinical studies are underway to test their safety and efficacy for treating COVID-19 patients. As per World Health Organization reports, so far more than 16 million people are affected by COVID-19 with a recovery of close to 10 million and deaths at 600,000 globally. SARS-CoV-2 infection is reported to cause extensive pulmonary damages in affected people. Given the large number of recoveries, it is important to follow-up the recovered patients for apparent lung function abnormalities. In this review, we discuss our understanding about the development of long-term pulmonary abnormalities such as lung fibrosis observed in patients recovered from coronavirus infections (SARS-CoV and MERS-CoV) and probable epigenetic therapeutic strategy to prevent the development of similar pulmonary abnormalities in SARS-CoV-2 recovered patients. In this regard, we address the use of U.S. Food and Drug Administration (FDA) approved histone deacetylase (HDAC) inhibitors therapy to manage pulmonary fibrosis and their underlying molecular mechanisms in managing the pathologic processes in COVID-19 recovered patients.

Natural products as LSD1 inhibitors for cancer therapy.

Natural products generally fall into the biologically relevant chemical space and always possess novel biological activities, thus making them a rich source of lead compounds for new drug discovery. With the recent technological advances, natural product-based drug discovery is now reaching a new era. Natural products have also shown promise in epigenetic drug discovery, some of them have advanced into clinical trials or are presently being used in clinic. The histone lysine specific demethylase 1 (LSD1), an important class of histone demethylases, has fundamental roles in the development of various pathological conditions. Targeting LSD1 has been recognized as a promising therapeutic option for cancer treatment. Notably, some natural products with different chemotypes including protoberberine alkaloids, flavones, polyphenols, and cyclic peptides have shown effectiveness against LSD1. These natural products provide novel scaffolds for developing new LSD1 inhibitors. In this review, we mainly discuss the identification of natural LSD1 inhibitors, analysis of the co-crystal structures of LSD1/natural product complex, antitumor activity and their modes of action. We also briefly discuss the challenges faced in this field. We believe this review will provide a landscape of natural LSD1 inhibitors.

Nrf2 Activator PB125® as a Potential Therapeutic Agent against COVID-19.

Nrf2 is a transcription factor that regulates cellular redox balance and the expression of a wide array of genes involved in immunity and inflammation, including antiviral actions. Nrf2 activity declines with age, making the elderly more susceptible to oxidative stress-mediated diseases, which include type 2 diabetes, chronic inflammation, and viral infections. Published evidence suggests that Nrf2 activity may regulate important mechanisms affecting viral susceptibility and replication. We examined gene expression levels by GeneChip microarray and by RNA-seq assays. We found that the potent Nrf2-activating composition PB125® downregulates ACE2 and TMPRSS2 mRNA expression in human liver-derived HepG2 cells. ACE2 is a surface receptor and TMPRSS2 activates the spike protein for SARS-CoV-2 entry into host cells. Furthermore, in endotoxin-stimulated primary human pulmonary artery endothelial cells, we report the marked downregulation by PB125 of 36 genes encoding cytokines. These include IL-1-beta, IL-6, TNF-α, the cell adhesion molecules ICAM-1, VCAM-1, and E-selectin, and a group of IFN-γ-induced genes. Many of these cytokines have been specifically identified in the "cytokine storm" observed in fatal cases of COVID-19, suggesting that Nrf2 activation may significantly decrease the intensity of the storm.