Epigenetic underpinnings of the autistic mind: Histone modifications and prefrontal excitation/inhibition imbalance.

Autism spectrum disorder (ASD) is complex neurobehavioral condition influenced by several cellular and molecular mechanisms that are often concerned with synaptogenesis and synaptic activity. Based on the excitation/inhibition (E/I) imbalance theory, ASD could be the result of disruption in excitatory and inhibitory synaptic transmission across the brain. The prefrontal cortex (PFC) is the chief regulator of executive function and can be affected by altered neuronal excitation and inhibition in the course of ASD. The molecular mechanisms involved in E/I imbalance are subject to epigenetic regulation. In ASD, altered enrichment and spreading of histone H3 and H4 modifications such as the activation-linked H3K4me2/3, H3K9ac, and H3K27ac, and repression-linked H3K9me2, H3K27me3, and H4K20me2 in the PFC result in dysregulation of molecules mediating synaptic excitation (ARC, EGR1, mGluR2, mGluR3, GluN2A, and GluN2B) and synaptic inhibition (BSN, EphA7, SLC6A1). Histone modifications are a dynamic component of the epigenetic regulatory elements with a pronounced effect on patterns of gene expression with regards to any biological process. The excitation/inhibition imbalance associated with ASD is based on the excitatory and inhibitory synaptic activity in different regions of the brain, including the PFC, the ultimate outcome of which is highly influenced by transcriptional activity of relevant genes.

Anti-cancer potential of zerumbone in cancer and glioma: current trends and future perspectives.

Plant-derived immunomodulators and antitumor factors have appealed lots of attention from natural product scientists for their efficiency and safety and their important contribution to well-designed targeted drug action and delivery mechanisms. Zerumbone (ZER), the chief component of Zingiber zerumbet rhizomes, has been examined for its wide-spectrum in the treatment of multi-targeted diseases. The rhizomes have been used as food flavoring agents in numerous cuisines and in flora medication. Numerous in vivo and in vitro experiments have prepared confirmation of ZER as a potent immunomodulator as well as a potential anti-tumor agent. This review is an interesting compilation of all the important results of the research carried out to date to investigate the immunomodulatory and anticancer properties of ZER. The ultimate goal of this comprehensive review is to supply updated information and a crucial evaluation on ZER, including its chemistry and immunomodulating and antitumour properties, which may be of principal importance to supply a novel pathway for subsequent investigation to discover new agents to treat cancers and immune-related sickness. In addition, updated information on the toxicology of ZER has been summarized to support its safety profile.

Percutaneous Coronary Intervention Associated with a Higher Risk of Hypoxemia and COVID-19 Severity.

OBJECTIVE: The primary goal of the present study was to measure the implications of hypoxemia in COVID-19 patients with a history of coronary artery disease (CAD). METHODS: A systematic search of the literature published from November 1, 2019 to May 1, 2021, was conducted on PubMed/MEDLINE, Embase, and Web of Science databases. Afterwards, an observational study was designed based on the electronic health records of COVID-19 patients hospitalized in a tertiary referral hospital during the same period. A total of 179 COVID-19 cases were divided into two groups: cases with a history of CAD and percutaneous coronary intervention (CAD/PCI+, n = 89) and controls (n = 90). Clinical data were extracted from the electronic database of the hospital and statistically analyzed. RESULTS: After the application of inclusion/exclusion criteria, only three studies were deemed eligible, one of which was concerned with the impact of CAD on the all-cause mortality of COVID-19. Results from our observational study indicated that the cases were older (median age: 74 vs. 45) and more likely to develop hypoxemia (25.8% vs. 8.8%) than the controls. CAD/PCI+ was correlated with a more severe COVID-19 (11% vs. 1%). Age was a moderately significant independent predictor of increased COVID-19 severity, while hypoxemia was not. CONCLUSION: Considering the negative impact of hypoxemia on the prognosis of COVID-19 and its higher prevalence among COVID-19 patients with underlying CAD, further research is warranted to unravel the negative effects of COVID-19 on the mechanisms of gas exchange and delivery in patients with pre-existing CAD.

Oncolytic viruses improve cancer immunotherapy by reprogramming solid tumor microenvironment.

Immunotherapies using immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T-cell therapy have achieved successful results against several types of human tumors, particularly hematological malignancies. However, their clinical results for the treatment of solid tumors remain poor and unsatisfactory. The immunosuppressive tumor microenvironment (TME) plays an important role by interfering with intratumoral T-cell infiltration, promoting effector T-cell exhaustion, upregulating inhibitory molecules, inducing hypoxia, and so on. Oncolytic viruses are an encouraging biocarrier that could be used in both natural and genetically engineered platforms to induce oncolysis in a targeted manner. Oncolytic virotherapy (OV) contributes to the reprogramming of the TME, thus synergizing the functional effects of current ICIs and CAR T-cell therapy to overcome resistant barriers in solid tumors. Here, we summarize the TME-related inhibitory factors affecting the therapeutic outcomes of ICIs and CAR T cells and discuss the potential of OV-based approaches to alleviate these barriers and improve future therapies for advanced solid tumors.

Involving stemness factors to improve CAR T-cell-based cancer immunotherapy.

Treatment with chimeric antigen receptor (CAR) T cells indicated remarkable clinical responses with liquid cancers such as hematological malignancies; however, their therapeutic efficacy faced with many challenges in solid tumors due to severe toxicities, antigen evasion, restricted and limited tumor tissue trafficking and infiltration, and, more importantly, immunosuppressive tumor microenvironment (TME) factors that impair the CAR T-cell function adds support survival of cancer stem cells (CSCs), responsible for tumor recurrence and resistance to current cancer therapies. Therefore, in-depth identification of TME and development of more potent CAR platform targeting CSCs may overcome the raised challenges, as presented in this review. We also discuss recent stemness-based innovations in CAR T-cell production and engineering to improve their efficacy in vivo, and finally, we propose solutions and strategies such as oncolytic virus-based therapy and combination therapy to revive the function of CAR T-cell therapy, especially in TME of solid tumors in future.

Resveratrol as an antitumor agent for glioblastoma multiforme: Targeting resistance and promoting apoptotic cell deaths.

Glioblastoma multiforme (GBM) is one of the most aggressive brain and spinal cord tumors. Despite the significant development in application of antitumor drugs, no significant increases have been observed in the survival rates of patients with GBM, as GBM cells acquire resistance to conventional anticancer therapeutic agents. Multiple studies have revealed that PI3K/Akt, MAPK, Nanog, STAT 3, and Wnt signaling pathways are involved in GBM progression and invasion. Besides, biological processes such as anti-apoptosis, autophagy, angiogenesis, and stemness promote GBM malignancy. Resveratrol (RESV) is a non-flavonoid polyphenol with high antitumor activity, the potential of which, regulating signaling pathways involved in cancer malignancy, have been demonstrated by many studies. Herein, we present the potential of RESV in both single and combination therapy- targeting various signaling pathways- which induce apoptotic cell death, re-sensitize cancer cells to radiotherapy, and induce chemo-sensitizing effects to eventually inhibit GBM progression.

The SARS-Cov-2 Proliferation Blocked by a Novel and Potent Main Protease Inhibitor via Computer-aided Drug Design.

The recent prevalence of novel "coronavirus disease 2019" has expanded quickly globally, causing a universal pandemic. Herein, an effort was constructed to design a potent drug to inhibit the main protease of SARS-Cov-2 (3CLp) by means of structure-based drug design. A large library of the compounds was used for virtual screening. After molecular docking and ADME studies, we selected a compound with a better binding affinity to the 3CLp active site and acceptable ADME properties compared to the selected positive control drug. Molecular dynamic (MD) simulation (200 ns) and Molecular Mechanics-Poisson Boltzmann Surface Area (MM-PBSA) were used for further analysis. MD simulation outcomes have proved that the 3CLp-ZINC31157475 complex possesses a considerable value of dynamic properties such as flexibility, stability, compactness, and binding energy. Our MM-PBSA computation illustrates that ZINC31157475 is more potent (-88.03 kcal mol-1) than nelfinavir (-19.54 kcal mol-1) against COVID-19 3CLp. Further, we have determined that the main residues of the 3CLp interact with ligands from per-residue binding energy. In conclusion, we suggest that ZINC31157475 can potentially treat COVID-19 by inhibition of the 3CLp. However, in-vitro and in-vivo study is essential for approval of this suggestion.

Using Ozone Therapy as an Option for Treatment of COVID-19 Patients: A Scoping Review.

Recent investigations are seeking a novel treatment to control the new pandemic of coronavirus 19 (COVID-19). The aim of this systematic review was to study the effect of ozone therapy on COVID-19 patients and the available supporting evidence. Electronic databases including MEDLINE (via PubMed), EMBASE, Cochrane Library (CENTRAL), and TRIP, clinical trial registries, and preprint sources were searched for published evidence-based articles. In addition, manual searching was conducted for articles published up to April 6, 2020, using MeSH and free text keywords with no language limitation. Articles were screened, categorized, and extracted for relative data. Data were reported in a descriptive manner. Among 234 articles, 9 were selected for review of the inclusion criteria. No published original articles were found regarding the efficacy of ozone therapy on COVID-19. Five review studies were found in which the potential role of systemic ozone therapy was concluded to be effective in controlling COVID-19 because of its antiviral, oxygenation, anti-inflammatory, oxidation balancing, and immunomodulation effects. Three ongoing clinical trials were registered in China. A preliminary report of an ongoing study in Italy on 46 patients (11 intubated and 35 non-intubated) showed that in 39 (84%) of the patients, an improvement was seen. In spite of the promising background data, as well as the expert opinions and a preliminary report indicating the effectiveness of ozone, there is still not enough evidence to confirm this as a viable treatment option for COVID-19.

Merkel cell carcinoma on the right calf in association with chronic lymphocytic leukemia: A case report.

This study showed a rare case of Merkel cell carcinoma (MCC) with atypical manifestations accompanied by chronic lymphocytic leukemia of B-cell type that underwent chemotherapy and had poor prognosis. The findings suggest that the physicians should consider MCC when performing diagnosis and assess all possible associated risk factors like neoplasms to achieve good prognosis.

Neurokinin-1 Receptor (NK-1R) Antagonists: Potential Targets in the Treatment of Glioblastoma Multiforme.

The current standard of care in glioblastoma multiforme (GBM), as the most morbid brain tumor, is not adequate, despite substantial progress in cancer therapy. Among patients receiving current standard treatments, including surgery, irradiation, and chemotherapy, the overall survival (OS) period with GBM is less than one year. The high mortality frequency of GBM is due to its aggressive nature, including accelerated growth, deregulated apoptosis, and invasion into surrounding tissues. The understanding of the molecular pathogenesis of GBM is, therefore, crucial for identifying, designing, and repurposing potential agents in future therapeutic approaches. In recent decades, it has been apparent that several neurotransmitters, specifically substance P (SP), an undecapeptide in the family of neuropeptides tachykinins, are found in astrocytes. After binding to the neurokinin-1 receptor (NK-1R), the SP controls cancer cell growth, exerts antiapoptotic impacts, stimulates cell invasion/metastasis, and activates vascularization. Since SP/NK-1R signaling pathway is a growth driver in many cancers, this potential mechanism is proposed as an additional target for treating GBM. Following an evaluation of the function of both SP and its NK-1R inhibitors in neoplastic cells, we recommend a unique and promising approach for the treatment of patients with GBM.