Evaluation of the relationship between serum levels of zinc, vitamin B12, vitamin D, and clinical outcomes in patients with COVID-19.

Due to the known anti-inflammatory and antiviral effects of zinc, 25(OH)D, and vitamin B12, in this study, we explored the association between serum levels of these micronutrients in coronavirus disease 2019 (COVID-19) patients at the time of admission and the clinical outcomes. This study was carried out on 293 patients with COVID-19, who were hospitalized at Imam Hassan hospital (Bojnourd, Iran). We collected demographic data, clinical characteristics, values of serum biochemical parameters in the first week of admission, and clinical outcomes from electronic medical records. We also measured serum levels of zinc, 25(OH)D, and vitamin B12 within 3 days of admission. Of the 293 hospitalized, the median age was 53 years, and 147 (50.17%) were female. Thirty-seven patients (12.62%) were admitted to the intensive care unit (ICU), and forty-two (14.32%) died. We found that the serum levels of zinc, vitamin B12, and 25(OH)D were lower in patients who died than those who were admitted to ICU or non-ICU and survived; however, these differences were not statistically significant for vitamin B12 and 25(OH)D (p > 0.05). The serum concentrations of zinc, vitamin B12, and 25(OH)D at the time of admission did not affect the length of hospital stay in patients with COVID-19. In general, it seems that serum levels of 25(OH)D, vitamin B12, and especially zinc at the time of admission can affect clinical outcomes in COVID-19 patients.

Recent advancements in decellularized matrix technology for bone tissue engineering.

The native extracellular matrix (ECM) provides a matrix to hold tissue/organ, defines the cellular fate and function, and retains growth factors. Such a matrix is considered as a most biomimetic scaffold for tissue engineering due to the biochemical and biological components, 3D hierarchical structure, and physicomechanical properties. Several attempts have been performed to decellularize allo- or xeno-graft tissues and used them for bone repairing and regeneration. Decellularized ECM (dECM) technology has been developed to create an in vivo-like microenvironment to promote cell adhesion, growth, and differentiation for tissue repair and regeneration. Decellularization is mediated through physical, chemical, and enzymatic methods. In this review, we describe the recent progress in bone decellularization and their applications as a scaffold, hydrogel, bioink, or particles in bone tissue engineering. Furthermore, we address the native dECM limitations and the potential of non-bone dECM, cell-based ECM, and engineered ECM (eECM) for in vitro osteogenic differentiation and in vivo bone regeneration.

Prospective therapeutic potential of Tanshinone IIA: An updated overview.

In the past decades, the branch of complementary and alternative medicine based therapeutics has gained considerable attention worldwide. Pharmacological efficacy of various traditional medicinal plants, their products and/or product derivatives have been explored on an increasing scale. Tanshinone IIA (Tan IIA) is a pharmacologically active lipophilic component of Salvia miltiorrhiza extract. Tan IIA shares a history of high repute in Traditional Chinese Medicine. Reckoning with these, the present review collates the pharmacological properties of Tan IIA with a special emphasis on its therapeutic potential against diverse diseases including cardiovascular diseases, cerebrovascular diseases, cancer, diabetes, obesity and neurogenerative diseases. Further, possible applications of various therapeutic preparations of Tan IIA were discussed with special emphasis on nano-based drug delivery formulations. Considering the tremendous advancement in the field of nanomedicine and the therapeutic potential of Tan IIA, the convergence of these two aspects can be foreseen with great promise in clinical application.

Neutrophil elastase inhibitor (sivelestat) may be a promising therapeutic option for management of acute lung injury/acute respiratory distress syndrome or disseminated intravascular coagulation in COVID-19.

WHAT IS KNOWN AND OBJECTIVE: This article summarizes the effects of sivelestat on acute lung injury/acute respiratory distress syndrome (ALI/ARDS) or ARDS with coagulopathy, both of which are frequently seen in patients with COVID-19. COMMENT: COVID-19 patients are more susceptible to thromboembolic events, including disseminated intravascular coagulation (DIC). Various studies have emphasized the role of neutrophil elastase (NE) in the development of DIC in patients with ARDS and sepsis. It has been shown that NE inhibition by sivelestat mitigates ALI through amelioration of injuries in alveolar epithelium and vascular endothelium, as well as reversing the neutrophil-mediated increased vascular permeability. WHAT IS NEW AND CONCLUSIONS: Sivelestat, a selective NE inhibitor, has not been evaluated for its possible therapeutic effects against SARS-CoV-2 infection. Based on its promising beneficial effects in underlying complications of COVID-19, sivelestat could be considered as a promising modality for better management of COVID-19-induced ALI/ARDS or coagulopathy.

Closing-Wedge and Opening-Wedge High Tibial Osteotomy as Successful Treatments of Symptomatic Medial Osteoarthritis of the Knee: A Randomized Controlled Trial.

Objectives: Closing-wedge high tibial osteotomy (CWHTO) and opening-wedge high tibial osteotomy (OWHTO) are commonly used osteotomy techniques for the symptomatic knee osteoarthritis treatment. However, there is no consensus on which method provides superior outcomes. In this study, we compared the clinical outcomes, radiologic outcomes, and postoperative complications of these techniques. Methods: In a randomized controlled trial, 76 patients with medial compartment knee osteoarthritis and associated varus malalignment were randomized into the CWHTO and OWHTO groups (n=38). The primary outcome measures were knee function evaluated by Knee Injury and Osteoarthritis Outcome Score (KOOS) and knee pain assessed by a visual analog scale. The secondary outcome measures were posterior tibial slope (PTS), tibial bone varus angle, and postoperative complications. Results: Both techniques significantly improved the clinical and radiologic outcome measures. The mean improvement of total KOOS was not significantly different between the CWHTO and OPHTO groups (P=0.55). Moreover, the improvement in various KOOS subscales was not significantly different between the two groups. The mean improvement of Visual Analogue Scale (VAS) was not significantly different between the CWHTO and OWHTO groups (P=0.89). The mean PTS change was not significantly different between the two groups (P=0.34). The mean improvement of the varus angle was not significantly different between the two groups (P=0.28). The rate of postoperative complications was not remarkably different between the CWHTO and OWHTO groups. Conclusion: Considering no observed superiority of each osteotomy technique over the other one, two techniques could be used interchangeably and based on the surgeon's preference.

The Virulent Hypothetical Proteins: The Potential Drug Target Involved in Bacterial Pathogenesis.

Hypothetical proteins (HPs) are non-predicted sequences that are identified only by open reading frames in sequenced genomes, but their protein products remain uncharacterized by any experimental means. The genome of every species consists of HPs that are involved in various cellular processes and signaling pathways. Annotation of HPs is important as they play a key role in disease mechanisms, drug designing, vaccine production, antibiotic production, and host adaptation. In the case of bacteria, 25-50% of the genome comprises HPs, which are involved in metabolic pathways and pathogenesis. The characterization of bacterial HPs helps to identify virulent proteins that are involved in pathogenesis. This can be done using in-silico studies, which provide sequence analogs, physiochemical properties, cellular or subcellular localization, structure and function validation, and protein-protein interactions. The most diverse types of virulent proteins are exotoxins, endotoxins, and adherent virulent factors that are encoded by virulent genes present on the chromosomal DNA of the bacteria. This review evaluates virulent HPs of pathogenic bacteria, such as Staphylococcus aureus, Chlamydia trachomatis, Fusobacterium nucleatum, and Yersinia pestis. The potential of these HPs as a drug target in bacteria-caused infectious diseases, along with the mode of action and treatment approaches, has been discussed.

Aloe vera for Prevention of Acute Radiation Proctitis in Colorectal Cancer a Preliminary Randomized, Placebo-Controlled Clinical Trial.

OBJECTIVE: To examine the preventive effects of Aloe vera in colorectal cancer patients undergoing radiotherapy. MATERIAL AND METHOD: Twenty colorectal cancer patients, who received radiation, were randomized to receive Aloe vera 3% or placebo ointment, 1 g twice daily for 6 weeks. At weekly visits, acute radiation proctitis (ARP) was evaluated by Radiation Therapy Oncology Group and clinical presentation criteria as the primary endpoint. We also evaluated secondary endpoints of quality of life, psychosocial status, by applying Hospital Anxiety-Depression (HAD) Scale and laboratory measures of quantitative measurement of C-reactive protein (CRP) as a marker for systemic inflammation. RESULTS: There was a significant improvement in the symptom index (before treatment vs. after treatment with Aloe vera) for diarrhea (p = 0.029, median score: 0.5 vs. 0.001). The overall primary and secondary outcomes favored Aloe group, while the measures of toxicity did not achieve a statistical significant difference. The lifestyle score improved significantly with A. vera (p = 004), and they also had a lower depression score in HAD scale (p = 0.008). Furthermore, quantitative CRP decreased significantly during the course of treatment with Aloe vera. CONCLUSION: The use of topical formulation of Aloe vera 3% diminishes the severity of ARP in colorectal cancer patients.

Simultaneous nanocarrier-mediated delivery of siRNAs and chemotherapeutic agents in cancer therapy and diagnosis: Recent advances.

Recently, investigations have revealed that RNA interference (RNAi) has a remarkable potential to decrease cancer burden by downregulating genes. Among various RNAi molecules, small interfering RNA (siRNA) has been more attractive for this goal and is able to silence a target pathological path and promote the degradation of a certain mRNA, resulting in either gain or loss of function of proteins. Moreover, therapeutic siRNAs have exhibited low side effects compared to other therapeutic molecular candidates. Nevertheless, siRNA delivery has its own limitations including quick degradation in circulation, ineffective internalization and low passive uptake by cells, possible toxicity against off-target sites, and inducing unfavorable immune responses. Therefore, delivery tools must be able to specifically direct siRNAs to their target locations without inflicting detrimental effects on other sites. To conquer the mentioned problems, nanocarrier-mediated delivery of siRNAs, using inorganic nanoparticles (NPs), polymers, and lipids, has been developed as a biocompatible delivery approach. In this review, we have discussed recent advances in the siRNA delivery methods that employ nanoparticles, lipids, and polymers, as well as the inorganic-based co-delivery systems used to deliver siRNAs and anticancer agents to target cells.

Nitric Oxide and Immune Responses in Cancer: Searching for New Therapeutic Strategies.

In recent years, there has been an increasing interest in understanding the mysterious functions of nitric oxide (NO) and how this pleiotropic signaling molecule contributes to tumorigenesis. This review attempts to expose and discuss the information available on the immunomodulatory role of NO in cancer and recent approaches to the role of NO donors in the area of immunotherapy. To address the goal, the following databases were searched to identify relevant literature concerning empirical evidence: The Cochrane Library, Pubmed, Medline, and EMBASE from 1980 through March 2020. Valuable attempts have been made to develop distinctive NO-based cancer therapy. Although the data do not allow generalization, the evidence seems to indicate that low/moderate levels may favor tumorigenesis, while higher levels would exert antitumor effects. In this sense, the use of NO donors could have an important therapeutic potential within immunotherapy, although there are still no clinical trials. The emerging understanding of NO-regulated immune responses in cancer may help unravel the recent features of this "doubleedged sword" in cancer physiological and pathologic processes and its potential use as a therapeutic agent for cancer treatment. In short, in this review, we discuss the complex cellular mechanism in which NO, as a pleiotropic signaling molecule, participates in cancer pathophysiology. We also debate the dual role of NO in cancer and tumor progression and clinical approaches for inducible nitric oxide synthase (iNOS) based therapy against cancer.

The expression of miR-17 and miR-29a in placenta-derived exosomes in LPS-induced abortion mice model: An experimental study.

BACKGROUND: The expression pattern of microRNAs in placenta-derived exosomes plays a crucial role in the regulation of immune responses and inflammation at the fetal-maternal interface. OBJECTIVE: Considering the immunomodulatory properties of miR-17 and miR-29a, we determined their expression levels in placenta-derived exosomes in a lipopolysaccharide (LPS)-induced abortion mice model. MATERIALS AND METHODS: A total of 14 pregnant BALB/c mice, aged 6-8 wk, were randomly divided into two groups (n = 7/each) on the gestational day 11.5. While the mice in the experimental group were treated with LPS, those in the control group were treated with Phosphate buffered saline; 5 hr after the treatment, the placental cells were isolated and cultured for 48 hr. Then, the cell culture supernatants were collected and used for isolation of exosomes. The isolated exosomes were confirmed by western blot and scanning electron microscopy. The miRNAs were then extracted from exosomes, and cDNA synthesized. The expression levels of miR-17 and miR-29a were evaluated by quantitative real-time PCR analysis. RESULTS: Our results showed that the expression levels of miR-29a in placenta-derived exosomes obtained from the experimental group increased significantly compared to the control group. Also, the expression levels of miR-17 in the placenta-derived exosomes obtained from the experimental group were found to decrease; however, it did not show significant changes compared with the control group (p > 0.05). CONCLUSION: Inflammatory reactions at the fetal-maternal interface can alter miRNAs expression patterns in placenta-derived exosomes, especially miRNAs with immunomodulatory effects such as miR-29a.

Aromatic hydrocarbon receptors in mitochondrial biogenesis and function.

Mitochondria are ubiquitous membrane-bound organelles that not only play a key role in maintaining cellular energy homeostasis and metabolism but also in signaling and apoptosis. Aryl hydrocarbons receptors (AhRs) are ligand-activated transcription factors that recognize a wide variety of xenobiotics, including polyaromatic hydrocarbons and dioxins, and activate diverse detoxification pathways. These receptors are also activated by natural dietary compounds and endogenous metabolites. In addition, AhRs can modulate the expression of a diverse array of genes related to mitochondrial biogenesis and function. The aim of the present review is to analyze scientific data available on the AhR signaling pathway and its interaction with the intracellular signaling pathways involved in mitochondrial functions, especially those related to cell cycle progression and apoptosis. Various evidence have reported the crosstalk between the AhR signaling pathway and the nuclear factor κB (NF-κB), tyrosine kinase receptor signaling and mitogen-activated protein kinases (MAPKs). The AhR signaling pathway seems to promote cell cycle progression in the absence of exogenous ligands, whereas the presence of exogenous ligands induces cell cycle arrest. However, its effects on apoptosis are controversial since activation or overexpression of AhR has been observed to induce or inhibit apoptosis depending on the cell type. Regarding the mitochondria, although activation by endogenous ligands is related to mitochondrial dysfunction, the effects of endogenous ligands are not well understood but point towards antiapoptotic effects and inducers of mitochondrial biogenesis.

A Perspective on Erythropoietin as a Potential Adjuvant Therapy for Acute Lung Injury/Acute Respiratory Distress Syndrome in Patients with COVID-19.

The novel coronavirus 2019-nCoV (SARS-CoV-2) infection that emerged in China in December 2019 has rapidly spread to become a global pandemic. This article summarizes the potential benefits of erythropoietin (EPO) in alleviating SARS-CoV-2 pathogenesis which is now called COVID-19. As with other coronavirus infection, the lethality of COVID-19 is associated with respiratory dysfunction due to overexpression of proinflammatory cytokines induced by the host immune responses. The resulting cytokine storm leads to the development of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Erythropoietin, well known for its role in the regulation of erythropoiesis, may have protective effects against ALI/ARDS induced by viral and other pathogens. EPO exerts antiapoptotic and cytoprotective properties under various pathological conditions. With a high safety profile, EPO promotes the production of endothelial progenitor cells and reduce inflammatory processes through inhibition of the nuclear factor-κB (NF-κB) and JAK-STAT3 signaling pathways. Thus, it may be considered as a safe drug candidate for COVID-19 patients if given at the early stage of the disease. The potential effects of erythropoietin on different aspects of ALI/ARDS associated with SARS-CoV-2 infection are reviewed.

The prophylaxis and treatment potential of supplements for COVID-19.

The global impact of the new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), infection that caused COVID-19 has been evident in the last few months from the unprecedented socioeconomic disruption to more than 600,000 deaths. The lack of vaccine and effective therapeutic agents for the disease prompted world-wide effort to test those antiviral therapeutics already in use for other diseases. Another interesting approach has been based on the pathological sequel of the disease that involve severe inflammatory reaction (or the cytokine storm) associated with pneumonia in critically ill patients. This article outlines the prophylaxis therapeutic potential of supplements vitamins and micronutrients in COVID-19. By ameliorating the inflammatory and oxidative stress associated with the disease and some direct antiviral effects, the application of these agents as adjuvants and other alternative approaches are discussed. Available clinical trials including those currently registered on these supplements are scrutinized.

Pharmacological treatments of COVID-19.

The viral infection due to the new coronavirus or coronavirus disease 2019 (COVID-19), which was reported for the first time in December 2019, was named by the World Health Organization (WHO) as Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV2), because of the very similar genome and also its related symptoms to SARS-CoV1. The ongoing COVID-19 pandemic with significant mortality, morbidity, and socioeconomic impact is considered by the WHO as a global public health emergency. Since there is no specific treatment available for SARS-CoV2 infection, and or COVID-19, several clinical and sub-clinical studies are currently undertaken to find a gold-standard therapeutic regimen with high efficacy and low side effect. Based on the published scientific evidence published to date, we summarized herein the effects of different potential therapies and up-to-date clinical trials. The review is intended to help readers aware of potentially effective COVID-19 treatment and provide useful references for future studies.

Comparing the effect of volar plate fixators and external fixators on outcome of patients with intra-articular distal radius fractures: A clinical trial.

BACKGROUND: Distal radius fractures (DRFs) are much more prone to malunion than unstable extra-articular fractures. There is no clear consensus concerning what the proper treatment should be, and the best approach to use for displaced DRFs remains challenging. OBJECTIVE: To compare the effect of two different therapeutic surgical methods, i.e., volar plate fixators and external fixators, on outcomes of patients with intra-articular distal radius fractures. METHODS: From May 2010 to November 2014, 76 subjects who had experienced intra-articular fractures of the distal radius were enrolled in this double-blind, randomized, controlled trial in Imam Ali Hospital in Bojnourd, Iran. The patients were divided into two groups, i.e., 1) patients who were treated with internal fixation using the volar plate (group A) and 2) patients who were treated with external fixators (group B). The primary outcome was a composite measure of the patient's quality of life using three different scores, i.e., 1) the MAYO score, 2) Disabilities of the Arm, Shoulder, and Hand (DASH (score, and 3) the Short Form (36) (SF-36) Health Survey score. RESULTS: A total of 76 patients were allocated randomly to groups A and B. The mean ages for external fixator cases and volar plate cases were 51.7 and 46.3, respectively. No significant age distribution was seen between the two groups (p=0.348). Gender distribution between the two groups was not significantly different (p=0.022). Grip power was significantly different between the two groups, but no significant differences were detected in range of motion (p=0.008, p=0.367, respectively). The MAYO score was significantly higher in the open reduction and internal fixation (ORIF) group, and, according to the SF-36 test, the ORIF group also a higher level of general mental and physical health, social functioning, and personal physical functioning than the other group. However, postoperatively, the mental discomfort and physical discomfort were more prevalent in the external fixator group. The DASH score was not significantly different between the two groups (p=0.124). CONCLUSIONS: ORIF and its subtitle, volar plate fixation, is a more preferred surgical procedure than the external fixator for the treatment of intra-articular distal radius fractures. This conclusion is important when one considers cost-effectiveness and an earlier return to work. TRIAL REGISTRATION: The trial is registered at the Thai Clinical Trial Registry (clinicaltrials.in.th) with the TCR identification number TCTR20150609002. FUNDING: The authors received no financial support for the research, authorship, and/or publication of this article.