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Rotavirus (RV) is the main pathogen that causes severe diarrhea in infants and children under 5 years of age. No specific antiviral therapies or licensed anti-rotavirus drugs are available. It is crucial to develop effective and low-toxicity anti-rotavirus small-molecule drugs that act on novel host targets. In this study, a new anti-rotavirus compound was selected by ELISA, and cell activity was detected from 453 small-molecule compounds. The anti-RV effects and underlying mechanisms of the screened compounds were explored. In vitro experimental results showed that the small-molecule compound ML241 has a good effect on inhibiting rotavirus proliferation and has low cytotoxicity during the virus adsorption, cell entry, and replication stages. In addition to its in vitro effects, ML241 also exerted anti-RV effects in a suckling mouse model. Transcriptome sequencing was performed after adding ML241 to cells infected with RV. The results showed that ML241 inhibited the phosphorylation of ERK1/2 in the MAPK signaling pathway, thereby inhibiting IκBα, activating the NF-κB signaling pathway, and playing an anti-RV role. These results provide an experimental basis for specific anti-RV small-molecule compounds or compound combinations, which is beneficial for the development of anti-RV drugs.

Background: Diarrhea poses a major threat to bovine calves leading to mortality and economic losses. Among the causes of calf diarrhea, bovine rotavirus is a major etiological agent and may result in dysbiosis of gut microbiota. The current study was designed to investigate the effect of probiotic Limosilactobacillus fermentum (Accession No.OR504458) on the microbial composition of rotavirus-infected calves using 16S metagenomic analysis technique. Screening of rotavirus infection in calves below one month of age was done through clinical signs and Reverse Transcriptase PCR. The healthy calves (n = 10) were taken as control while the infected calves (n = 10) before treatment was designated as diarrheal group were treated with Probiotic for 5 days. All the calves were screened for the presence of rotavirus infection on each day and fecal scoring was done to assess the fecal consistency. Infected calves after treatment were designated as recovered group. Fecal samples from healthy, recovered and diarrheal (infected calves before sampling) were processed for DNA extraction while four samples from each group were processed for 16S metagenomic analysis using Illumina sequencing technique and analyzed via QIIME 2., Results: The results show that Firmicutes were more abundant in the healthy and recovered group than in the diarrheal group. At the same time Proteobacteria was higher in abundance in the diarrheal group. Order Oscillospirales dominated healthy and recovered calves and Enterobacterials dominated the diarrheal group. Alpha diversity indices show that diversity indices based on richness were higher in the healthy group and lower in the diarrheal group while a mixed pattern of clustering between diarrheal and recovered groups samples in PCA plots based on beta diversity indices was observed., Conclusion: It is concluded that probiotic Limosilactobacillus Fermentum N-30 ameliorate the dysbiosis caused by rotavirus diarrhea and may be used to prevent diarrhea in pre-weaned calves after further exploration., (© 2024. The Author(s).)

Group A rotaviruses are the most common cause of gastroenteritis in children under five years of age worldwide. Rotavirus gastroenteritis can be related to mild to severe diarrhea in children and in some cases, can lead to death due to severe dehydration. Approximately 146,480 people die annually from rotavirus infection worldwide, and most of these deaths occur in low-income countries in Africa and Asia. Since there are no specific effective drugs to treat rotavirus infections, and infected patients can only be treated supportively, new antiviral agents need to be developed. Copper oxide nanoparticles (CuO NPs) have a wide range of applications in the magnetic and electrical industries, as well as in biology. The antiviral activity of nanoparticles (CuO NPs) is well documented. This study aimed to investigate the antiviral effect of CuO NPs on rotaviruses. The cytotoxic effects of CuO NPs on MA-104 cells were examined by methyl thiazolyl tetrazolium assay. In addition, the anti-rotavirus activity of CuO NPs was evaluated by TCID 50 and real-time polymerase chain reaction PCR assay. Our results showed that exposure of rotavirus-infected cells to various non-toxic concentrations of CuO NPs did not cause a decrease in viral titer, compared to the control. However, the virucidal effect of CuO NPs on rotavirus was observed at concentrations of 80 and 100 μg/ml ( P <0.001). Our study suggested that CuO NPs had significant antiviral activity against rotavirus replication. However, the exact mechanism of anti-rotavirus activity of CuO NPs remained unknown. According to the virucidal assay, it appears that the loss of capsid integrity and genome disruption in the presence of CuO NPs are possible mechanisms of its anti-rotavirus activity., Competing Interests: The authors declare that they have no conflict of interest.

Background: Aspirin is widely used to treat various clinical symptoms. Evidence suggests that aspirin has antiviral properties, but little is known about its specific effect against rotavirus., Methods: MA104, Caco-2, and CV-1 cells were infected with rotavirus, and aspirin was added after 12 h. Viral mRNA and titer levels were measured by qRT-PCR and immunofluorescence assays. For in vivo validation, forty specific-pathogen-free SD rats were randomly divided into oral aspirin (ASP) groups and control (NC) groups. 16 S rRNA gene sequencing was performed to identify gut microbiota. After 6 months of continuous ASP/NC administration, the rats were infected with rotavirus. Fecal samples were collected over a 30-day time course, and viral levels were quantified. Proinflammatory cytokines/chemokine levels were measured by ELISA., Results: Aspirin inhibited rotavirus infection in cell lines and in rats. The effects of aspirin on viral replication were associated with the alteration of gut microbiota composition by aspirin, including increased abundance of Firmicutes and decreased abundance of Bacteroidetes after aspirin treatment. Mechanistically, aspirin reduced IL-2 and IL-10 levels, and increased IRF-1 and COX-2 levels. Aspirin blocked rotavirus replication in vitro and in vivo, which might be related to effects on IRF-1, COX-2, chemokines, and gut microbial composition., Conclusion: These results indicate that long-term oral aspirin administration reduces rotavirus infection. Intestinal virus infection may be suppressed in elderly patients who take aspirin for a long time. The change of their Gut microbiota may lead to functional disorder of the intestinal tract, which may provide some reference for clinical adjuvant probiotics treatment., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Rotavirus (RV) is one of the most common pathogens causing diarrhea in infants and young children worldwide. Routinely, antiviral therapy, intestinal mucosa protection, and fluid supplementation are used in clinic, however this is not efficacious in some severe cases. Zinc supplementation has previously been shown to improve resolution of symptoms from infectious diarrhea., Methods: In this study differences in response rate, duration of hyperthermia, vomiting, and diarrhea, and the persistence time of cough and lung rales in groups were compared. 16SrDNA gene sequencing technology was used to analyze and compare changes in the intestinal microflora of children with RV enteritis who received the conventional treatment with or without the zinc preparation. In addition, the correlations between the differential bacterial species and the related inflammatory factors were determined., Results: Conventional therapy combined with the zinc preparation significantly shortened the duration of hyperthermia, vomiting, and diarrhea compared with the conventional treatment alone. In addition, the time to symptom relief showed that the absorption time of cough and lung rales was significantly shorter in the combination treatment group than that in the conventional treatment group in the children with pneumonia. Further, compared with the conventional treatment, the combined treatment significantly increased the diversity and abundances of florae as compared with the conventional treatment. This combination therapy containing zinc preparation markedly increased the abundances of Faecalibacterium, Bacteroidales, Ruminoccoccoccus, and Lachnospiraceae at the genus level. The LEfSe analysis suggested that Clostridiumbolteae were most significantly altered after the combination therapy. In addition, a correlation analysis revealed significantly negative correlations between the inflammatory factors especially IL-6, TNF-a, CRP and some intestinal florae such as Bacteroides, Faecalibacterium, Blautia, Parabacteroides, Subdoligranulum , and Flavonifractor., Conclusion: Compared with the conventional therapy alone, the combined therapy with the zinc preparation significantly improves symptoms caused by RV. The combination therapy containing the zinc preparation significantly increases the diversity and abundances of some beneficial groups of bacteria. Further, The presence of these groups was further negatively correlated with relevant inflammatory factors. More importantly, this combination therapy containing the zinc preparation provides a reference for the clinical management of children with RV enteritis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xu, Zhang, Huo, Tao, Jin, Zhang, Wang, Zhu, Li, Yao and Ge.)

Interferons are a group of glycoproteins that are expressed in various cell types in their inflammatory responses to infections. In this study, we explored the protective effects of porcine interferon-λ3 (PIFN-λ3) on intestinal inflammation and injury in mice induced by porcine rotavirus (PRV). BALB/c mice were administrated by PIFN-λ3 or phosphate buffer solution (PBS) for three days prior to PRV infection. We show that PRV infection caused acute inflammatory responses in mice, as indicated by increases in serum concentrations of inflammatory cytokines such as the interlukin-1β (IL-1β), interlukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) (P < 0.05). However, PIFN-λ3 administration not only decreased their concentrations but also elevated the concentrations of immunoglobulin (Ig) M and IgG in the PRV challenged mice (P < 0.05). PRV infection significantly decreased the jejunal villus height and the ratio of villus height to crypt depth (V/C); however, PIFN-λ3 treatment significantly elevated the villus height and the abundance of tight junction protein ZO-1 in the jejunum (P < 0.05). Moreover, PIFN-λ3 decreased the replication of PRV in the jejunal epithelium, but significantly increased the abundance of sIgA and the activities of maltase and sucrase in the PRV-challenged mice (P < 0.05). Interestingly, PIFN-λ3 elevated the expression levels of sodium/glucose cotransporter 1 (SGLT1) and mucin 2 (MUC2) in the PRV-challenged mice (P < 0.05). Moreover, PIFN-λ3 significantly increased the expression levels of IL-10, signal transducer and activator of transcription 1 (STAT1), and critical interferon-stimulated genes such as the 2'-5' oligoadenylate synthetase-like 1 (OASL1), interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) and radical S-adenosyl methionine domain containing 2 (RSAD2) in the jejunum upon PRV infection (P < 0.05). The anti-virus and anti-inflammatory effect of PIFN-λ3 should make it an attractive candidate to prevent various pathogen-induced bowel diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Viral infections are described as modifying host gene expression; however, there is limited insight regarding rotavirus (RV) infections. This study aimed to assess the changes in intestinal gene expression after RV infection in a preclinical model, and the effect of 2-fucosyllactose (2'-FL) on this process. From days 2 to 8 of life, rats were supplemented with the dietary oligosaccharide 2'-FL or vehicle. In addition, an RV was inoculated on day 5 to nonsupplemented animals (RV group) and to 2'-FL-fed animals (RV+2'-FL group). Incidence and severity of diarrhea were established. A portion from the middle part of the small intestine was excised for gene expression analysis by microarray kit and qPCR. In nonsupplemented animals, RV-induced diarrhea upregulated host antiviral genes (e.g., Oas1a , Irf7 , Ifi44 , Isg15 ) and downregulated several genes involved in absorptive processes and intestinal maturation (e.g., Onecut2 , and Ccl19 ). The 2'-FL-supplemented and infected animals had less diarrhea; however, their gene expression was affected in a similar way as the control-infected animals, with the exception of some immunity/maturation markers that were differentially expressed (e.g., Ccl12 and Afp ). Overall, assessing the expression of these key genes may be useful in the evaluation of the efficacy of nutritional interventions or treatments for RV infection.

Rotavirus (RV) causes 200,000 deaths per year and imposes a serious burden to public health and livestock farming worldwide. Currently, rehydration (oral and intravenous) remains the main strategy for the treatment of rotavirus gastroenteritis (RVGE), and no specific drugs are available. This review discusses the viral replication cycle in detail and outlines possible therapeutic approaches including immunotherapy, probiotic-assisted therapy, anti-enteric secretory drugs, Chinese medicine, and natural compounds. We present the latest advances in the field of rotavirus antivirals and highlights the potential use of Chinese medicine and natural compounds as therapeutic agents. This review provides an important reference for rotavirus prevention and treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jiang, Tang, Song, Tong and Fan.)

Background: Considering the role of calcium in the replication and morphogenesis of rotaviruses, it is hypothesized that decreased cytosolic calcium levels by using calcium channel blockers can subsequently interfere with rotavirus replication., Objective: The present study investigated the effects of two calcium ion channel blockers, amlodipine and diltiazem, against human rotavirus infection., Methods: Cytotoxic effects of the drugs on MA-104 cells were evaluated using the neutral red assay. The effects of amlodipine and diltiazem at non-toxic concentrations on human rotavirus were examined using cytopathic effect inhibition, TCID 50 , and real-time PCR assays., Results: The highest inhibitory effect was obtained at concentrations of 0.5 μg/ml of amlodipine and 3 μg/ml of diltiazem, leading to 4.6 and 5.5 logarithmic reductions in infectious rotavirus titer and four- and a five-fold increase in the C t values compared to the virus control, respectively ( p -value < 0.001). Conversely, infectious rotavirus titers were significantly elevated compared to the virus control at concentrations above 0.9 μg/ml of amlodipine and above 25 μg/ml of diltiazem., Conclusion: Our study suggests that in addition to cardiovascular diseases, calcium channel blockers at their optimal doses may also be used to treat gastroenteritis caused by rotavirus infection., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Rotavirus is the foremost cause of acute gastroenteritis among infants in resource-poor countries, causing severe morbidity and mortality. The currently available rotavirus vaccines are effective in reducing severity of the disease but not the infection rates, thus antivirals as an adjunct therapy are needed to reduce the morbidity in children. Viruses rely on host cellular machinery for nearly every step of the replication cycle. Therefore, targeting host factors that are indispensable for virus replication could be a promising strategy., Objectives: To assess the therapeutic potential of ivermectin and importazole against rotaviruses., Methods: Antirotaviral activity of importazole and ivermectin was measured against various rotavirus strains (RV-SA11, RV-Wa, RV-A5-13, RV-EW) in vitro and in vivo by quantifying viral protein expression by western blot, analysing viroplasm formation by confocal microscopy, and measuring virus yield by plaque assay., Results: Importin-β1 and Ran were found to be induced during rotavirus infection. Knocking down importin-β1 severely impaired rotavirus replication, suggesting a critical role for importin-β1 in the rotavirus life cycle. In vitro studies revealed that treatment of ivermectin and importazole resulted in reduced synthesis of viral proteins, diminished production of infectious virus particles, and decrease in viroplasm-positive cells. Mechanistic study proved that both drugs perform antirotavirus activity by inhibiting the function of importin-β1. In vivo investigations in mice also confirmed the antirotavirus potential of importazole and ivermectin at non-toxic doses. Treatments of rotavirus-infected mice with either drug resulted in diminished shedding of viral particles in the stool sample, reduced expression of viral protein in the small intestine and restoration of damaged intestinal villi comapared to untreated infected mice., Conclusions: The study highlights the potential of importazole and ivermectin as antirotavirus therapeutics., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The efficacy of Lacticaseibacillus rhamonosus GG (LGG) for the treatment of children with acute gastroenteritis has been debated based on most recent evidence. Previous evidence demonstrated that LGG mainly benefits children with Rotavirus infection compared to other aetiologies. However, Rotavirus immunisation (RVI) has been implemented worldwide since 2006. We aimed to investigate whether the efficacy of LGG in children with gastroenteritis vary according to RVI status. The MEDLINE, Embase and Cochrane library databases were searched for relevant randomised controlled trials (RCT) up to April 2022. The duration of diarrhoea and episodes lasting >48 h were considered as primary outcomes. The date of vaccine introduction and RVI coverage were reviewed for all countries where trials were conducted. Among the 15 RCTs included in the analysis (n=3,465), only 5 showed a low risk of bias. In RCT conducted before the introduction of RVI (n=2,932), LGG was effective in reducing the duration of diarrhoea compared with placebo or standard care (Median -23.80 h, 95% confidence interval (CI) -36.59 to -11.02]). Only 2 RCTs (n=1,072) reported data of populations partially immunised against Rotavirus with an overall coverage of 44 and 67%, respectively. In this population, LGG showed no efficacy in reducing the duration of diarrhoea (Median -5.34, 95%CI -12.9 to 2.22). Similarly, LGG reduced the risk of diarrhoea lasting >48 h in children not immunised against Rotavirus (RR 0.73, 95%CI 0.54-0.99), but not in population partially immunised (RR 0.98, 95%CI 0.87 to 1.11). The implementation of RVI might affect the efficacy of LGG modifying local epidemiology and susceptibility of the target population to selected probiotics.

Background: Rotavirus is the leading cause of severe dehydrating gastroenteritis among children younger than 5 years in low-income and middle-income countries. Two vaccines-Rotavac and Rotasiil-are used in routine immunisation in India. The safety and immunogenicity of these vaccines administered in a mixed regimen is not documented. We therefore aimed to compare the safety and seroresponse of recipients of a mixed regimen versus a single regimen., Methods: We did a multicentre, open-label, randomised, controlled, phase 4, non-inferiority trial at two sites in India. We recruited healthy infants aged 6-8 weeks. Infants with systemic disorders, weight-for-height Z scores of less than minus three SDs, or a history of persistent diarrhoea were excluded. Eligible infants were randomly allocated to six groups in equal numbers to receive either the single vaccine regimen (ie, Rotavac-Rotavac-Rotavac [group 1] or Rotasiil-Rotasiil-Rotasiil [group 2]) or the mixed vaccine regimen (ie, Rotavac-Rotasiil-Rotavac [group 3], Rotasiil-Rotavac-Rotasiil [group 4], Rotavac-Rotasiil-Rotasiil [group 5], or Rotasiil-Rotavac-Rotavac [group 6]). Randomisation was done using an online software by site in blocks of at least 12. The primary outcome was seroresponse to rotavirus vaccine, measured using rotavirus-specific serum IgA antibodies 4 weeks after the third dose. The seroresponse rates were compared between recipients of the four mixed vaccine regimens (consisting of various combinations of Rotavac and Rotasiil) with recipients of the single vaccine regimens (consisting of Rotavac or Rotasiil only for all three doses). The non-inferiority margin was set at 10%. Safety follow-ups were done for the duration of study participation. This trial was registered with the Clinical Trials Registry India, number CTRI/2018/08/015317., Findings: Between March 25, 2019, and Jan 15, 2020, a total of 1979 eligible infants were randomly assigned to receive a single vaccine regimen (n=659; 329 in group 1 and 330 in group 2) or a mixed vaccine regimen (n=1320; 329 each in groups 3 and 4, and 331 each in groups 5 and 6). All eligible participants received the first dose, 1925 (97·3%) of 1979 received the second dose, and 1894 (95·7%) received all three doses of vaccine. 1852 (93·6%) of 1979 participants completed the follow-up. The immunogenicity analysis consisted of 1839 infants (1238 [67·3%] in the mixed vaccine regimen and 601 [32·7%] in the single vaccine regimen; 13 samples were insufficient in quantity) who completed vaccination and provided post-vaccination sera. The seroresponse rate in the mixed vaccine regimen group (33·5% [95% CI 30·9-36·2]) was non-inferior compared with the single vaccine regimen group (29·6% [26·1-33·4]); the seroresponse rate difference was 3·9% (95% CI -0·7 to 8·3). The proportion of participants with any type of solicited adverse events was 90·9% (95% CI 88·4-93·0) in the single vaccine regimen group and 91·1% (89·5-92·6) in the mixed vaccine regimen group. No vaccine-related serious adverse events or intussusception were reported during the study., Interpretation: Rotavac and Rotasiil can be safely used in an interchangeable manner for routine immunisation since the seroresponse was non-inferior in the mixed vaccine regimen compared with the single vaccine regimen. These results allow for flexibility in administering the vaccines, helping to overcome vaccine shortages and supply chain issues, and targeting migrant populations easily., Funding: Ministry of Health and Family Welfare, Government of India., Translation: For the Hindi translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Human rotaviruses are the utmost etiologic agents of infantile gastroenteritis in children under five years of age. To reduce childhood morbidity and mortality caused by this rotavirus infection, numerous efforts are being made worldwide in the form of better and universal immunisation programmes. Though few vaccines are in action, the lack of approved antiviral agents that have potential combative effects against the rotavirus infection in the host, remains a point of concern. This review focuses on recent insights into the development of naturally derived, RNA-silencing-based drug substances that show their anti-rotaviral activities by targeting and influencing different host and/or viral factors that contribute directly or indirectly to successful viral pathogenesis., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

The leading cause of gastroenteritis among young children worldwide is the Group A rotaviruses (RV), which produce a wide range of symptoms, from a limited diarrhea to severe dehydration and even death. After an RV infection, immunity is not complete and less severe re-infections usually occur. These infections could be ameliorated by nutritional interventions with bioactive compounds, such as prebiotics. The aim of this research was to study the impact of a particular galactooligosaccharide (B-GOS) on the RV symptomatology and immune response during two consecutive infections. Lewis neonatal rats were inoculated with SA11 (first RV infection) on day 6 of life and with EDIM (second RV infection) on day 17 of life. B-GOS group was administered by oral gavage with a daily dose of B-GOS between days three to nine of life. Clinical and immunological variables were assessed during both infective processes. In the first infection, after the prebiotic intervention with B-GOS, a lower incidence, duration, and overall severity of the diarrhea (p < 0.05) was observed. In addition, it improved another severity indicator, the fecal weight output, during the diarrhea period (p < 0.05). The second RV infection failed in provoking diarrhea in the groups studied. The immune response during first infection with SA11 was not affected by B-GOS administration and had no impact on second infection, but the prebiotic intervention significantly increased IFN-γ and TNF-α intestinal production after the second infection (p < 0.05). In summary, B-GOS supplementation is able to reduce the incidence and severity of the RV-associated diarrhea and to influence the immune response against RV infections.

Rotavirus is the most important etiological agent of infectious diarrhea in children under 5 years of age with more than 125,000 deaths occurring annually worldwide. The present study aims to determine the effect of curcumin, a natural polyphenol compound, on rotavirus in a cell culture model. The anti-viral activity of curcumin was evaluated by reverse-transcriptase quantitative PCR (RT-qPCR), TCID50, and western blot techniques to assess CC50 in curcumin-treated MA104 cells as well as EC50 and SI within the infected MA104 cell line. Our findings supported that curcumin exerted an inhibitory influence against rotavirus in a dose-dependent manner and decreased the viral titer and VP6 expression by ~99% at a concentration of 30 μM (p Keywords: curcumin; rotavirus; RT-qPCR; in vitro; anti-rotavirus agent.

Probiotics are live microorganisms that, when administered in adequate amount helps in reducing the duration of diarrhoea. Objective of this double blind randomized controlled clinical trial was to assess the efficacy of probiotics in treatment of acute rotavirus & non rotavirus watery diarrhoea among children aged 6 months to 2 years admitted at diarrhoea corner of Paediatrics Department of Mymensingh Medical College Hospital from October 2017 to May 2019. It was a double blind randomized controlled clinical trial. Total 500 sample were divided into Group A=ORS, zinc plus placebo (n=250) and Group B=ORS, zinc plus probiotics (n=250). Both Group A and Group B consisted of children presented with rotavirus and non-rotavirus diarrhoea. Placebo or probiotics were given once daily for 5 days which was prepared and coded by department of Pharmacology. Stool specimens were taken to Microbiology Department of MMCH for rotavirus detection. Rotavirus was detected by Polyacrylamide gel electrophoresis (PAGE). Data was analyzed by computer using SPSS program version 23.0. A total of 500 children with acute watery diarrhoea were included. Among them 188 children were diagnosed as rotavirus positive. Among group A found 89 rotaviral and 161 non rotaviral diarrhoea patients. Among group B found 99 rotaviral and 151 non rotaviral diarrhoea patients. Baseline characteristics were similar in both groups. The duration of diarrhoea, hospital stay, and fever was significantly lesser in probiotics group when compared with control (p<0.001). But duration of vomiting did not reduce significantly in probiotics group. Frequency of stools reduced significantly in probiotics group.

Human noroviruses (HuNoVs) are acute viral gastroenteritis pathogens that affect all age groups, yet no approved vaccines and drugs to treat HuNoV infection are available. In this study, we screened an antiviral compound library to identify compound(s) showing anti-HuNoV activity using a human intestinal enteroid (HIE) culture system in which HuNoVs are able to replicate reproducibly. Dasabuvir (DSB), which has been developed as an anti-hepatitis C virus agent, was found to inhibit HuNoV infection in HIEs at micromolar concentrations. Dasabuvir also inhibited severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human rotavirus A (RVA) infection in HIEs. To our knowledge, this is the first study to screen an antiviral compound library for HuNoV using HIEs, and we successfully identified dasabuvir as a novel anti-HuNoV inhibitor that warrants further investigation. IMPORTANCE Although there is an urgent need to develop effective antiviral therapy directed against HuNoV infection, compound screening to identify anti-HuNoV drug candidates has not been reported so far. Using a human HIE culture system, our compound screening successfully identified dasabuvir as a novel anti-HuNoV inhibitor. Dasabuvir's inhibitory effect was also demonstrated in the cases of SARS-CoV-2 and RVA infection, highlighting the usefulness of the HIE platform for screening antiviral agents against various viruses that target the intestines.

Context: 18β-Glycyrrhetinic acid (18β-GA), a pentacyclic triterpenoid saponin metabolite of glycyrrhizin, exhibits several biological activities., Objective: We investigated the effects of 18β-GA on MA104 cells infected with rotavirus (RV) and its potential mechanism of action., Materials and Methods: Cell Counting Kit-8 was used to assess tissue culture infective dose 50 (TCID 50 ) and 50% cellular cytotoxicity (CC 50 ) concentration. MA104 cells infected with RV SA11 were treated with 18β-GA (1, 2, 4, and 8 μg/mL, respectively). Cytopathic effects were observed. The virus inhibition rate, concentration for 50% of maximal effect (EC 50 ), and selection index (SI) were calculated. Cell cycle, cell apoptosis, and mRNA and protein expression related to the Fas/FasL pathway were detected., Results: TCID 50 of RV SA11 was 10 -4.47 /100 µL; the CC 50 of 18β-GA on MA104 cells was 86.92 µg/mL. 18β-GA showed significant antiviral activity; EC 50 was 3.14 μg/mL, and SI was 27.68. The ratio of MA104 cells infected with RV SA11 in the G0/G1 phase and the G2/M phase decreased and increased, respectively, after 18β-GA treatment. 18β-GA significantly induced apoptosis in the infected cells. Furthermore, after 18β-GA treatment, the mRNA and protein expression levels of Fas, FasL, caspase 3, and Bcl-2 decreased, whereas the expression levels of Bax increased., Discussion and Conclusions: The study demonstrates that 18β-GA may be a promising candidate for the treatment of RV SA11 infection and provides theoretical support for the clinical development of glycyrrhizic acid compounds for the treatment of RV infection.

Rotavirus (RV), as the main cause of diarrhea in children under 5 years, contributes to various childhood diseases. Valeriana jatamansi Jones is a traditional Chinese herb and possesses antiviral effects. In this study we investigated the potential mechanisms of V. jatamansi Jones in RV-induced diarrhea. MTT assay was performed to evaluate cell proliferation and the diarrhea mice model was constructed using SA11 infection. Mice were administered V. jatamansi Jones and ribavirin. Diarrhea score was used to evaluate the treatment effect. The enzyme-linked immunosorbent assay was performed to detect the level of cytokines. Western blot and quantitative reverse transcription-PCR were used to determine protein and mRNA levels, respectively. Hematoxylin-eosin staining was applied to detect the pathological change of the small intestine. TdT-mediated dUTP nick-end labeling was conducted to determine the apoptosis rate. The results showed V. jatamansi Jones promoted MA104 proliferation. V. jatamansi Jones downregulated phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) in protein level, which was consistent with the immunohistochemistry results. Moreover, V. jatamansi Jones combined with ribavirin regulated interleukin-1β (IL-1β), interferon γ, IL-6, tumor necrosis factor α, and IL-10, and suppressed secretory immunoglobulin A secretion to remove viruses and inhibit dehydration. V. jatamansi Jones + ribavirin facilitated the apoptosis of small intestine cells. In conclusion, V. jatamansi Jones may inhibit RV-induced diarrhea through PI3K/AKT signaling pathway, and could therefore be a potential therapy for diarrhea.

Background: Despite the global roll-out of rotavirus vaccines (RotaTeq/Rotarix / ROTAVAC/Rotasiil), mortality and morbidity due to group A rotavirus (RVA) remains high in sub-Saharan Africa, causing 104,000 deaths and 600,000 hospitalizations yearly. In Cameroon, Rotarix™ was introduced in March 2014, but, routine laboratory diagnosis of rotavirus infection is not yet a common practice, and vaccine effectiveness studies to determine the impact of vaccine introduction have not been done. Thus, studies examining RVA prevalence post vaccine introduction are needed. The study aim was to determine RVA prevalence in severe diarrhoea cases in Littoral region, Cameroon and investigate the role of other diarrheagenic pathogens in RVA-positive cases., Methods: We carried out a study among hospitalized children < 5 years of age, presenting with acute gastroenteritis in selected hospitals of the Littoral region of Cameroon, from May 2015 to April 2016. Diarrheic stool samples and socio-demographic data including immunization and breastfeeding status were collected from these participating children. Samples were screened by ELISA (ProSpecT™ Rotavirus) for detection of RVA antigen and by gel-based RT-PCR for detection of the VP6 gene. Co-infection was assessed by multiplexed molecular detection of diarrheal pathogens using the Luminex xTAG GPP assay., Results: The ELISA assay detected RVA antigen in 54.6% (71/130) of specimens, with 45, positive by VP6 RT-PCR and 54, positive using Luminex xTAG GPP. Luminex GPP was able to detect all 45 VP6 RT-PCR positive samples. Co-infections were found in 63.0% (34/54) of Luminex positive RVA infections, with Shigella (35.3%; 12/34) and ETEC (29.4%; 10/34) detected frequently. Of the 71 ELISA positive RVA cases, 57.8% (41/71) were fully vaccinated, receiving two doses of Rotarix., Conclusion: This study provides insight on RVA prevalence in Cameroon, which could be useful for post-vaccine epidemiological studies, highlights higher than expected RVA prevalence in vaccinated children hospitalized for diarrhoea and provides the trend of RVA co-infection with other enteric pathogens. RVA genotyping is needed to determine circulating rotavirus genotypes in Cameroon, including those causing disease in vaccinated children.

Group A rotaviruses (RVAs) are the major cause of severe acute gastroenteritis (AGE) in children under 5 years of age, annually resulting in nearly 130,000 deaths worldwide. Social conditions in developing countries that contribute to decreased oral rehydration and vaccine efficacy and the lack of approved antiviral drugs position RVA as a global health concern. In this minireview, we present an update in the field of antiviral compounds, mainly in relation to the latest findings in RVA virion structure and the viral replication cycle. In turn, we attempt to provide a perspective on the possible treatments for RVA-associated AGE, with special focus on novel approaches, such as those representing broad-spectrum therapeutic options. In this context, the modulation of host factors, lipid droplets, and the viral polymerase, which is highly conserved among AGE-causing viruses, are analyzed as possible drug targets., (Copyright © 2021 Tohmé and Delgui.)

Rotavirus (RV) infection is a leading cause of severe, dehydrating gastroenteritis in children < 5 years of age, and by now, the prevention and treatment of RV are still the major public health problems due to a lack of specific clinical drugs. Thus, the aims of this study are to explore the anti-RV effect of baicalin and its influence on glucose metabolism. Here, we demonstrated for the first time that baicalin had an anti-RV attachment effect with the strongest effect at a concentration of 100 μM, and also inhibited the replication of RV at concentrations of 100, 125, 150, 175, and 200 μM. Moreover, baicalin helped to overcome the weight loss and reduced the diarrhea rate and score with the best therapeutic effect at a concentration of 0.3 mg/g in RV-infected neonatal mice. Interestingly, baicalin decreased glucose consumption in RV-infected Caco-2 cells with the optimal concentration of 125 μM. Next, metabolomic analysis indicated that there were 68 differentially expressed metabolites, including an increase in pyruvic acid, asparagine, histidine and serine, and a decrease in dihydroxyacetone phosphate, which suggested that the underlying signaling pathway was gluconeogenesis. Further studies demonstrated that baicalin inhibited gluconeogenesis via improving glucose 6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxylase (PEPCK). Moreover, baicalin upregulated the potential gluconeogenesis proteins named salt inducible kinase 2, pyruvate dehydrogenase kinase 1, AKT serine/threonine kinase 1 and down-regulated phosphorylated c-Jun NH2-terminal kinase, which are associated with G-6-Pase and PEPCK expressions. Therefore, baicalin improved the gluconeogenesis disruption caused by RV., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Rotavirus A is one of the leading causes of acute gastroenteritis in children in the first years of life. Rotavirus infection is currently classified as a preventable infection. The most abundant rotavirion protein is VP6., Material and Methods: Phylogenetic analysis and calculation of phylodynamic characteristics were carried out for 262 nucleotide sequences of the VP6 gene of rotavirus species A, isolated in Russia, using the BEAST v.1.10.4 software package. The derivation and analysis of amino acid sequences was performed using the MEGAX program., Results: This study provides phylodynamic characteristics of the rotaviruses in Russia based on the sequences coding VP6 protein. Bayesian analysis showed the circulation of rotaviruses of three sublineages of genotype I1 and three sublineages of genotype I2 in Russia. The level of accumulation of mutations was established, which turned out to be similar for genotypes I1 and I2 and amounted to 7.732E-4 and 1.008E-3 nucleotides/site/year, respectively. The effective population sizes based on nucleotide sequences of the VP6 I1 and I2 genotypes are relatively stable while after the 2000s there is a tendency of its decreasing. Comparative analysis of the amino acid sequences in the region of the intracellular neutralization sites A (231-260 aa) and B (265-292 aa) made it possible to reveal a mutation in position V252I in a proportion of Russian strains of genotype I1 some strains of genotypes I1 and I2 had mutation I281V. These substitutions were not associated with any sublineages to which the strains belong. The analysis of three T-cell epitopes revealed four amino acid differences (in aa positions 305, 315, 342, 348) that were associated with the first or second genogroup., Conclusion: Based on the phylodynamic characteristics and amino acid composition of antigenic determinants, it was concluded that the VP6 protein is highly stable and could potentially be a good model for development of a rotavirus vaccine.

Rotavirus is the most common cause of severe diarrhea among infants and young children and is responsible for more than 200,000 pediatric deaths per year. There is currently no pharmacological treatment for rotavirus infection in clinical activity. Although cholesterol synthesis has been proven to play a key role in the infections of multiple viruses, little is known about the relationship between cholesterol biosynthesis and rotavirus replication. The models of rotavirus infected two cell lines and a human small intestinal organoid were used. We investigated the effects of cholesterol biosynthesis, including inhibition, enhancement, and their combinations on rotavirus replication on these models. The knockdown of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) was built by small hairpin RNAs in Caco2 cells. In all these models, inhibition of cholesterol synthesis by statins or HMGCR knockdown had a significant inhibitory effect on rotavirus replication. The result was further confirmed by the other inhibitors: 6-fluoromevalonate, Zaragozic acid A and U18666A, in the cholesterol biosynthesis pathway. Conversely, enhancement of cholesterol production increased rotavirus replication, suggesting that cholesterol homeostasis is relevant for rotavirus replication. The effects of all these compounds toward rotavirus were further confirmed with a clinical rotavirus isolate. We concluded that rotavirus replication is dependent on cholesterol biosynthesis. To be specific, inhibition of cholesterol synthesis can downregulate rotavirus replication; on the contrary, rotavirus replication is upregulated. Statin treatment is potentially an effective novel clinical anti-rotavirus strategy.

Recombinant viruses expressing fluorescent or luminescent reporter proteins are used to quantitate and visualize viral replication and transmission. Here, we used a split NanoLuc luciferase (NLuc) system comprising large LgBiT and small HiBiT peptide fragments to generate stable reporter rotaviruses (RVs). Reporter RVs expressing NSP1-HiBiT fusion protein were generated by placing an 11 amino acid HiBiT peptide tag at the C-terminus of the intact simian RV NSP1 open reading frame or truncated human RV NSP1 open reading frame. Virus-infected cell lysates exhibited NLuc activity that paralleled virus replication. The antiviral activity of neutralizing antibodies and antiviral reagents against the recombinant HiBiT reporter viruses were monitored by measuring reductions in NLuc expression. These findings demonstrate that the HiBiT reporter RV systems are powerful tools for studying the viral life cycle and pathogenesis, and a robust platform for developing novel antiviral drugs., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Rotavirus infection is the main cause of severe dehydration enteritis in children under 5 years old. It gives rise to malnutrition and even death in children even though there were rotavirus vaccines. However, there is no effective anti-virus drugs for rotavirus, supporting treatments are used in the clinics. Traditional Chinese medicine (TCM) has been treating diarrhea for many years. Gegen Huangqin Huanglian Decoction (GHHD)is a classic prescription for diarrhea in TCM. With the development of clinical trials and basic studies, GHHD has been proved that a good curative effect on diarrhea. Therefore, a systematic review is necessary to improve available evidence for GHHD in therapy of children under 5 years old with rotavirus enteritis., Methods: Different studies from various databases will be involved in this study. Only randomized controlled trials of rotavirus enteritis patients diagnosed with Guidelines for the Treatment of Acute Gastroenteritis in Outpatient Pediatrics, which released by the Washington International Children's Medical Center, Zhu Futang's Practical Pediatrics (7 th Edition), and the 2016 clinical practice guidelines for children with acute infectious diarrhea in China. We will search the literature in the databases from China Conference Paper Database, manual searching. Electronic database includes PubMed, Embase, Cochrane Library, Web of Science, CNKI (China National Knowledge Internet), WanFang, VIP (Chongqing VIP), and CBM (China Biomedical Literature CDROM Database). The primary outcomes include the total effective rate, the time of stopping diarrhea, the level of IL-6 serum concentration, fecal microflora ratio, the conversion of fecal rotavirus antigen. The secondary outcomes include clinical efficacy and the quantitative integral of TCM symptom, recovery time of stool character, treatment period. Besides, incidence of adverse events (such as irritation and toxicity) and costs will be also considered. Data will be extracted by 2 researchers independently, risk of bias of the meta-analysis will be evaluated based on the Cochrane Handbook for Systematic Reviews of Interventions. All data analysis will be conducted by data statistics software Review Manager V.5.3 and Stata V.12.0., Results: This study will synthesize and provide high-quality evidence based on the data of the currently published GHHD for the treatment of children rotavirus enteritis, in terms of the total effective rate, the time of stopping diarrhea, the level of IL-6 serum concentration, fecal microflora ratio, stool rotavirus antigen, clinical efficacy and the quantitative integral of TCM symptom, recovery time of stool character, treatment period, and safety., Conclusion: This systematic review aims to evaluated the benefits and harms of GHHD for the treatment of children rotavirus enteritis reported in randomized controlled trials, and provide more options for clinicians and patients to treat children rotavirus enteritis., Registration Number: INPLASY2020100023.

Bacterial flagellin can elicit production of TLR5-mediated IL-22 and NLRC4-mediated IL-18 cytokines that act in concert to cure and prevent rotavirus (RV) infection. This study investigated the mechanism by which these cytokines act to impede RV. Although IL-18 and IL-22 induce each other's expression, we found that IL-18 and IL-22 both impeded RV independently of one another and did so by distinct mechanisms that involved activation of their cognate receptors in intestinal epithelial cells (IEC). IL-22 drove IEC proliferation and migration toward villus tips, which resulted in increased extrusion of highly differentiated IEC that serve as the site of RV replication. In contrast, IL-18 induced cell death of RV-infected IEC thus directly interrupting the RV replication cycle, resulting in spewing of incompetent virus into the intestinal lumen and causing a rapid drop in the number of RV-infected IEC. Together, these actions resulted in rapid and complete expulsion of RV, even in hosts with severely compromised immune systems. These results suggest that a cocktail of IL-18 and IL-22 might be a means of treating viral infections that preferentially target short-lived epithelial cells., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Rotavirus (RV) is the primary causative agent for viral gastroenteritis among infants and young children worldwide. Currently, no clinically approved and effective antiviral drug for the treatment of RV infection is available., Purpose: We investigated the potential anti-RV activity of resveratrol and underlying mechanisms by which resveratrol acted against RV., Methods: The anti-RV activity of resveratrol in vitro was evaluated using plaque reduction assays. The effects of resveratrol on yield of virion progeny, viral polyprotein expression and genomic RNA synthesis were respectively investigated using enzyme-linked immunosorbent assays, western blotting and qRT-PCR assays. Further, we also measured the antiviral effect of resveratrol by evaluation of antigen clearance and assessment of changes in proinflammatory cytokines/chemokines in RV-infected neonatal mouse model., Results: Our results indicated that 20 μM of resveratrol significantly inhibited RV replication in Caco-2 cell line by suppressing RV RNA synthesis, protein expression, viroplasm plaque formation, progeny virion production, and RV-induced cytopathy independent of the different strains and cell lines of RV that we used. Analysis of the effect of time post-addition of resveratrol indicated that its application inhibited early processes in the RV replication cycle. Further study of the underlying mechanism of anti-RV activity indicated that resveratrol inhibited RV replication by suppressing expression of heat-shock protein 90 (HSP90) mRNA and protein, and that the effect occurred in a dose-dependent manner. Overexpression of HSP90 was found to have attenuated the inhibitory effect of resveratrol on RV replication. Interestingly, the application of resveratrol were found to down-regulate the level of inhibition of RV-mediated MEK1/2 and ERK phosphorylation. Using a RV-infected suckling mice model, we found that application of resveratrol significantly lessened the severity of diarrhea, decreased viral titers, and relieved associated symptoms. Levels of mRNA expression of interleukin-2, interleukin-10, tumor necrosis factor-α, interferon-γ, macrophage inflammatory protein 1, and monocyte chemotactic protein-1 were all found to have been sharply reduced in intestinal tissue from mice which had been treated with resveratrol (10 or 20 mg/kg) after RV infection (p < 0.05)., Conclusion: These findings implied that resveratrol exhibits antiviral activity and could be a promising treatment for rotavirus infection., Competing Interests: Declaration of Competing Interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Rotavirus is the leading cause of acute gastroenteritis among young children worldwide. However, agents specifically designed to treat rotavirus infection have not been developed yet. In this study, the anti-rotavirus and anti-inflammatory effects of genipin, a chemical compound found in the fruit of Gardenia jasminoides, were evaluated. Genipin had an antiviral effect against the human rotavirus Wa and SA-11 strains in vitro, and it inhibited two distinct stages of the viral replication cycle: attachment and penetration (early stage) in pre-treatment and assembly and release (late stage) in post-treatment. Additionally, genipin downregulated nitric oxide synthase and pro-inflammatory cytokines in lipopolysaccharide-stimulated RAW264.7 cells and rotavirus-infected Caco-2 cells. Oral administration of genipin before and after viral infection with the murine rotavirus epidemic diarrhea of infant mice strain led to a reduced duration of diarrhea and faecal viral shedding and to decreased destruction of the enteric epithelium. Genipin could have potential as a natural compound with preventive and therapeutic effects against infection and colitis caused by rotavirus.

Objective: This meta-analysis aims to uncover the therapeutic efficacy of probiotics on acute rotavirus diarrhea (RVD) in children., Materials and Methods: Randomized controlled studies reporting therapeutic efficacy of probiotics on acute RVD in children published before 1st June 2019 were searched in PubMed, EMBASE, and Cochrane. The citations in all searched literature were manually examined. Data were extracted from eligible literature for calculating STD Mean Difference (SMD) and its corresponding 95% confidence interval (CI). Subsequently, the association between therapeutic efficacy of probiotics and acute RVD in children was evaluated. Moreover, data were weighted by an inverse variance and analyzed by a fixed or random effect model. Heterogeneity test was applied in the enrolled literature. Sensitivity and publication bias was examined. STATA 12.0 was used for meta-analysis., Results: A total of 19 independent Randomized Controlled Trials (RCTs) involving 1,624 children with acute RVD were enrolled in this study. Three pieces of literature were excluded through sensitivity and publication bias analyses. Data extracted from eligible literature indicated that probiotics could markedly reduce the occurrence of acute RVD in children (SMD=-0.49, 95% CI=-0.74-0.25). Subgroup analysis conducted based on ethnicity uncovered a poor therapeutic efficacy of probiotics on reducing the occurrence of acute RVD in Asian children (SMD=-0.45, 95% CI=-0.94-0.04), which was markedly significant in Caucasian children (SMD=-0.54, 95% CI=-0.78--0.30). In addition, the subgroup analysis based on the probiotic subtypes found a pronounced efficacy of both Lactobacillus acidophilus (SMD=-0.67, 95% CI=-0.92-0.42) and non-Lactobacillus acidophilus probiotic (SMD=-0.45, 95% CI=-0.77-0.14) on the occurrence of acute RVD in children., Conclusions: Probiotics could reduce the occurrence of acute RVD in children, especially in Caucasian population. Our findings still needed to be further validated in a multi-center institution with larger sample size and more qualified data.

Introduction: Immunocompromised children are susceptible to infectious diarrhea. Oral administration of human serum immunoglobulins to treat immunocompromised patients with viral gastroenteritis caused by viruses like rotavirus and norovirus has been reported., Objective: The aim of this study was to assess the efficacy of oral immunoglobulin (OIG) in treating hospitalized immunocompromised children with diarrheal illness., Methods: We conducted a retrospective cohort review of the Mayo Clinic electronic medical records from January 1, 2005, through April 30, 2019. We included children who were immunocompromised and received OIG as a treatment for a diarrheal illness that was classified as acute (< 4 weeks) or chronic (> 4 weeks) at the time of their treatment. Response to therapy was defined by 50% reduction in stool output., Results: Nineteen children were identified (11 males); average age at the time of treatment was 11 (0.25-18) years. In the acute diarrhea cohort, the mean duration of symptoms was 9.5 days (4-21). In the chronic diarrhea cohort, the mean duration of symptoms was 41 days (28-90). All 19 children were treated with OIG with doses in the range of 100-300 mg/kg/day for 1-5 days. Eighteen patients (95%) had improvement. Overall average time to response was 3.1 (1-9) days after receiving the OIG., Conclusion: Oral administration of human serum immunoglobulin in immunocompromised children presenting with acute and chronic diarrheal illness appeared helpful in reducing stool output by 50% in the majority of patients.

Rotavirus is one of the most important causative agents of gastroenteritis in both infants and children worldwide, resulting in high mortality and morbidity, mainly in low-income, developing countries. Respective analysis of medical records of newborns hospitalized with acute gastroenteritis showed that the use of &#945;2b-interferon in complex pharmacotherapy was characterized by faster reverse development of clinical manifestations of the disease than in patients who did not receive interferon. In our study, we also aimed to estimate the effectiveness of &#945;2b-interferon supplementation in combination pharmacotherapy of newborns with suspected rotavirus infection. Achievement of this goal was possible with the construction of a decision tree model and determination of decision rules for inclusion of &#945;2b-interferon supplementation into the complex pharmacotherapy. The input parameters of the model were hospitalization days of patients stratified by such signs as the presence or absence of rotavirus infection, as well as the additional inclusion of &#945;2b-interferon supplementation in complex pharmacotherapy. The criterion for prediction and decision-making was global retrospective rotavirus prevalence. The feature of the simulation was that the costs were expressed as relative to each other, which allowed unifying the proposed methodology. Retrospective analysis of the clinical database of Ukrainian newborns with acute diarrhea has proved that the decision of &#945;2b-interferon supplementation as additional treatment could be cost-saving under 7.4 times its lower price.

Rotavirus (RV) induced diarrhea has been a major reason affecting children healthy under 5 years old especially in developing countries. Although specific vaccines have preventive effects, antiviral therapy is essential for the diarrhea patients. Ziyuglycoside II is a traditional Chinese herb which has been proven to possess anti-virus effects. This study aimed to investigate the roles of Ziyuglycoside II in rotavirus-induced diarrhea and the underlying molecular mechanism. We found that normal MA104 cells treated with RV became swollen and gather together. However, Ziyuglycoside II treatment inhibited cell growth in a dose- and time dependent manner and suppressed RV replication. Moreover, Ziyuglycoside II reversed RV-induced downregulation of anti-inflammatory cytokine interleukin (IL)-10 and upregulation of pro-inflammatory factors, such as interferon-γ (IFN-γ), IL-1β, IL-6, and tumor necrosis factor (TNF-α). Moreover, Ziyuglycoside II administration and ribavirin blocked toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling pathway both in mRNA and protein level, which was paralleled with immunohistochemical assay. Additionally, Ziyuglycoside II administration improved diarrhea symptoms and decreased diarrhea scores. Ziyuglycoside II and ribavirin inhibited the apoptosis of small intestine epithelial cells induced by RV. Taken together, RV treatment induced diarrhea. Ziyuglycoside II administration inhibited TLR4/NF-κB pathway and inflammatory response and improved RV-induced diarrhea. The inhibitory effects of Ziyuglycoside II on RV-induced diarrhea predicted Ziyuglycoside II may be a promising drug for diarrhea.

Background: Probiotics can be used for the treatment of viral gastroenteritis., Objective: This systematic review is to evaluate the evidence regarding the effect of probiotics on human cases of viral gastroenteritis., Methods: The objective of this review is to evaluate the effectiveness of probiotics against placebo or standard treatment for viral gastroenteritis. A comprehensive search of Cochrane Library, EMBASE, MEDLINE via PubMed and Ovid databases, and unpublished studies (till 27 January 2018) was conducted followed by a process of study selection and critical appraisal by two independent reviewers. Randomized controlled trials assessing probiotic administration in human subjects infected with any species of gastroenteritis viruses were considered for inclusion. Only studies with a confirmed viral cause of infection were included. This study was developed using the JBI methodology for systematic reviews, which is in accordance with the PRISMA guideline. Meta-analysis was conducted where feasible. Data were pooled using the inverse variance method with random effects models and expressed as Mean Differences (MDs) with 95% Confidence Intervals (CIs). Heterogeneity was assessed by Cochran Q statistic and quantified by the I2 statistic. We included 17 RCTs, containing 3,082 patients., Results: Probiotics can improve symptoms of viral gastroenteritis, including the duration of diarrhea (mean difference 0.7 days, 95% CI 0.31 to 1.09 days, n = 740, ten trials) and duration of hospitalization (mean difference 0.76 days, 95% CI 0.61 to 0.92 days, n = 329, four trials)., Conclusion: The results of this review show that the administration of probiotics in patients with viral gastroenteritis should be considered., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Rotavirus is one of the leading causes of severe acute gastroenteritis in children under 5 years of age, mainly affecting developing countries. Once the disease is acquired, no specific treatment is available; as such, the development of new drugs for effective antirotaviral treatment is critical. Ursolic acid is a pentacyclic triterpenoid with antiviral activity, which has been studied extensively in vitro and in vivo. To study the potential antirotaviral activity of ursolic acid, its toxic potential for viral particles (virucidal effect) and cultured cells (cytotoxicity) was analysed. No effect on virion infectivity was observed with treatments of up to 40 µM ursolic acid, while incipient cytotoxicity started to be evident with 20 µM ursolic acid. The antiviral potential of ursolic acid was evaluated in in-vitro rotavirus infections, demonstrating that 10 µM ursolic acid inhibits rotavirus replication (observed by a decrease in viral titre and the level of the main viral proteins) and affects viral particle maturation (a process associated with the endoplasmic reticulum) 15 h post infection. Interestingly, ursolic acid was also found to hamper the early stages of the viral replication cycle, as a significant reduction in the number and size of viroplasms, consistent with a decrease in VP6 and NSP2 viral proteins, was observed 4 h post infection. As such, these observations demonstrate that ursolic acid exhibits antiviral activity, suggesting that this chemical could be used as a new treatment for rotavirus., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Colonization of the gut in early life can be altered through multiple environmental factors. The present study aimed to investigate the effects of 2'-fucosyllactose (2'-FL), a mixture of short-chain galactooligosaccharides/long-chain fructooligosaccharides (scGOS/lcFOS) 9:1 and their combination (scGOS/lcFOS/2'-FL) on dysbiosis induced during rotavirus (RV) diarrhea in neonatal rats, elucidating crosstalk between bacteria and the immune system. The dietary interventions were administered daily by oral gavage at days 2-8 of life in neonatal Lewis rats. On day 5, RV SA11 was intragastrically delivered to induce infection and diarrhea assessment, microbiota composition, and gene expression of Toll-like receptors (TLRs) in the small intestine were studied. All dietary interventions showed reduction in clinical variables of RV-induced diarrhea. RV infection increased TLR2 expression, whereas 2'-FL boosted TLR5 and TLR7 expressions and scGOS/lcFOS increased that of TLR9. RV-infected rats displayed an intestinal dysbiosis that was effectively prevented by the dietary interventions, and consequently, their microbiota was more similar to microbiota of the noninfected groups. The preventive effect of 2'-FL, scGOS/lcFOS, and their combination on dysbiosis associated to RV diarrhea in rats could be due to changes in the crosstalk between gut microbiota and the innate immune system.

Background: Rotavirus (RV) can cause vomiting and diarrhea in infants and children, and could be treated clinically with immunoglobulin Y (IgY), which is an immunoglobulin extracted from chicken yolk. There is no systematic evaluation of immunoglobulin in the treatment of rotavirus enteritis. Therefore, we systematically evaluated rotavirus enteritis with oral immunoglobulin Y therapy using meta-analysis., Methods: We conducted a systematic search in CNKI, WANFANG DATA, VIP, PubMed, and the Cochrane Library databases (up to April 30, 2018). Using Revman 5.3 software for meta-analysis., Results: A total of 2626 subjects with rotavirus diarrhea from 17 randomized clinical trials were included in the meta-analysis. Of these, 1347 subjects received oral immunoglobulin Y and 1279 subjects received conventional treatment. The results of the meta-analysis indicated that the total number of effective cases and effective rates of immunoglobulin Y in treatment of rotavirus enteritis in infants and children was statistically different from that in the control group (odds ratio [OR] = 3.87, 95% confidence interval [CI] (3.17, 4.74), P < .00001) and (OR = 3.63, 95% CI [2.75, 4.80], P < .00001)., Conclusions: Immunoglobulin Y is effective in the treatment of infantile rotavirus enteritis. Oral immunoglobulin Y can be widely used in the treatment of rotavirus enteritis in clinic.

Background: Acute gastroenteritis (AGE) is a major cause of pediatric morbidity and mortality around the world. It remains a frequent reason for infection-related admissions to emergency units among all age groups. Following the Syrian refugee crisis and insufficient clean water in our region, we sought to assess the etiological and epidemiological factors pertaining to AGE in South Lebanon., Methods: In this multi-center cross sectional clinical study, we analyzed the demographic, clinical and laboratory data of 619 Lebanese children from the age of 1 month to 5 years old who were admitted with AGE to pediatrics departments of three tertiary care centers in South Lebanon., Results: Our results revealed that males had a higher incidence of AGE (57.3%) than females. Enteropathogens were identified in 332/619 (53.6%) patients. Single pathogens were found in 294/619 (47.5%) patients, distributed as follows: Entamoeba histolytica in 172/619 (27.8%) patients, rotavirus in 84/619 (13.6%), and adenovirus in 38/619 (6.1%). Mixed co-pathogens were identified in 38/619 (6.1%) patients. Analyzing the clinical manifestations indicated that E. histolytica caused the most severe AGE. In addition, children who received rotavirus vaccine were significantly less prone to rotavirus infection., Conclusions: Our findings alluded to the high prevalence of E. histolytica and other unidentified enteropathogens as major potential causes of pediatric AGE in hospitalized Lebanese children. This should drive us to widen our diagnostic panel by adopting new diagnostic techniques other than the routinely used ones (particularly specific for the pathogenic amoeba E. histolytica and for the unidentified enteropathogens), and to improve health services in this unfortunate area of the world where insanitary water supplies and lack of personal hygiene represent a major problem.

Viral gastroenteritis is an important cause of morbidity and mortality worldwide, being particularly severe for children under the age of five. The most common viral agents of gastroenteritis are noroviruses, rotaviruses, sapoviruses, astroviruses and adenoviruses, however, no specific antiviral treatment exists today against any of these pathogens. We here discuss the feasibility of developing a broad-spectrum antiviral treatment against these diarrhea-causing viruses. This review focuses on the viral polymerase as an antiviral target, as this is the most conserved viral protein among the diverse viral families to which these viruses belong to. We describe the functional and structural similarities of the different viral polymerases, the antiviral effect of reported polymerase inhibitors and highlight common features that might be exploited in an attempt of designing such pan-polymerase inhibitor.

A human-porcine reassortant rotavirus, strain R1207, was identified from 74 group A rotaviruses detected in 197 (37.6%) stool samples collected from patients who attended a tertiary care hospital in Ragama, Sri Lanka. This is the first report of a human-porcine reassortant rotavirus in Sri Lanka. The patient was a 12-month-old boy who had been hospitalized with fever and acute diarrhea with a duration of 6 days. The family had pigs at home before the birth of this boy. However, the neighbors still practice pig farming. The genotype constellation of R1207 was G4-P[6]-I1-R1-C1-M1-A1-N1-T1-E1-H1. This is based on the assignment of all the eleven gene segments a full genome-based genotyping system. R1207 showed a 4-2-3-2 genomic electrophoretic migration pattern, which is characteristic of group A rotaviruses. Our analyses revealed that five (NSP2, NSP4, VP1, VP2, and VP7) of the 11 genes were closely related to the respective genes of porcine strains. Although the remaining six genes (NSP1, NSP3, NSP5, VP3, VP4, and VP6) were related to human strains, with the exception of the gene sequence of NSP1, all of these human strains were human-porcine reassortants. With a genogroup 1 genetic backbone, this strain was possibly formed via multiple genetic reassortments. We do not know whether this strain is circulating in pigs, as no data are available on porcine rotaviruses in Sri Lanka. Surveillance should be strengthened to determine the epidemiology of this genotype of rotavirus in Sri Lanka and to assess whether the infection was limited or sustained by ongoing human-to-human transmission., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Rotavirus (RV) is considered to be the most common cause of gastroenteritis among infants aged less than 5 years old. Human milk bioactive compounds have the ability to modulate the diarrheic process caused by several intestinal pathogens. This study aimed to evaluate the potential protective role of a specific human milk oligosaccharide, 2'-fucosyllactose (2'-FL), a mixture of the prebiotic short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides 9:1 (GOS/FOS) and their combination (2'-FL+GOS/FOS) on RV-induced diarrhea in suckling rats. The nutritional intervention was performed from the second to the sixteenth day of life by oral gavage and on day 5 an RV strain was orally administered to induce infection. Fecal samples were scored daily to assess the clinical pattern of severity, incidence and duration of diarrhea. Blood and tissues were obtained at day 8 and 16 in order to evaluate the effects on the epithelial barrier and the mucosal and systemic immune responses. In the assessment of severity, incidence and duration of diarrhea, both 2'-FL and GOS/FOS displayed a beneficial effect in terms of amelioration. However, the mechanisms involved seemed to differ: 2'-FL displayed a direct ability to promote intestinal maturation and to enhance neonatal immune responses, while GOS/FOS induced an intestinal trophic effect and an RV-blocking action. The combination of 2'-FL and GOS/FOS showed additive effects in some variables. Therefore, it could be a good strategy to add these compounds in combination to infant formulas, to protect against human RV-induced diarrhea in children.

Antimicrobial overuse contributes to antimicrobial resistance. Empiric use of antimicrobials for diarrheal illness is warranted only in a minority of cases, because of its self-limiting nature and multifactorial etiology. This study aims to describe the factors contributing to antimicrobial overuse for diarrheal disease among children less than 5 years of age in rural Bangladesh. A total of 3,570 children less than 5 years of age presenting with diarrhea in a tertiary level hospital were enrolled in the study. The rate of antimicrobial use at home was 1,395 (39%), compared with 2,084 (89%) during a hospital visit. In a multivariate analysis, factors associated with antimicrobial use at home included residence located more than 5 miles from a hospital; use of zinc and oral rehydration salts at home; vomiting; greater than 10 stools per 24 hours; diarrheal duration greater than 3 days; and rotavirus diarrhea ( P < 0.05 for all). Characteristics of children more likely to be given antimicrobials in a health-care setting included greater than 10 stools per 24 hours; duration of diarrhea greater than 3 days; use of antimicrobials before hospital presentation; fever (≥ 37.8°C); rectal straining; and Shigella infection ( P < 0.05 for all). The most commonly used drugs in rotavirus diarrhea were azithromycin and erythromycin, both before hospital presentation and during hospital admission. Our study underscores the importance of diligent vigilance on the rationale use of antimicrobials both at home and in health-care facilities with a special concern for children less than 5 years of age living in rural Bangladesh.

We previously identified, by a natural-product screen, resveratrol oligomers as inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Here, we report the resveratrol dimer trans-ε-viniferin (TV) and tetramer r-2-viniferin (RV) as inhibitors of the intestinal calcium-activated chloride channel (CaCC) and demonstrate their antisecretory efficacy in a neonatal mouse model of rotaviral diarrhea. Short-circuit measurements show inhibition of CaCC current in the human colonic cell line HT-29 by TV and RV with IC 50 ∼1 and 20μM, respectively. TV primarily inhibited the physiologically relevant, long-term CaCC current following agonist stimulation, without effect on cytoplasmic Ca 2+ signaling. TV and RV inhibited short-circuit current in mouse colon as well. In a neonatal mouse model of rotaviral secretory diarrhea produced by oral inoculation with rotavirus, 2μg TV or 11μg RV inhibited secretory diarrhea by >50%, without effect on the rotaviral infection. Our results support the antisecretory efficacy of non-toxic, natural-product resveratrol oligomers for diarrheas produced by CaCC activation. Because these compounds also inhibit the CFTR chloride channel, they may be useful for antisecretory therapy of a wide range of diarrheas., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Rotaviruses may produce prolonged and severe disease in allogeneic hematopoietic cell transplant (HCT) recipients. Nitazoxanide and enterally administered human immunoglobulins are potential therapeutic options. This retrospective study describes the clinical course of rotavirus infection in pediatric allogeneic HCT recipients and a single-center experience with nitazoxanide and oral immunoglobulins as potential treatment options., Methods: We identified 36 patients who had positive stool rotavirus antigen assays after allogeneic HCT from May 30, 2012, to July 31, 2015. Clinical, microbiologic and treatment data were collected and analyzed using descriptive statistics., Results: Forty-nine discrete episodes of rotavirus infection were identified among these 36 patients for a cumulative incidence of 19.7%. For these 49 episodes, the median day to infection after HCT was day 82, and the median duration of diarrhea was 17.5 days (range 4-122). Nitazoxanide and enteral immunoglobulins were prescribed for 41 episodes. The median duration of clinical symptoms after initiation of nitazoxanide was 11 days (range 2-85), 23 days (range 10-107) after enteral immunoglobulins and 26 days (range 6-90) after a combination of nitazoxanide and enteral immunoglobulins (P = 0.1). No adverse effects of either treatment were documented, but efficacy could not be assessed in this patient population., Conclusions: In pediatric HCT recipients, the clinical illness produced by rotaviruses is prolonged compared with otherwise healthy children. Nitazoxanide appears safe, but its efficacy for this indication requires further study.

Background: Acute gastroenteritis (AGE) can be caused by a wide array of pathogens, including bacteria, viruses, and parasites. A prospective study to investigate the epidemiology and clinical presentation in young children hospitalized with AGE was conducted in a medical center in southern Taiwan., Methods: Patients aged less than 5 years who was hospitalized due to AGE in National Cheng Kung University Hospital were enrolled from July 2014 to June 2016. The demographic information, clinical features and laboratory data were collected by chart reviews, and stool samples were sent to Centers of Disease Control, Taiwan (Taiwan CDC) for a panel of pathogen identification consisting of two viruses, nine bacteria, and five parasites., Results: Totally 441 patients were enrolled in this study. Salmonella spp. was the leading cause of disease (21.8%), followed by norovirus (17.0%), Clostridium difficile (9.5%), and rotavirus (9.3%). Norovirus identification rate was the highest among patients less than 6 months of age, while Salmonella was highest among patients between 2 and 3 years old. Patients with Salmonella infection frequently presented with fever, lethargy, bloody stool, and elevated serum level of C-reactive protein (CRP); norovirus and rotavirus infection frequently presented with vomiting. Salmonella gastroenteritis also resulted in longer hospitalization and more frequent antibiotics administration. C. difficile could be isolated from both gastroenteritis patients and control children., Conclusion: Salmonella spp. was the most common pathogen of AGE in hospitalized children in southern Taiwan during 2014-2016, followed by norovirus and rotavirus. Further monitoring of epidemiology characteristics among cardinal pathogens of pediatric gastroenteritis is necessary., (Copyright © 2017. Published by Elsevier B.V.)

Background: Rotavirus is the leading cause of viral gastroenteritis in children, and it is anticipated that the introduction of the Rotarix™ vaccine (GlaxoSmithKline Biologicals S.A., Rixensart, Belgium) into the Irish immunisation schedule will result in a significant reduction of rotavirus-associated disease. In the pre- and post-vaccination eras, it is important to determine circulating strains of rotavirus to assess vaccine effectiveness, to monitor vaccine failures, and to detect potential emerging strains., Aim: This study was a collaboration between the Temple Street Children's University Hospital (TSCUH), Dublin, and the National Virus Reference Laboratory (NVRL), Dublin, to determine the then circulating rotavirus strains in a paediatric hospital., Method: In the 2015/2016 period (July 2015-June 2016) 89 faecal samples from paediatric patients (53 from TSCUH, 36 from other hospitals) were characterised., Results: The results showed G1P[8] to be the predominant genotype (57%), followed by G9P[8] (34%), G4P[8] (6%), G2P[4] (2%), and G12P[8] (1%)., Conclusion: This distribution of genotypes is comparable to those found in other European countries prior to vaccination suggesting that the vaccine should be highly efficacious in the Irish population.

Background: Rotavirus and norovirus cause acute gastroenteritis with severe diarrhoea and vomiting, symptoms that may lead to severe dehydration and death. The objective of this randomized double-blinded placebo-controlled study was to investigate whether ondansetron, a serotonin receptor antagonist could attenuate rotavirus- and norovirus-induced vomiting and diarrhoea, which would facilitate oral rehydration and possibly accelerate recovery and reduce need for hospitalization., Methods: Children with acute gastroenteritis, aged 6 months to 16 years where enrolled (n = 104) and randomized to one single oral dose (0.15mg/kg) of ondansetron (n = 52) or placebo (n = 52). The number of diarrhoea and vomiting episodes during the 24 hours following treatment was reported as well as the number of days with symptoms. Pathogens in faeces were diagnosed by real-time PCR. Outcome parameters were analyzed for rotavirus- and norovirus-positive children., Results: One dose of oral ondansetron reduced duration of rotavirus clinical symptoms (p = 0.014), with a median of two days. Furthermore, ondansetron reduced diarrhea episodes, most pronounced in children that had been sick for more than 3 days before treatment (p = 0.028)., Conclusion: Ondansetron may be a beneficial treatment for children with rotavirus gastroenteritis., Trial Registration: European Clinical Trial Database EudraCT 2011-005700-15.

A non-blinded randomized clinical trial was conducted to assess the immunomodulatory potential of β-glucan (BG) in piglet diarrhoea associated with type A rotavirus infection. A total of 12 rotavirus-infected diarrheic piglets were randomly divided into two groups: wherein six rotavirus-infected piglets were treated with supportive treatment (ST) and other six rotavirus-infected piglets were treated with BG along with ST (ST-BG). Simultaneously, six healthy piglets were also included in the study which served as control. In rotavirus-infected piglets, marked increase of Intestinal Fatty Acid Binding Protein-2 (I-FABP2), nitric oxide (NOx), Interferon-γ (IFN-γ) concentrations and decrease of immunoglobulin G (IgG) were noticed compared to healthy piglets. The faecal consistency and dehydration scores were significantly higher in rotavirus-infected piglets than healthy piglets. The ST-BG treatment progressively reduced the I-FABP2 and increased the IgG concentrations over the time in rotavirus-infected piglets compared to piglets received only ST. A pronounced enhancement of NOx and IFN-γ concentrations was observed initially on day 3 and thereafter the values reduced on day 5 in ST-BG treated piglets in comparison to piglets which received only ST. Additionally, ST-BG treatment significantly reduced faecal consistency and dehydration scores on day 3 compared to ST in rotavirus-infected piglets. These findings point that BG represents a potential additional therapeutic option to improve the health condition and reduce the piglet mortality from rotavirus associated diarrhoea where porcine rotavirus vaccine is not available., (Copyright © 2017 Elsevier B.V. All rights reserved.)