Recent development and fighting strategies for lincosamide antibiotic resistance.

SUMMARYLincosamides constitute an important class of antibiotics used against a wide range of pathogens, including methicillin-resistant Staphylococcus aureus. However, due to the misuse of lincosamide and co-selection pressure, the resistance to lincosamide has become a serious concern. It is urgently needed to carefully understand the phenomenon and mechanism of lincosamide resistance to effectively prevent and control lincosamide resistance. To date, six mobile lincosamide resistance classes, including lnu, cfr, erm, vga, lsa, and sal, have been identified. These lincosamide resistance genes are frequently found on mobile genetic elements (MGEs), such as plasmids, transposons, integrative and conjugative elements, genomic islands, and prophages. Additionally, MGEs harbor the genes that confer resistance not only to antimicrobial agents of other classes but also to metals and biocides. The ultimate purpose of discovering and summarizing bacterial resistance is to prevent, control, and combat resistance effectively. This review highlights four promising strategies, including chemical modification of antibiotics, the development of antimicrobial peptides, the initiation of bacterial self-destruct program, and antimicrobial stewardship, to fight against resistance and safeguard global health.

Cancer Metabolism: The Role of ROS in DNA Damage and Induction of Apoptosis in Cancer Cells.

Cancer is a huge challenge for people worldwide. High reactive oxygen species (ROS) levels are a recognized hallmark of cancer and an important aspect of cancer treatment research. Abnormally elevated ROS levels are often attributable to alterations in cellular metabolic activities and increased oxidative stress, which affects both the development and maintenance of cancer. Moderately high levels of ROS are beneficial to maintain tumor cell genesis and development, while toxic levels of ROS have been shown to be an important force in destroying cancer cells. ROS has become an important anticancer target based on the proapoptotic effect of toxic levels of ROS. Therefore, this review summarizes the role of increased ROS in DNA damage and the apoptosis of cancer cells caused by changes in cancer cell metabolism, as well as various anticancer therapies targeting ROS generation, in order to provide references for cancer therapies based on ROS generation.

Study on the Metabolic Transformation Rule of Enrofloxacin Combined with Tilmicosin in Laying Hens.

There is often abuse of drugs in livestock and poultry production, and the improper use of drugs leads to the existence of a low level of residues in eggs, which is a potential threat to human safety. Enrofloxacin (EF) and tilmicosin (TIM) are regularly combined for the prevention and treatment of poultry diseases. The current studies on EF or TIM mainly focus on a single drug, and the effects of the combined application of these two antibiotics on EF metabolism in laying hens are rarely reported. In this study, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine the residual EF and TIM in laying hens and to investigate the effect of TIM on the EF metabolism in laying hens. In this paper, we first establish a method that can detect EF and TIM simultaneously. Secondly, the results showed that the highest concentration of EF in the egg samples was 974.92 ± 441.71 µg/kg on the 5th day of treatment. The highest concentration of EF in the egg samples of the combined administration group was 1256.41 ± 226.10 µg/kg on the 5th day of administration. The results showed that when EF and TIM were used in combination, the residue of EF in the eggs was increased, the elimination rate of EF was decreased, and the half-life of EF was increased. Therefore, the use of EF and TIM in combination should be treated with greater care and supervision should be strengthened to avoid risks to human health.

Study of MDM2 as Prognostic Biomarker in Brain-LGG Cancer and Bioactive Phytochemicals Inhibit the p53-MDM2 Pathway: A Computational Drug Development Approach.

An evaluation of the expression and predictive significance of the MDM2 gene in brain lower-grade glioma (LGG) cancer was carried out using onco-informatics pipelines. Several transcriptome servers were used to measure the differential expression of the targeted MDM2 gene and search mutations and copy number variations. GENT2, Gene Expression Profiling Interactive Analysis, Onco-Lnc, and PrognoScan were used to figure out the survival rate of LGG cancer patients. The protein-protein interaction networks between MDM2 gene and its co-expressed genes were constructed by Gene-MANIA tool. Identified bioactive phytochemicals were evaluated through molecular docking using Schrödinger Suite Software, with the MDM2 (PDB ID: 1RV1) target. Protein-ligand interactions were observed with key residues of the macromolecular target. A molecular dynamics simulation of the novel bioactive compounds with the targeted protein was performed. Phytochemicals targeting MDM2 protein, such as Taxifolin and (-)-Epicatechin, have been shown with more highly stable results as compared to the control drug, and hence, concluded that phytochemicals with bioactive potential might be alternative therapeutic options for the management of LGG patients. Our once informatics-based designed pipeline has indicated that the MDM2 gene may have been a predictive biomarker for LGG cancer and selected phytochemicals possessed outstanding interaction results within the macromolecular target's active site after utilizing in silico approaches. In vitro and in vivo experiments are recommended to confirm these outcomes.

NRF-2α and mitophagy underlie enhanced mitochondrial functions and biogenesis induced by T-2 toxin in GH3 cells.

T-2 toxin is a natural contaminant in grain cereals produced by species of Fusarium. Studies indicate that T-2 toxin can positively affect mitochondrial function, but the underlying mechanism is unclear. In this study, we examined the role of nuclear respiratory factor 2α (NRF-2α) in T-2 toxin-activated mitochondrial biogenesis and the direct target genes of NRF-2α. Furthermore, we investigated T-2 toxin-induced autophagy and mitophagy, and the role of mitophagy in changes in mitochondrial function and apoptosis. It was found that T-2 toxin significantly increased NRF-2α levels and nuclear localization of NRF-2α was induced. NRF-2α deletion significantly increased the production of reactive oxygen species (ROS), abrogated T-2 toxin-induced increases in ATP and mitochondrial complex I activity, and inhibited the mitochondrial DNA copy number. Meanwhile, With chromatin immunoprecipitation sequencing (ChIP-Seq), various novel NRF-2α target genes were identified, such as mitochondrial iron-sulphur subunits (Ndufs 3,7) and mitochondrial transcription factors (Tfam, Tfb1m, and Tfb2m). Some target genes were also involved in mitochondrial fusion and fission (Drp1), mitochondrial translation (Yars2) and splicing (Ddx55), and mitophagy. Further studies showed that T-2 toxin induced Atg5 dependent autophagy and Atg5/PINK1-dependent mitophagy. In addition, mitophagy defects increase ROS production, inhibit ATP levels and the expression of genes related to mitochondrial dynamics, and promote apoptosis in the presence of T-2 toxins. Altogether, these results suggest that NRF-2α plays a critical role in promoting mitochondrial function and biogenesis through regulation of mitochondrial genes, and, interestingly, mitophagy caused by T-2 toxin positively affected mitochondrial function and protected cell survival against T-2 toxin.

Application of EdU-Based DNA Synthesis Assay to Measure Hepatocyte Proliferation In Situ During Liver Regeneration.

Monitoring hepatocyte proliferation in situ following partial hepatectomy is widely used to characterize cytokines, growth factors and signaling molecules and pathways as well as the regulatory mechanisms involved in liver regeneration. Periodic measurement of the liver/body mass ratio estimates the rate of liver regeneration, which is often supplemented by evaluating the proportion of proliferating hepatocytes using a synthetic nucleoside analog such as 5-bromo-2'-deoxyuridine (BrdU) or the nuclear accumulation of proliferating cell nuclear antigen (PCNA) in proliferating cells. The introduction of the thymidine analog 5-ethynyl-2'deoxyuridine (EdU) and its detection by "click chemistry" using fluorescently labeled reagents has simplified the evaluation of live cell proliferation as it eliminates certain limitations of antibody-mediated detection of BrdU. Here, we describe the EdU-based measurement of hepatocyte proliferation during liver regeneration and correlate the results with that of Ki67 and PCNA-based assays.

Bioinformatics-Based Approaches to Study Virus-Host Interactions During SARS-CoV-2 Infection.

As the knowledge of biomolecules is increasing from the last decades, it is helping the researchers to understand the unsolved issues regarding virology. Recent technologies in high-throughput sequencing are providing the swift generation of SARS-CoV-2 genomic data with the basic inside of viral infection. Owing to various virus-host protein interactions, high-throughput technologies are unable to provide complete details of viral pathogenesis. Identifying the virus-host protein interactions using bioinformatics approaches can assist in understanding the mechanism of SARS-CoV-2 infection and pathogenesis. In this chapter, recent integrative bioinformatics approaches are discussed to help the virologists and computational biologists in the identification of structurally similar proteins of human and SARS-CoV-2 virus, and to predict the potential of virus-host interactions. Considering experimental and time limitations for effective viral drug development, computational aided drug design (CADD) can reduce the gap between drug prediction and development. More research with respect to evolutionary solutions could be helpful to make a new pipeline for virus-host protein-protein interactions and provide more understanding to disclose the cases of host switch, and also expand the virulence of the pathogen and host range in developing viral infections.

Cardioprotective effect of silicon-built restraint device (ASD), for left ventricular remodeling in rat heart failure model.

This study aims to evaluate the feasibility and cardio-protective effects of biocompatible silicon-built restraint device (ASD) in the rat's heart failure (HF) model. The performance and compliance characteristics of the ASD device were assessed in vitro by adopting a pneumatic drive and ball burst test. Sprague-Dawley (SD) rats were divided into four groups (n = 6); control, HF, HF + CSD, and HF + ASD groups, respectively. Heart failure was developed by left anterior descending (LAD) coronary artery ligation in all groups except the control group. The ASD and CSD devices were implanted in the heart of HF + ASD and HF + CSD groups, respectively. The ASD's functional and expansion ability was found to be safe and suitable for attenuating ventricular remodeling. ASD-treated rats showed normal heart rhythm, demonstrated by smooth -ST and asymmetrical T-wave. At the same time, hemodynamic parameters of the HF + ASD group improved systolic and diastolic functions, reducing ventricular wall stress, which indicated reverse remodeling. The BNP values were reduced in the HF + ASD group, which confirmed ASD feasibility and reversed remodeling at a molecular level. Furthermore, the HF + ASD group with no fibrosis suggests that ASD has significant curative effects on the heart muscles. In conclusion, ASD was found to be a promising restraint therapy than the previously standard restraint therapies. Stepwise ASD fabrication process (a) 3D computer model of ASD was generated by using Rhinoceros 5.0 software (b) 3D blue wax model of ASD (c) Silicon was prepared by mixing the solutions (as per manufacturer instruction) (d) Blue wax model of ASD was immersed into liquid Silicon (e) ASD model was put into the oven for 3 hours at 50 °C. (f) Blue wax started melting from the ASD model (g) ASD model was built from pure silicon (h) Two access lines were linked to the ASD device, which was connected with an implantable catheter (Port-a-cath), scale bar 100 µm. (Nikon Ldx 2.0).

Coexistence of virulence and ß-lactamase genes in avian pathogenic Escherichia coli.

Emergence of multidrug resistance in E. coli and advent of newer strains is becoming serious concern which requires keen observations. This study was designed to find the ciprofloxacin resistant E. coli isolates co-existed with multi-drug resistance along with ß-lactamase production from poultry source, and finally the genome sequencing of these strains to explore genetic variations. Study constituted on isolation of n = 225 E. coli from broiler farms of central China which were further subjected to identification of resistance against ciprofloxacin followed by antibiogram of n = 26 antibiotics and identification of ß-lactamase production. Whole genome resequencing was performed using Illumina HiSeq 4000 system. PCR results revealed predominant ß-lactamase genes i.e.CTX-M, CTX-M-1, CTX-M3, TEM-1 and OXA. Furthermore, the MDR isolates were containing most of the tested virulence genes. The most prevalent virulence genes were pap-C, fim-C, fim-H, iuc-D, irp-2, tra-T, iro-N and iut-A. The single nucleotide polymorphisms (SNPs) loci mentioned in this data give valuable genetic markers to growing high-throughput techniques for fine-determination of genotyping of MDR and virulent isolates. Characterization of SNPs on functional basis shed new bits of knowledge on the evolution, disease transmission and pathogenesis of MDR E. coli isolates. In conclusion, these findings provide evidence that most of poultry E. coli are MDR, ß-lactamase producers, and virulent which could be a zoonotic threat to the humans. The whole genome resequencing data provide higher resolution of resistance and virulence characteristics in E. coli which can further be used for the development of prevention and treatment strategies.

Therapeutic interventions to urologic chronic pelvic pain syndrome and UPOINT system for clinical phenotyping: How far are we?

The assessment and management of urologic chronic pelvic pain syndrome (UCPPS), is controversial. It is classified by voiding symptoms, pelvic pain, and bladder pain, which is weekly treated, weekly understood, and bothersome. In the aspect of clinical efforts and research to help people with this syndrome have been hampered by the deficiency of a widely reliable, accepted, and a valuable tool to evaluate the patient symptoms and quality of life (QoL) impact. However, the etiology comes into sight is multifactorial, and available treatment options have been imprecise considerably in present years. We compiled the published literature on the assessment of the syndrome, a tentative role of pharmacological and non-pharmacological (conservative, alternative, and invasive therapy) interventions in eradicating the disease as well as improving symptoms. The previously published literature on animal models has established the association of immune systems in the etiology, pathogenesis, and progression of the disease. The UPOINT system for clinical phenotyping of UCPPS patients has six predefined domains that direct multimodal therapy, which would lead to significant symptom improvement in the medical field. The narrative review aims to scrutinize the fluctuating scientist's views on the evaluation of patient and multimodal treatment of the UPOINT system.

Comparative Genomic Characterization of Buffalo Fibronectin Type III Domain Proteins: Exploring the Novel Role of FNDC5/Irisin as a Ligand of Gonadal Receptors.

FN-III proteins are widely distributed in mammals and are usually involved in cellular growth, differentiation, and adhesion. The FNDC5/irisin regulates energy metabolism and is present in different tissues (liver, brain, etc.). The present study aimed to investigate the physiochemical characteristics and the evolution of FN-III proteins and FNDC5/irisin as a ligand targeting the gonadal receptors including androgen (AR), DDB1 and CUL4 associated factor 6 (DCAF6), estrogen-related receptor ß (ERR-ß), estrogen-related receptor γ (ERR-γ), Krüppel-like factor 15 (KLF15), and nuclear receptor subfamily 3 group C member 1 (NR3C1). Moreover, the putative role of irisin in folliculogenesis and spermatogenesis was also elucidated. We presented the molecular structure and function of 29 FN-III genes widely distributed in the buffalo genome. Phylogenetic analysis, motif, and conserved domain pattern demonstrated the evolutionary well-conserved nature of FN-III proteins with a variety of stable to unstable, hydrophobic to hydrophilic, and thermostable to thermo-unstable properties. The comparative structural configuration of FNDC5 revealed amino acid variations but still the FNDC5 structure of humans, buffalo, and cattle was quite similar to each other. For the first time, we predicted the binding scores and interface residues of FNDC5/irisin as a ligand for six representative receptors having a functional role in energy homeostasis, and a significant involvement in folliculogenesis and spermatogenesis in buffalo.

RNA-seq-based transcriptome analysis of a cefquinome-treated, highly resistant, and virulent MRSA strain.

The emergence and dissemination of methicillin-resistant Staphylococcus aureus (MRSA) strains of animal origin that are resistant to several antibiotics is of great concern. Cefquinome is a fourth-generation cephalosporin developed specifically for veterinary use. The mechanism of MRSA resistance to cefquinome is still not established. Therefore, we designed this study to evaluate the effect of cefquinome on the transcriptome of MRSA1679a, a strain that was isolated from a chicken. The transcriptome analysis indicated that multiple efflux pumps (QacA, NorB, Bcr, and ABCb) were upregulated in MRSA1679a as a resistance mechanism to expel cefquinome. Additionally, penicillin-binding protein 1A was overexpressed, which conferred resistance to cefquinome, a ß-lactam antibiotic. Adhesion and the biofilm-forming capacity of the MRSA strain was also enhanced in addition to overexpression of many stress-related genes. Genes related to carbohydrate metabolism, secretion systems, and transport activity were also significantly upregulated in MRSA1679a. In conclusion, global transcription was triggered to overcome the stress induced by cefquinome, and the MRSA1679a showed a great genetic potential to survive in this challenging environment. This study provides a profound understanding of MRSA1679a as a potentially important pathogen and identifies key resistance characteristics of MRSA against cefquinome. Studies should be aimed to demonstrate multidrug resistance mechanisms of virulent strains by exposing to different antibiotic combinations.

Systems pharmacology-based dissection of mechanisms of Tibetan medicinal compound Ruteng as an effective treatment for collagen-induced arthritis rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Ruteng (CRT) is a prescribed formulation based on the theory of Tibetan medicine for the treatment of yellow-water-disease. It is consisted with 7 medicinal material include Boswellia carterii Birdw (named "Ruxiang" in Chinese); Tinospora sinensis (Lour.) Merr. (named "Kuan-Jin-Teng" in Chinese), Cassia obtusifolia L (named "Jue-Ming-Zi" in Chinese); Abelmoschus manihot (L.) Medic (named "Huang-Kui-Zi" in Chinese); Terminalia chebula Retz. (named "He-Zi" in Chinese); Lamiophlomis rotata (Benth.) Kudo (named "Du-Yi-Wei" in Chinese) and Pyrethrum tatsienense (Bur. et Franch.) Ling (named "Da-Jian-Ju" in Chinese). They are widely distributed in Tibet area of China and have been used to treat rheumatism, jaundice, and skin diseases for centuries. AIM OF THE STUDY: The present study was conducted to investigate the anti-arthritis effect of CRT and to disclose the systems pharmacology-based dissection of mechanisms. MATERIALS AND METHODS: The chemical constituents in CRT were identified using HPLC method, and CRT candidate targets against RA were screened by network pharmacology-based analysis and further experimentally validated based on collagen-induced arthritis (CIA) rat model. Furthermore, therapeutic mechanisms and pathways of CRT were investigated. RESULTS: 391 potential targets (protein) were predicted against 92 active ingredients of 7 medicinal materials in CRT. Enrichment analysis and molecular docking studies also enforced the practiced results. X-ray based physiological imaging showed the attenuated effect of CRT on paw swelling, synovial joints and cartilage with improved inflammation in CIA rats. Moreover, the expression of biomarkers associated with RA such as MMP1, MMP3 and MMP13 and TNF-a, COX2 and iNOS are down-regulated in ankle joints, serum, or liver. CONCLUSION: In conclusion, CRT compound could attenuate RA symptoms and active ingredients of this compound could be considered for drug designing to treat RA.

SILAC proteomics implicates SOCS1 in modulating cellular macromolecular complexes and the ubiquitin conjugating enzyme UBE2D involved in MET receptor tyrosine kinase downregulation.

Suppressor of Cytokine Signaling 1 (SOCS1) functions as a tumor suppressor in hepatocellular carcinoma and many other types of cancers. SOCS1 mediates its functions by inhibiting tyrosine kinases, promoting ubiquitination and proteasomal degradation of signal transducing proteins, and by modulating transcription factors. Here, we studied the impact of SOCS1 on the hepatocyte proteome using Stable Isotopic Labelling of Amino acids in Cell culture (SILAC)-based mass spectrometry on the Hepa1-6 murine HCC cell line stably expressing wildtype SOCS1 or a mutant SOCS1 with impaired SH2 domain. As SOCS1 regulates the hepatocyte growth factor (HGF) receptor, the MET receptor tyrosine kinase (RTK), the SILAC-labelled cells were stimulated or not with HGF. Following mass spectrometry analysis, differentially modulated proteins were identified, quantified and analyzed for pathway enrichment. Of the 3440 proteins identified in Hepa-SOCS1 cells at steady state, 181 proteins were significantly modulated compared to control cells. The SH2 domain mutation and HGF increased the number of differentially modulated proteins. Protein interaction network analysis revealed enrichment of SOCS1-modulated proteins within multiprotein complexes such as ubiquitin conjugating enzymes, proteasome, mRNA spliceosome, mRNA exosome and mitochondrial ribosome. Notably, the expression of UBE2D ubiquitin conjugating enzyme, which is implicated in the control of growth factor receptor tyrosine kinase signaling, was found to be regulated by SOCS1. These findings suggest that SOCS1, induced by cytokines, growth factors and diverse other stimuli, has the potential to dynamically modulate of large macromolecular regulatory complexes to help maintain cellular homeostasis.

Metabolism and Mechanism of Human Cytochrome P450 Enzyme 1A2.

Human cytochrome P450 enzyme 1A2 (CYP1A2) is one of the most important cytochrome P450 (CYP) enzymes in the liver, accounting for 13% to 15% of hepatic CYP enzymes. CYP1A2 metabolises many clinical drugs, such as phenacetin, caffeine, clozapine, tacrine, propranolol, and mexiletine. CYP1A2 also metabolises certain precarcinogens such as aflatoxins, mycotoxins, nitrosamines, and endogenous substances such as steroids. The regulation of CYP1A2 is influenced by many factors. The transcription of CYP1A2 involves not only the aromatic hydrocarbon receptor pathway but also many additional transcription factors, and CYP1A2 expression may be affected by transcription coactivators and compression factors. Degradation of CYP1A2 mRNA and protein, alternative splicing, RNA stability, regulatory microRNAs, and DNA methylation are also known to affect the regulation of CYP1A2. Many factors can lead to changes in the activity of CYP1A2. Smoking, polycyclic aromatic hydrocarbon ingestion, and certain drugs (e.g., omeprazole) increase its activity, while many clinical drugs such as theophylline, fluvoxamine, quinolone antibiotics, verapamil, cimetidine, and oral contraceptives can inhibit CYP1A2 activity. Here, we review the drugs metabolised by CYP1A2, the metabolic mechanism of CYP1A2, and various factors that influence CYP1A2 metabolism. The metabolic mechanism of CYP1A2 is of great significance in the development of personalised medicine and CYP1A2 target-based drugs.

A glimpse into the efficacy of alternative therapies in the management of benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a common disease that can cause uncomfortable lower urinary tract symptoms. The occurrence of symptomatic BPH develops after the age of 40 years and increases gradually with age to reach more than 50% at the age of 60 years and severely disturbs the quality of life of the patients. Alpha-blockers and 5­alpha reductase inhibitors are first-line agents used for the treatment of BPH. Due to the adverse effects of these conventional therapies, many patients turn to phytotherapy and other alternative therapies. This review covers alternative therapies, i.e., phytotherapy (cernilton, eviprostat, quercetin, saw palmetto and pumpkin seed) and physical therapy (acupuncture, aquablation, pulsed electromagnetic field, prostate urethral lift, radial extracorporeal shock wave therapy, thermobalancing therapy, and transurethral needle ablation) commonly used in the management of BPH.

Molecular Docking Studies Reveal Rhein from rhubarb (Rheum rhabarbarum) as a Putative Inhibitor of ATP-binding Cassette Super-family G member 2.

BACKGROUND: ATP-binding cassette Super-family G member 2 protein is an active ATPbinding cassette transporter with the potential to combat cancer stem cells. OBJECTIVE: Due to the lack of potential ATP-binding cassette Super-family G member 2 inhibitors, we screened natural inhibitors, which could be a safe source to control multidrug resistance by blocking the regulation of ATP-binding cassette Super-family G member 2 protein. METHODS: Three-dimensional structure of ATP-binding cassette Super-family G member 2 protein downloaded from the protein databank and chemical structures of 166 selected compounds of the training dataset were retrieved from PubChem. Drug-likeness and docking analysis was conducted to shortlist the dataset for pharmacophore generation. LigandScout 4.1.5 used for pharmacophorebased screening of Zbc library of ZINC database and Autodock Vina were utilized for molecular docking against the predicted active pocket of the target protein to evaluate the potential association of protein and ligands. The physiochemical properties of novel compounds were calculated by admetSAR respectively. RESULTS: Through pharmacophore-based screening, ZINC4098704 (Rhein) was identified as a lead compound which demonstrates the least binding energy (-8.5) and the highest binding affinity with the target protein and showed optimal physiochemical profile. This compound is highly recommended for a laboratory test to confirm its activity as an ATP-binding cassette Super-family G member 2 inhibitors. CONCLUSION: Our computer-based study systematically selected natural lead compounds, which could be effective in inhibiting ATP-binding cassette Super-family G member 2 and may help reverse the effect of multidrug resistance to increase the effectiveness of chemotherapy in cancer treatment.

ADE and hyperinflammation in SARS-CoV2 infection- comparison with dengue hemorrhagic fever and feline infectious peritonitis.

The COVID-19 pandemic has rapidly spread around the world with significant morbidity and mortality in a subset of patients including the elderly. The poorer outcomes are associated with 'cytokine storm-like' immune responses, otherwise referred to as 'hyperinflammation'. While most of the infected individuals show minimal or no symptoms and recover spontaneously, a small proportion of the patients exhibit severe symptoms characterized by extreme dyspnea and low tissue oxygen levels, with extensive damage to the lungs referred to as acute respiratory distress symptom (ARDS). The consensus is that the hyperinflammatory response of the host is akin to the cytokine storm observed during sepsis and is the major cause of death. Uncertainties remain on the factors that lead to hyperinflammatory response in some but not all individuals. Hyperinflammation is a common feature in different viral infections such as dengue where existing low-titer antibodies to the virus enhances the infection in immune cells through a process called antibody-dependent enhancement or ADE. ADE has been reported following vaccination or secondary infections with other corona, Ebola and dengue virus. Detailed analysis has shown that antibodies to any viral epitope can induce ADE when present in sub-optimal titers or is of low affinity. In this review we will discuss ADE in the context of dengue and coronavirus infections including Covid-19.

Sodium aescinate and its bioactive components induce degranulation via oxidative stress in RBL-2H3 mast cells.

Sodium aescinate (SA) is a vital salt of sodium escin from Aesculus wilsonii Rehd seeds. SA injection (SAI) has received great success in treating cerebral edema, venous reflux disease and other inflammatory conditions. Recently, high incidences of immediate hypersensitivity reactions were reported after SA infusion, which raised questions on safety and risk associated with its clinical application. This study was designed to check whether SAI and its four components induce degranulation using RBL-2H3 mast cells. For this purpose, we evaluated different treatment levels of SAI (20, 40, 60, 80 and 100 µg ml-1) and its four characteristic components, SA-A, SA-B, SA-C and SA-D, at 60 µg ml-1 in different tests including cell viability test, ß-hexosaminidase and histamine assays, oxidative stress indices, apoptosis analysis and intracellular calcium ions in RBL-2H3 cells. Our results demonstrated that SAI at 80 µg ml-1 and 100 µg ml-1, and its two components (SA-B and SA-D) at 60 µg ml-1 were responsible for disturbing cell morphology and cell viability, elevated levels of ß-hexosaminidase, histamine, modulation of oxidative stress indices, induced apoptosis and increase in intracellular calcium ions in RBL-2H3 cells, when compared with the control. Our results demonstrated for the first time that SAI was more likely to induce immediate hypersensitivity reactions attributable to degranulation via oxidative stress caused by SA-B and SA-D components. These results would not only be useful for the safety of end user but also for the industry to improve the quality of SA infusion.