Small-molecule metabolites in SARS-CoV-2 treatment: a comprehensive review.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has quickly spread all over the world. In this respect, traditional medicinal chemistry, repurposing, and computational approaches have been exploited to develop novel medicines for treating this condition. The effectiveness of chemicals and testing methods in the identification of new promising therapies, and the extent of preparedness for future pandemics, have been further highly advantaged by recent breakthroughs in introducing noble small compounds for clinical testing purposes. Currently, numerous studies are developing small-molecule (SM) therapeutic products for inhibiting SARS-CoV-2 infection and replication, as well as managing the disease-related outcomes. Transmembrane serine protease (TMPRSS2)-inhibiting medicinal products can thus prevent the entry of the SARS-CoV-2 into the cells, and constrain its spreading along with the morbidity and mortality due to the coronavirus disease 2019 (COVID-19), particularly when co-administered with inhibitors such as chloroquine (CQ) and dihydroorotate dehydrogenase (DHODH). The present review demonstrates that the clinical-stage therapeutic agents, targeting additional viral proteins, might improve the effectiveness of COVID-19 treatment if applied as an adjuvant therapy side-by-side with RNA-dependent RNA polymerase (RdRp) inhibitors.

Investigate the immunogenic and protective effect of trivalent chimeric protein containing IpaD-StxB-TolC antigens as a vaccine candidate against S. dysenteri and S. flexneri.

BACKGROUNDS: Shigella spp. causes bloody diarrhea and leads to death, especially in children. Chimeric proteins containing virulence factors can prevent Shigella infection. The purpose of this study is to investigate the immunogenic and protective effect of trivalent chimeric protein containing IpaD-StxB-TolC antigens against shiga toxin, S. dysenteri and S. flexneri in vitro and in vivo conditions. METHODS: Recombinant vector was transferred to E. coli BL21. The expression of the chimeric protein was confirmed by SDS PAGE and purified using the Ni-NTA column. Mice were immunized with recombinant protein and antibody titer was evaluated by ELISA. 10, 25 and 50 LD50 of Shiga toxin neutralization was evaluated in vitro (Vero cell line) and in vivo conditions. Also, the challenge of immunized mice with 10, 25 and 50 LD50 of S. dysentery and S. flexneri was done. RESULTS: The expression and purification of the recombinant protein with 60.6 kDa was done. ELISA showed increased antibody titer against the chimeric protein. MTT assay indicated that 1/8000 dilution of the sera had a 51% of cell viability against the toxin in Vero cell line. The challenge of mice immunized with toxin showed that the mice had complete protection against 10 and 25 LD50 of toxin and had 40% survival against 50 LD50. Mice receiving 10 and 25 LD50 of S. dysenteri and S. flexneri had 100% protection and in 50 LD50 the survival rate was 60 and 50%, respectively. Organ burden showed that the amount of bacterial colonization in immunized mice was 1 × 104 CFU/mL, which was significantly different from the control group. CONCLUSION: This study showed that chimeric proteins can create favorable immunogenicity in the host as vaccine candidates.

Antibacterial and antibiofilm effects of green synthesized selenium nanoparticles on clinical Klebsiella pneumoniae isolates.

Nanotechnology covers many disciplines, including the biological sciences. In this study, selenium nanoparticles (Se-NPs) were synthesized using Artemisia annua extract and investigated against clinical strains of klebsiella pneumoniae (K. pneumoniae) for their anti-biofilm effects. In this experimental study, from May 1998 to September 1998, 50 clinical samples of blood, urine, and sputum were collected, and K. pneumoniae strains were isolated using microbiological methods. Subsequently, the antibacterial effects of Se-NPs at concentrations of 12-25-50-100/5-6/3-25/125 µg/mL were studied. Finally, biofilm-producing strains were isolated, and the expression of mrkA biofilm gene was studied in real-time strains treated with Se-NPs using real-time polymerase chain reaction (PCR). Out of 50 clinical samples, 20 strains of K. pneumoniae were isolated. Minimum inhibitory concentration (MIC) results of Se-NPs showed that Se-NPs were capable of significant cell killing. Real-time PCR results also showed that mrkA gene expression was significantly reduced in strains treated with Se-NPs. According to this study, Se-NPs could reduce bacterial growth and biofilm formation, therefore, could be considered a candidate drug in the medical application for infections caused by K. pneumoniae.

Investigation of the antibacterial and biofilm inhibitory activities ofPrangos acaulis(DC.) Bornm in nanoparticulated formulation.

Here in, a chitosan-based nanoformulation ofP.acauliswas evaluated for its antibacterial and antibiofilm inhibitory activities against some known food-borne bacteria. The FTIR, FE-SEM, DLS and zeta-potential analysis were performed for confirming loading process, morphological appearance, hydrodynamic diameter and surface charge of the nanoparticles respectively. The results confirmed that, the nanoparticles had semi-spherical shape with the mean hydrodynamic diameter and surface charge of 89.8 ± 5.8 nm and 10.78 ± 2.7 mv respectively. Furthermore, the FTIR analysis approved that the nanoparticles were successfully loaded with ethyl acetate fraction fromP.acaulis. The antibacterial and biofilm inhibitory activities of the nanoformulated fraction were significantly increased against the tested Gram positive strains than free sample. The results also confirmed that the fraction release from the nanoparticles follows a sustained manner release after 30 h in a logarithmic pattern. Based on the obtained results, chitosan based nanoformulation ofP. acauliscan be considered for more evaluations to serve as an alternative natural antibiotic.

Overview of the pre-clinical and clinical studies about the use of CAR-T cell therapy of cancer combined with oncolytic viruses.

BACKGROUND: Cancer is one of the critical issues of the global health system with a high mortality rate even with the available therapies, so using novel therapeutic approaches to reduce the mortality rate and increase the quality of life is sensed more than ever. MAIN BODY: CAR-T cell therapy and oncolytic viruses are innovative cancer therapeutic approaches with fewer complications than common treatments such as chemotherapy and radiotherapy and significantly improve the quality of life. Oncolytic viruses can selectively proliferate in the cancer cells and destroy them. The specificity of oncolytic viruses potentially maintains the normal cells and tissues intact. T-cells are genetically manipulated and armed against the specific antigens of the tumor cells in CAR-T cell therapy. Eventually, they are returned to the body and act against the tumor cells. Nowadays, virology and oncology researchers intend to improve the efficacy of immunotherapy by utilizing CAR-T cells in combination with oncolytic viruses. CONCLUSION: Using CAR-T cells along with oncolytic viruses can enhance the efficacy of CAR-T cell therapy in destroying the solid tumors, increasing the permeability of the tumor cells for T-cells, reducing the disturbing effects of the immune system, and increasing the success chance in the treatment of this hazardous disease. In recent years, significant progress has been achieved in using oncolytic viruses alone and in combination with other therapeutic approaches such as CAR-T cell therapy in pre-clinical and clinical investigations. This principle necessitates a deeper consideration of these treatment strategies. This review intends to curtly investigate each of these therapeutic methods, lonely and in combination form. We will also point to the pre-clinical and clinical studies about the use of CAR-T cell therapy combined with oncolytic viruses.

Molecular Characterization of Antibiotic Resistance and Genetic Diversity of Klebsiella pneumoniae Strains.

The aims of this study were the molecular characterization of antibiotic resistance and genotyping of Klebsiella pneumoniae strains isolated from clinical cases in Tehran, Iran. A total of 100 different types of clinical human samples were collected from a major teaching hospital in Tehran, Iran. Bacterial isolates were identified using standard microbiological tests. Antimicrobial susceptibility testing was done according to the latest CLSI guidelines. PCR was used to amplify the gyrA gene in quinolone-resistant isolates and sequencing was performed for the detection of probable mutations between the isolates. The occurrence of plasmid-mediated quinolone resistance genes (qnrA, qnrB, and qnrS) was also investigated by PCR. Finally, genotyping of the strains was performed by PFGE in a standard condition. The susceptibility pattern revealed a high and low level of resistance against meropenem (20%) and trimethoprim (37%), respectively. PCR and sequencing detected mutation in the gyrA gene in 51% of quinolone-resistant K. pneumoniae. According to the susceptibility report, among nalidixic acid-resistant strains, 60.5%, 50%, and 42.9% of isolates contained qnrA, qnrB, and qnrS, respectively. Among ciprofloxacin-resistant strains, qnrA was the most frequent PMQR gene. The PFGE differentiated the strains into 31 different genetic clusters so that the highest number (7/66) was in category A. Our results indicated that the frequency of resistance to various antibiotics particularly trimethoprim, nalidixic acid, and cefoxitin are increasing. The presence of qnr (S and A) genes and point mutation of the gyrA gene were likely to be responsible for the resistance toward nalidixic acid and ciprofloxacin in our strains. Also, the results obtained from genotyping indicated that the K. pneumoniae strains isolated in this study belonged to the diverse clones.

An updated review of the association of host genetic factors with susceptibility and resistance to COVID-19.

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in human populations sparked a global pandemic of the coronavirus disease 2019 (COVID-19). According to preliminary data, about 14% of cases are considered severe and 5% of cases result in critical illness and, reported case fatality rates vary from 1% to more than 7%. However, the symptoms of the disease and the clinical outcome are very different in infected people. In view of these differences, it is clearly apparent that to gain insight into the biology of the SARS-CoV-2, it is important to study not just the infectious particle in itself but also to investigate the virus-host cell interactions that occur during infection. This review seeks to consider the various aspects of genetic factors in determining the susceptibility and host resistance to SARS-CoV-2 throughout the recently published literature.

Nanoparticles and nanoformulated drugs as promising delivery system in treatment of microbial-induced CNS infection: a systematic review of literature.

Central nervous system (CNS) infection is a global health problem with high rate of mortality and associated morbidities. Viruses, bacteria, fungi, and protozoa parasites are the main cause of CNS infection. Various medications are currently used for treatment of brain infections, but most of them do not have enough efficiency because the majority of conventional drugs cannot pass the blood-brain barrier (BBB) to combat the pathogens. Nanotechnology has provided promising approaches to solve this issue, since nanoparticles (NPs) can facilitate the drugs entrance through the BBB. Herein, we systematically reviewed all available literature to provide evidences for practicality of NPs in treatment of CNS infection. A systematic literature search was performed on January 29, 2021, in Web of Science, PubMed, Scopus, Science Direct, Embase, Ovid, and Google Scholar using "CNS infections" and "NPs/nanoformulation" including all their equivalent terms as keyword. Due to lack of human studies, no strict inclusion criteria were defined, and all relevant documents were included. After several steps of article selection, a total of 29 documents were collected and used for data synthesis. The results showed that drug-loaded NPs is fairly safe and can be a promising approach in developing anti-infective agents for treatment of CNS infection, since nanoformulated drugs could act up to tenfold more efficient that drug alone. Findings of this review indicate the importance of NPs and nanoformulation of drugs to enhance the efficiency of treatment and warrant the safety of treatment in human studies; however, clinical trials are required to confirm such efficiency and safety in clinical practice.

A case-based systematic review on the SARS-COVID-2-associated cerebrovascular diseases and the possible virus routes of entry.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sparked a global pandemic that continues to affect various facets of human existence. Many sources reported virus-induced acute cerebrovascular disorders. Systematically, this paper reviews the case studies of COVID-19-related acute cerebrovascular diseases such as ischaemic stroke, intracerebral hemorrhage, and cerebral sinus thrombosis. We also spoke about how SARS-CoV-2 can infect the brain and trigger the aforementioned disorders. We stated that SARS-CoV-2 neuroinvasion and BBB dysfunction could cause the observed disorders; however, further research is required to specify the mechanisms and pathogenesis of the virus.

A case report of simultaneous autoimmune and COVID-19 encephalitis.

COVID-19 encephalitis is a rare condition usually presenting with altered mental status. Simultaneous presence of anti-NMDAR antibody and SARS-CoV-2 virus in CSF is a very rare condition described in a few case reports so far. On the other hand, brain edema is an unusual presentation of anti-NMDAR encephalitis. Herein, we reported a case with simultaneous detection of anti-NMDAR antibody and SARS-CoV-2 virus in her cerebrospinal fluid (CSF) presenting with brain edema, altered mental status, seizures, and respiratory symptoms.

Central nervous system vasculopathy associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): a novel case report from Iran.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents respiratory symptoms as the most common clinical manifestations. Similar to some other viral infections, it can cause severe neurological damages. Here, we describe a 40-year-old man case who initially was admitted to a major hospital with presenting 7 days with weak flu-like symptoms (cough) and fever then presented neurology signs for 3 days. Physical examination and brain magnetic resonance imaging (MRI) showed cerebral vasculopathy. Molecular testing was performed on nasopharyngeal swab by real-time reverse transcription polymerase chain reaction (RT-PCR) which was positive for SARS-CoV-2. The patient received supportive cares and was treated with routine antiplatelet therapy. He was improved and discharged 10 days after admission with no symptoms. Our findings report a 40-year-old man with flu-like symptoms that indicate cerebral vasculopathy that was discharged with no symptoms. Therefore, physicians should be monitor patients with worsening or progressive central nervous system results. The pathobiology of this virus is still incompletely known; therefore, extensive studies are needed to reveal the effect of COVID-19 on the nervous system.

Guillain-Barré syndrome associated with COVID-19: a case report study.

Acute respiratory distress syndrome (ARDS) caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is spreading around the world. Patients with coronavirus disease 2019 (COVID-19) typically present fever, cough, and respiratory illnesses. It has been revealed that the comorbidities can turn it into severe types, and the managements meet unpredicted complications. Here, we report a case of coronavirus disease 2019 (COVID-19) coincidence with confirmed acute Guillain-Barré syndrome (GBS). Ten days after admission and therapeutic process, the patient developed autonomic dysfunction. Despite respiratory support and receiving intravenous immunoglobulin, the patient died due to cardiac arrest. Albeit it is yet scientifically doubtful, there are raising concerns toward a possible association between GBS and SARS-CoV-2 infection, demonstrating potential neurological symptoms of COVID-19.

Long non-coding RNAs and microorganism-associated cancers.

Cancerous cells are abnormal cells characterized by aberrant growth and proliferation, which can involve various types of cells and tissues. Through numerous signalling pathways, many mechanisms are involved in cells that keep them normal. These signalling pathways are tightly set by different proteins whose expression is regulated by a large number of factors. In other words, when a regulating factor does not act properly or undergoes a change in its function or expression, the result will be that the subordinate gene and subsequently the related protein will show deranged expression and activity. This leads to disordered signalling pathways which bring about uncontrolled proliferation in cells. One of the most significant factors in adjusting the expression of genes is noncoding RNAs. It should be noted that all underlying causes initiating malignancy try to alter the main regulatory factors in cellular processes and gene expression and direct the cell to an unregulated state. Microorganisms have been identified as one of the important elements to direct normal cells to abnormality. That is, they probably agitate the malignant traits through manipulating significant factors such as ncRNAs in given cells using their own or host-related factors. The present study is aimed at examining how the long noncoding RNAs are involved in microorganism-mediated cancers.

Effects of Curcumin and Its Analogues on Infectious Diseases.

Infectious diseases (IDs) are life-threatening illnesses, which result from the spread of pathogenic microorganisms such as bacteria, viruses, fungi, and parasites. IDs are a major challenge for the healthcare systems around the world, leading to a wide variety of clinical manifestations and complications. Despite the capability of frontline-approved medications to partially prevent or mitigate the invasion and subsequent damage of IDs to host tissues and cells, problems such as drug resistance, insufficient efficacy, unpleasant side effects, and high expenses stand in the way of their beneficial applications. One strategy is to evaluate currently explored and available bioactive compounds as possible anti-microbial agents. The natural polyphenol curcumin has been postulated to possess various properties including anti-microbial activities. Studies have shown that it possess pleiotropic effects against bacterial- and parasitic-associating IDs including drug-resistant strains. Curcumin can also potentiate the efficacy of available anti-bacterial and anti-parasitic drugs in a synergistic fashion. In this review, we summarize the findings of these studies along with reported controversies of native curcumin and its analogues, alone and in combination, toward its application in future studies as a natural anti-bacterial and anti-parasitic agent.

Emerging Technologies for the Treatment of COVID-19.

The new coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), turned into a pandemic affecting more than 200 countries. Due to the high rate of transmission and mortality, finding specific and effective treatment options for this infection is currently of urgent importance. Emerging technologies have created a promising platform for developing novel treatment options for various viral diseases such as the SARS-CoV-2 virus. Here, we have described potential novel therapeutic options based on the structure and pathophysiological mechanism of the SARS-CoV-2 virus, as well as the results of previous studies on similar viruses such as SARS and MERS. Many of these approaches can be used for controlling viral infection by reducing the viral damage or by increasing the potency of the host response. Owing to their high sensitivity, specificity, and reproducibility, siRNAs, aptamers, nanobodies, neutralizing antibodies, and different types of peptides can be used for interference with viral replication or for blocking internalization. Receptor agonists and interferon-inducing agents are also potential options to balance and enhance the innate immune response against SARS-CoV-2. Solid evidence on the efficacy and safety of such novel technologies is yet to be established although many well-designed clinical trials are underway to address these issues.

Epidemiology of COVID-19: An updated review.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a zoonotic infection, is responsible for COVID-19 pandemic and also is known as a public health concern. However, so far, the origin of the causative virus and its intermediate hosts is yet to be fully determined. SARS-CoV-2 contains nearly 30,000 letters of RNA that allows the virus to infect cells and hijack them to make new viruses. On the other hand, among 14 detected mutations in the SARS-CoV-2 S protein that provide advantages to virus for transmission and evasion form treatment, the D614G mutation (substitution of aspartic acid [D] with glycine [G] in codon 614 was particular which could provide the facilitation of the transmission of the virus and virulence. To date, in contrary to the global effort to come up with various aspects of SARS-CoV-2, there are still great pitfalls in the knowledge of this disease and many angles remain unclear. That's why, the monitoring and periodical investigation of this emerging infection in an epidemiological study seems to be essential. The present study characterizes the current epidemiological status (i.e., possible transmission route, mortality and morbidity risk, emerging SARS-CoV-2 variants, and clinical feature) of the SARS-CoV-2 in the world during these pandemic.

Molecular characterization of Shigella species isolated from diarrheal patients in Tehran, Iran: phylogenetic typing and its association with virulence gene profiles and a novel description of Shigella invasion associated locus.

The present study aims to employ a multiplex PCR-based method for phylogenetic typing of Shigella and determine the frequency of several virulence genes among Shigella phylogenetic clades and species. Species identification, phylogenetic typing of 44 previously diagnosed Shigella isolates, and frequency of virulence genes and loci, virA, virB, virF, ipaBCD, ial, sen, and set1A were investigated through performing several PCR assays. Distribution of virulence genes among Shigella phylogenetic clades and species was determined by the statistical analysis. The identities of 40 isolates out of 44 were confirmed as Shigella, and these isolates were classified in four phylogenetic clades, S1 (7.5%), S2 (52.5%), S3 (20%), and S5 (20%) and 4 species, S. sonnei (52.5%), S. flexneri (22.5%), S. dysenteriae (20%), and S. boydii (5%). The prevalence of virA, virB, virF, ipaBCD, ial, sen, and set1A was determined as 67.5%, 72.5%, 72.5%, 65%, 75%, 40%, and 5%, respectively. The presence of sen, uidA, or set1A was found to be statistically correlated with either of Shigella phylogenetic clades or species. A significant statistically association was also determined between set1A and Shigella phylogenetic clades. Furthermore, the nucleotide sequence of invasion-associated locus (ial) was determined and mapped on Shigella genome through in silico analysis. The current study shows the distribution of Shigella isolates and its key virulence genes within the five recently described phylogenetic clades for the first time in the Asia. This is also the first description of ial nucleotide sequence and its exact location on Shigella genome after its initial identification.

Aptamers, the bivalent agents as probes and therapies for coronavirus infections: A systematic review.

The recently known coronavirus, SARS-CoV-2, has turn into the greatest global health challenge, affecting a large number of societies. The lack of specific treatment and gold-standard diagnostic system has made the situation more complicated. Efforts have led to production of several diagnostic kits that are associated with limitations such as inadequate sensitivity and accuracy. Aptamers as multipotent biological probes could be promising candidates to design sensitive and specific biosensors. Although few studies have introduced specific aptamer types of coronavirus, they may help us select the best approach to obtain specific aptamers for this virus. On the other hand, some of already-introduced aptamers have shown the inhibitory effects on coronavirus that could be applied as therapeutics. The present study has provided a systematic overview on use of aptamer-based biosensors and drugs to diagnose and treat coronavirus.

Interactions of GF-17 derived from LL-37 antimicrobial peptide with bacterial membranes: a molecular dynamics simulation study.

Human cathelicidin LL-37 has recently attracted interest as a potential therapeutic agent, mostly because of its ability to kill a wide variety of pathogens and cancer cells. In this study, we used molecular dynamics simulation aimed to get insights that help to correlate with the antibacterial activity of previously designed LL-37 anticancer derivative (i.e. GF-17). Two independent molecular dynamics simulation involving four units of GF-17 peptide in the mixture (9:1) of 1,2-dipalmitoyl-sn-glycero-3-phosphorylethanolamine (DPPE) and 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG), and the pure DPPG lipids were performed. Various properties of membranes such as mass density distributions, area per lipid, bilayer thickness, and lateral diffusion were examined in both systems. The results showed that the thickness of the bilayer was not affected by the presence of GF-17, while the area per lipid and lateral diffusion of lipids showed an increase. Moreover, the potential of the mean force (PMF) method was used to calculate the free energy profile for transferring GF-17 from the bulk water into both kinds of membranes. It revealed that penetration of GF-17 into the DPPG membrane was more favorable than the DPPE/DPPG membrane, and there was no energy barrier for crossing through the bilayer center. Investigation of the radius of gyration (Rg) and root mean square fluctuation (RMSF) of peptides in two membranes showed that GF-17 had more compactness and rigidity in the pure DPPG system. By examining the secondary structure of GF-17 peptide, it was seen that the α-helix, and coil structures in both DPPE/DPPG and pure DPPG membranes are dominant.

A contemporary review on pathogenesis and immunity of COVID-19 infection.

Emerging of the COVID-19 pandemic has raised interests in the field of biology and pathogenesis of coronaviruses; including interactions between host immune reactions specific, and viral factors. Deep knowledge about the interaction between coronaviruses and the host factors could be useful to provide a better support for the disease sufferers and be advantageous for managing and treatment of the lung infection caused by the virus. At this study, we reviewed the updated information on the pathogenesis of the COVID-19 and the immune responses toward it, with a special focus on structure, genetics, and viral accessory proteins, viral replication, viral receptors, the human immune reactions, cytopathic effects, and host-related factors.