Resveratrol inhibits respiratory syncytial virus replication by targeting heparan sulfate proteoglycans.

Resveratrol, renowned as an antioxidant, also exhibits significant potential in combatting severe respiratory infections, particularly the respiratory syncytial virus (RSV). Nevertheless, the specific mechanism underlying its inhibition of RSV replication remains unexplored. Heparan sulfate proteoglycans (HSPGs) play a pivotal role as attachment factors for numerous viruses, offering a promising avenue for countering viral infections. Our research has unveiled that resveratrol effectively curbs RSV infection in a dose-dependent manner. Remarkably, resveratrol disrupts the early stages of RSV infection by engaging with HSPGs, rather than interacting with RSV surface proteins like fusion (F) protein and glycoprotein (G). Resveratrol's affinity appears to be predominantly directed towards the negatively charged sites on HSPGs, thus impeding the binding of viral receptors. In an in vivo study involving RSV-infected mice, resveratrol demonstrates its potential by ameliorating pulmonary pathology. This improvement is attributed to the inhibition of pro-inflammatory cytokine expression and a reduction in viral load within the lungs. Notably, resveratrol specifically alleviates inflammation characterized by an abundance of neutrophils in RSV-infected mice. In summation, our data first shows how resveratrol combats RSV infection through interactions with HSPGs, positioning it as a promising candidate for innovative drug development targeting RSV infections. Our study provides insight into the mechanism of resveratrol antiviral infection.

Interface-Stabilized Fiber Sensor for Real-Time Monitoring of Amniotic Fluid During Pregnancy.

Diseases in pregnancy endanger millions of fetuses worldwide every year. The onset of these diseases can be early warned by the dynamic abnormalities of biochemicals in amniotic fluid, thus requiring real-time monitoring. However, when continuously penetrated by detection devices, the amnion is prone to loss of robustness and rupture, which is difficult to regenerate. Here, an interface-stabilized fiber sensor is presented for real-time monitoring of biochemical dynamics in amniotic fluid during pregnancy. The sensor is seamlessly integrated into the amnion through tissue adhesion, amniotic regeneration, and uniform stress distribution, posing no risk to the amniotic fluid environment. The sensor demonstrates a response performance of less than 0.3% fluctuation under complex dynamic conditions and an accuracy of more than 98% from the second to the third trimester. By applying it to early warning of diseases such as intrauterine hypoxia, intrauterine infection, and fetal growth restriction, fetal survival increases to 95% with timely intervention.

Jiangqi Pingxiao formula regulates dendritic cell apoptosis in an autophagy-dependent manner through the AMPK/mTOR pathway in a murine model of OVA-induced asthma.

ETHNOPHARMACOLOGICAL RELEVANCE: Allergic asthma is a recurring respiratory condition that typically manifests during childhood or adolescence. It is characterized by a dominant type II immune response triggered by the identification and capturing of inhaled allergens by dendritic cells (DCs). Jiangqi Pingxiao Formula (JQPXF), a prescription medicine used for the treatment of pediatric asthma, has been clinically proven to be both safe and effective. However, its mechanism of action in the treatment of asthma has not been fully been fully elucidated. Recent research suggests that several natural compounds have the potential to target dendritic cells (DCs) and alleviate ovalbumin (OVA)-induced asthma, which may also be found within JQPXF. AIM OF THE STUDY: This study aimed to elucidate the effect of JQPXF on OVA-induced asthma model and its molecular mechanism targeting DCs. MATERIALS AND METHODS: The main constituents of JQPXF were analyzed by ultra performance liquid chromatography (UPLC). An asthma model was established by OVA. Hematoxylin-eosin staining and measurement of respiratory function was used to evaluate the treatment effect of JQPXF on asthmatic mice. Cytokine (IL-5, IL-13 and IgE) concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Flow cytometry was employed to evaluate inflammatory cell infiltration (T helper 2 cells and DCs) in vivo and DC survival in vivo and vitro. Western blot and immunofluorescence were used to verify the molecular mechanisms. RESULTS: The results suggest that JQPXF can ameliorate pathological conditions and improve lung function in asthmatic mice, as well as the Th2 cells. Treatment with JQPXF significantly reduced the number of DCs and increased the number of Propidium iodide+ (PI) DCs. Furthermore, JQPXF upregulated protein levels of the pro-apoptotic factors Cleaved-caspase-3 and Bax, while downregulating the anti-apoptotic factor Bcl-2. Simultaneously, JQPXF increased autophagy levels by facilitating p62 degradation and promoting translation from LC3B I to LC3B II of DCs in vitro, as well as reducing the integrated optical density (IOD) of p62 within the CD11c-positive area in the lung. 3-Methyladenine (3-MA) was used to block autophagic flux and the apoptotic effect of JQPXF on DCs was abolished in vitro, with the number of DCs decreased by JQPXF being reversed in vivo. We further investigated the upstream key regulator of autophagy, the AMPK/mTOR pathway, and found that JQPXF increased AMPK phosphorylation while decreasing mTOR phosphorylation levels. Additionally, we employed Compound C (CC) as an AMPK inhibitor to inhibit this signaling pathway, and our findings revealed that both autophagic flux and apoptotic levels in DCs were abolished in vitro. CONCLUSIONS: In summary, we have demonstrated that JQPXF could alleviate type II inflammation in an asthmatic model by promoting the apoptosis of DCs through an autophagy-dependent mechanism, achieved by regulating the AMPK/mTOR signaling pathway.

SEPTIN2 suppresses an IFN-γ-independent, proinflammatory macrophage activation pathway.

Interferon-gamma (IFN-γ) signaling is necessary for the proinflammatory activation of macrophages but IFN-γ-independent pathways, for which the initiating stimuli and downstream mechanisms are lesser known, also contribute. Here we identify, by high-content screening, SEPTIN2 (SEPT2) as a negative regulation of IFN-γ-independent macrophage autoactivation. Mechanistically, endoplasmic reticulum (ER) stress induces the expression of SEPT2, which balances the competition between acetylation and ubiquitination of heat shock protein 5 at position Lysine 327, thereby alleviating ER stress and constraining M1-like polarization and proinflammatory cytokine release. Disruption of this negative feedback regulation leads to the accumulation of unfolded proteins, resulting in accelerated M1-like polarization, excessive inflammation and tissue damage. Our study thus uncovers an IFN-γ-independent macrophage proinflammatory autoactivation pathway and suggests that SEPT2 may play a role in the prevention or resolution of inflammation during infection.

Implantable Zinc-Oxygen Battery for In Situ Electrical Stimulation-Promoted Neural Regeneration.

Electrical stimulation is a promising strategy for treating neural diseases. However, current energy suppliers cannot provide effective power for in situ electrical stimulation. Here, an implantable tubular zinc-oxygen battery is reported as the power source for in situ electrical stimulation during the neural repair. The battery exhibited a high volumetric energy density of 231.4 mWh cm-3 based on the entire anode and cathode in vivo. Due to its superior electrochemical properties and biosafety, the battery can be directly wrapped around the nerve to provide in situ electrical stimulation with a minimal size of 0.86 mm3 . The cell and animal experiments demonstrated that the zinc-oxygen battery-based nerve tissue engineering conduit effectively promoted regeneration of the injured long-segment sciatic nerve, proving its promising applications for powering implantable neural electronics in the future.

Discovery of N-Acyl Amino Acids and Novel Related N-, O-Acyl Lipids by Integrating Molecular Networking and an Extended In Silico Spectral Library.

Research on novel bioactive lipids has garnered increasing interest. Although lipids can be identified by searching mass spectral libraries, the discovery of novel lipids remains challenging as the query spectra of such lipids are not included in libraries. In this study, we propose a strategy to discover novel carboxylic acid-containing acyl lipids by integrating molecular networking with an extended in silico spectral library. Derivatization was performed to improve the response of this method. The tandem mass spectrometry spectra enriched by derivatization facilitated the formation of molecular networking and 244 nodes were annotated. We constructed consensus spectra for these annotations based on molecular networking and developed an extended in silico spectral library based on these consensus spectra. The spectral library included 6879 in silico molecules covering 12,179 spectra. Using this integration strategy, 653 acyl lipids were discovered. Among these, O-acyl lactic acids and N-lactoyl amino acid-conjugated lipids were annotated as novel acyl lipids. Compared with conventional methods, our proposed method allows for the discovery of novel acyl lipids, and extended in silico libraries significantly increase the size of the spectral library.

Analysis of temporal metabolic rewiring for human respiratory syncytial virus infection by integrating metabolomics and proteomics.

INTRODUCTION: Human respiratory syncytial virus (HRSV) infection causes significant morbidity, and no effective treatments are currently available. Viral infections induce substantial metabolic changes in the infected cells to optimize viral production. Metabolites that reflect the interactions between host cells and viruses provided an opportunity to identify the pathways underlying severe infections. OBJECTIVE: To better understand the metabolic changes caused by HRSV infection, we analyzed temporal metabolic profiling to provide novel targets for therapeutic strategies for inhaled HRSV infection. METHODS: The epithelial cells and BALB/c mice were infected with HRSV. Protein and mRNA levels of inflammation factors were measured by using quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Untargeted metabolomics, lipidomics and proteomics were performed using liquid chromatography coupled with mass spectrometry to profile the metabolic phenotypic alterations in HRSV infection. RESULTS: In this study, we evaluated the inflammatory responses in vivo and in vitro and investigated the temporal metabolic rewiring of HRSV infection in epithelial cells. We combined metabolomics and proteomic analyses to demonstrate that the redox imbalance was further provoked by increasing glycolysis and anaplerotic reactions. These responses created an oxidant-rich microenvironment that elevated reactive oxygen species levels and exacerbated glutathione consumption. CONCLUSION: These observations indicate that adjusting for metabolic events during a viral infection could represent a valuable approach for reshaping the outcome of infections.

Immunosuppression by opioids: Mechanisms of action on innate and adaptive immunity.

Opioids are excellent analgesics for the clinical treatment of various types of acute and chronic pain, particularly cancer-related pain. Nevertheless, it is well known that opioids have some nasty side effects, including immunosuppression, which is commonly overlooked. As a result, the incidence of opportunistic bacterial and viral infections increases in patients with long-term opioid use. Nowadays, there are no effective medications to alleviate opioid-induced immunosuppression. Understanding the underlying molecular mechanism of opioids in immunosuppression can enable researchers to devise effective therapeutic interventions. This review comprehensively summarized the exogenous opioids-induced immunosuppressive effects and their underlying mechanisms, the regulatory roles of endogenous opioids on the immune system, the potential link between opioid immunosuppressive effect and the function of the central nervous system (CNS), and the future perspectives in this field.

Platycodon grandiflorus root extract activates hepatic PI3K/PIP3/Akt insulin signaling by enriching gut Akkermansia muciniphila in high fat diet fed mice.

BACKGROUND: Increasing hepatic insulin signaling is found to be an important mechanism of Platycodon grandiflorus root to alleviate metabolic syndrome (MetS) symptoms such as insulin resistance, obesity, hyperlipidemia and hepatic steatosis, but the details are not yet clear. Since the main constituents of Platycodon grandiflorus root were hard to be absorbed by gastrointestinal tract, getting opportunity to interact with gut microbiota, we speculate the gut microorganisms may mediate its effect. PURPOSE: Our work aimed to confirm the critical role of gut microbes in the intervention of Platycodon grandiflorus root extract (PRE) on MetS, and investigate the mechanism. METHODS: Biochemical analyses, glucose tolerance test and hepatic lipidomics analysis were used to evaluate the anti-MetS effect of PRE on high fat diet (HFD) fed mice. Perform 16S rDNA analysis, qPCR analysis and in vitro co-incubation experiment to study its effect on gut microbes, followed by fecal microbiota transplantation (FMT) experiment and antibiotics intervention experiment. Also, the effect of Akkermansia muciniphila treatment on HFD mice was investigated. RESULTS: PRE alleviated lipid accumulation and insulin resistance in HFD mice and remodeled the fecal microbiome. It also increased the gene expression of colonic tight junction proteins, alleviated metabolic endotoxemia and inflammation, so that reduced TNF-α induced hepatic JNK-dependent IRS-1 serine phosphorylation and the impairment of PI3K/PIP3/Akt insulin signaling pathway. A. muciniphila was one of the most significantly enriched microbes by PRE treatment, and its administration to HFD mice showed similar effects to PRE, repairing the gut barrier and activating hepatic PI3K/PIP3/Akt pathway. Finally, anti-MetS effect of PRE could be delivered to FMT recipients, and PRE could not further attenuate MetS in gut microbiota depleted mice. CONCLUSION: We demonstrated for the first time that PRE alleviated MetS in a gut microbiota dependent manner, and found activation of hepatic insulin signaling mediated by gut A. muciniphila was a potential mechanism of it.

Compound 511 ameliorates MRSA-induced lung injury by attenuating morphine-induced immunosuppression in mice via PI3K/AKT/mTOR pathway.

BACKGROUND: Opioids are widely used in clinical practice. However, their long-term administration causes respiratory depression, addiction, tolerance, and severe immunosuppression. Traditional Chinese medicine (TCM) can alleviate opioid-induced adverse effects. Compound 511 is particularly developed for treating opioid addiction, based on Jiumi Liangfang, an ancient Chinese drug treatment and rehabilitation monograph completed in 1833 A.D. It is an herbal formula containing eight plants, each of them contributing to the overall pharmacological effect of the product: Panax ginseng C. A. Meyer (8.8%), Astragalus membranaceus (Fisch.) (18.2%), Datura metel Linn. (10.95%), Corydalis yanhusuo W. T. Wang (14.6%), Acanthopanar gracilistµlus W. W. Smith (10.95%), Ophiopogon japonicus (Linn. f.) Ker-Gawl. (10.95%), Gynostemma pentaphyllum (Thunb.) Makino (10.95%), Polygala arvensis Willd. (14.6%). This formula effectively ameliorates opioid-induced immunosuppression. However, the underlying mechanism remains unclear. PURPOSE: To reveal the effects of Compound 511 on the immune response of morphine-induced immunosuppressive mice and their potential underlying molecular mechanism. This study provides information for a better clinical approach and scientific use of opioids. METHODS: Immunosuppression was induced in mice by repeated morphine administration. Th1/Th2/Th17/Treg cell levels were measured using flow cytometry. Splenic transcription factors of Th1/Th2/Th17/Treg and outputs of the regulatory PI3K/AKT/mTOR signaling pathway were determined. Subsequently, methicillin-resistant Staphylococcus aureus (MRSA) was administered intranasally to morphine-induced immunosuppressive mice pretreated with Compound 511. Their lung inflammatory status was assessed using micro-computer tomography (CT), hematoxylin and eosin (H&E) staining, and enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared to morphine, Compound 511 significantly decreased the immune organ indexes of mice, corrected the Th1/Th2 and Treg/Th17 imbalance in the immune organs and peripheral blood, reduced the mRNA levels of FOXP3 and GATA3, and increased those of STAT3 and T-bet in the spleen. It improved immune function and reduced MRSA-induced lung inflammation. CONCLUSION: Compound 511 ameliorates opioid-induced immunosuppression by regulating the balance of Th1/Th2 and Th17/Treg via PI3K/AKT/mTOR signaling pathway. Thus, it effectively reduces susceptibility of morphine-induced immunosuppressive mice to MRSA infection.

Cyclophosphamide Induces Lipid and Metabolite Perturbation in Amniotic Fluid during Rat Embryonic Development.

Cyclophosphamide (CP) has been proven to be an embryo-fetal toxic. However, the mechanism responsible for the toxicity of the teratogenic agent has not been fully explored. This study aimed to examine the teratogenicity of CP when administered in the sensitive period of pregnant rats. The effect of CP on the lipid and metabolic profiles of amniotic fluid was evaluated using a UHPLC-Q-Exactive Orbitrap MS-based method. Metabolome analysis was performed using the MS-DIAL software with LipidBlast and NIST. Initially, we identified 636 and 154 lipid compounds in the positive and negative ion modes and 118 metabolites for differential analysis. Mainly 4 types of oxidized lipids in the amniotic fluid were found to accumulate most significantly after CP treatment, including very-long-chain unsaturated fatty acids (VLCUFAs), polyunsaturated fatty acid (PUFA)-containing triglycerides (TGs), oxidized phosphatidylcholine (PC), and sphingomyelin (SM). Tryptophan and some long-chain saturated fatty acids were lowered pronouncedly after CP treatment. These findings suggest that CP may exert teratogenic toxicity on pregnant rats through maternal and fetal oxidative stress. The UHPLC-Q-Exactive Orbitrap MS-based lipidomics approach is worthy of wider application for evaluating the potential toxicity of other agents (toxicants) during embryonic development.

Development of mRNA vaccines against respiratory syncytial virus (RSV).

Respiratory syncytial virus (RSV) is a single-stranded negative-sense RNA virus that is the primary etiologic pathogen of bronchitis and pneumonia in infants and the elderly. Currently, no preventative vaccine has been approved for RSV infection. However, advances in the characterization, and structural resolution, of the RSV surface fusion glycoprotein have revolutionized RSV vaccine development by providing a new target for preventive interventions. In general, six different approaches have been adopted in the development of preventative RSV therapeutics, namely, particle-based vaccines, vector-based vaccines, live-attenuated or chimeric vaccines, subunit vaccines, mRNA vaccines, and monoclonal antibodies. Among these preventive interventions, MVA-BN-RSV, RSVpreF3, RSVpreF, Ad26. RSV.preF, nirsevimab, clesrovimab and mRNA-1345 is being tested in phase 3 clinical trials, and displays the most promising in infant or elderly populations. Accompanied by the huge success of mRNA vaccines in COVID-19, mRNA vaccines have been rapidly developed, with many having entered clinical studies, in which they have demonstrated encouraging results and acceptable safety profiles. In fact, Moderna has received FDA approval, granting fast-track designation for an investigational single-dose mRNA-1345 vaccine against RSV in adults over 60 years of age. Hence, mRNA vaccines may represent a new, more successful, chapter in the continued battle to develop effective preventative measures against RSV. This review discusses the structure, life cycle, and brief history of RSV, while also presenting the current advancements in RSV preventatives, with a focus on the latest progress in RSV mRNA vaccine development. Finally, future prospects for this field are presented.

Insights Gained Into the Treatment of COVID19 by Pulmonary Surfactant and Its Components.

Pulmonary surfactant constitutes an important barrier that pathogens must cross to gain access to the rest of the organism via the respiratory surface. The presence of pulmonary surfactant prevents the dissemination of pathogens, modulates immune responses, and optimizes lung biophysical activity. Thus, the application of pulmonary surfactant for the treatment of respiratory diseases provides an effective strategy. Currently, several clinical trials are investigating the use of surfactant preparations to treat patients with coronavirus disease 2019 (COVID-19). Some factors have been considered in the application of pulmonary surfactant for the treatment COVID-19, such as mechanical ventilation strategy, timing of treatment, dose delivered, method of delivery, and preparation utilized. This review supplements this list with two additional factors: accurate measurement of surfactants in patients and proper selection of pulmonary surfactant components. This review provides a reference for ongoing exogenous surfactant trials involving patients with COVID-19 and provides insight for the development of surfactant preparations for the treatment of viral respiratory infections.

Potential Therapeutic Applications of Pulmonary Surfactant Lipids in the Host Defence Against Respiratory Viral Infections.

Pulmonary surfactant is a complex and highly surface-active material. It covers the alveolar epithelium and consists of 90% lipids and 10% proteins. Pulmonary surfactant lipids together with pulmonary surfactant proteins facilitate breathing by reducing surface tension of the air-water interface within the lungs, thereby preventing alveolar collapse and the mechanical work required to breathe. Moreover, pulmonary surfactant lipids, such as phosphatidylglycerol and phosphatidylinositol, and pulmonary surfactant proteins, such as surfactant protein A and D, participate in the pulmonary host defense and modify immune responses. Emerging data have shown that pulmonary surfactant lipids modulate the inflammatory response and antiviral effects in some respiratory viral infections, and pulmonary surfactant lipids have shown promise for therapeutic applications in some respiratory viral infections. Here, we briefly review the composition, antiviral properties, and potential therapeutic applications of pulmonary surfactant lipids in respiratory viral infections.

In-silico-library-based method enables rapid and comprehensive annotation of cardiolipins and cardiolipin oxidation products using high resolution tandem mass spectrometer.

Accumulated evidences suggest that cardiolipins (CLs) and cardiolipin oxidation products (oxCLs) are a class of essential molecules that play critical roles in many physiological functions. Diversity of four acyl chains leads to high structure complexity for cardiolipin species including CLs, monolysocardiolipins (MLCLs) and their oxCLs. The ability to rapidly identify CL species can be implemented by the match of mass spectrometry (MS)-based in-silico spectral database. In this study, after optimizing the chromatography conditions and MS detection, an in-silico library containing 377,754 simulated tandem mass spectra deducing from 31,578 CLs to 52,160 of MLCLs was successfully augmented based on LipidBlast templates. For the construction of the oxCLs' library, twenty-five fatty acyls oxidation products relating to nine oxidation types were permuted and combined. A total of 42,180 oxCL spectra were predicted based on the experimental measurements of oxCLs forming by artificially oxidation. Applying the in-silico database to murine mitochondria and cell samples enabled the sensitive and comprehensive annotation of 86 MLCLs, 307 CLs and 112 oxCLs with high annotation confidence. Compared to the conventional method, our proposed in-silico database provides a more comprehensive interpretation for CL species' characterization with high throughput and sensitivity in nontarget lipidomic study.

iTRAQ-Based Proteomics Reveals Gu-Ben-Fang-Xiao Decoction Alleviates Airway Remodeling via Reducing Extracellular Matrix Deposition in a Murine Model of Chronic Remission Asthma.

Airway remodeling is a primary pathological feature of asthma. The current therapy for asthma mainly targets reducing inflammation but not particularly airway remodeling. Therefore, it is worthwhile to develop alternative and more effective therapies to attenuate remodeling. Gu-Ben-Fang-Xiao Decoction (GBFXD) has been used to effectively and safely treat asthma for decades. In this study, GBFXD regulated airway inflammation, collagen deposition, and the molecules relevant to airway remodeling such as Vimentin, α-SMA, hydroxyproline, and E-cadherin in chronic remission asthma (CRA) murine model. Proteomic analysis indicated that the overlapping differentially expressed proteins (DEPs) (Model/Control and GBFXD/Model) were mainly collagens and laminins, which were extracellular matrix (ECM) proteins. In addition, the KEGG analysis showed that GBFXD could regulate pathways related to airway remodeling including ECM-receptor interactions, focal adhesion, and the PI3K/AKT signaling pathway, which were the top three significantly enriched pathways containing the most DEPs for both Model/Control and GBFXD/Model. Further validation research showed that GBFXD regulated reticulon-4 (RTN4) and suppressed the activation of the PI3K/AKT pathway to alleviate ECM proteins deposition. In conclusion, our findings indicate that GBFXD possibly regulate the PI3K/AKT pathway via RTN4 to improve airway remodeling, which provides a new insight into the molecular mechanism of GBFXD for the treatment of CRA.

Gu-Ben-Fang-Xiao decoction modulates lipid metabolism by activating the AMPK pathway in asthma remission.

Gu-Ben-Fang-Xiao decoction (GBFXD), derived from the traditional Chinese medicine Yu-Ping-Feng-San, is widely used in clinical settings and has obvious curative effects in respiratory diseases. GBFXD regulates cholesterol transport and lipid metabolism in chronic persistent asthma. There is evidence for its beneficial effects in the remission stage of asthma; however, its metabolic regulatory effects and underlying mechanisms during asthma remission are unclear. In the present study, we used liquid chromatography-mass spectrometry (LC-MS) to analyse the metabolic profile of mouse serum during asthma remission. The acquired LC-MS data were subjected to a multivariate analysis for identification of significantly altered metabolites. In total, 42 metabolites were significantly differentially expressed among the control, model, and GBFXD groups. In particular, levels of fatty acids, acylcarnitines, phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols, triglycerides, and diacylglycerols were altered during asthma remission. GBFXD may maintain lipid homeostasis on the lung surface by modulating lipid metabolism and may thereby alleviate asthma. We further quantified hypogeic acid (FA 16:1) based on targeted metabolomics and found that GBFXD may regulate fatty acid metabolism by activating the AMP-activated protein kinase (AMPK) pathway. These results support the use of GBFXD in patients with asthma remission.

Probiotics protect against RSV infection by modulating the microbiota-alveolar-macrophage axis.

Respiratory syncytial virus (RSV) is leading cause of respiratory tract infections in early childhood. Gut microbiota is closely related with the pulmonary antiviral immunity. Recent evidence shows that gut dysbiosis is involved in the pathogenesis of RSV infection. Therefore; pharmacological and therapeutic strategies aiming to readjust the gut dysbiosis are increasingly important for the treatment of RSV infection. In this study, we evaluated the therapeutic effects of a probiotic mixture on RSV-infected mice. This probiotic mixture consisted of Lactobacillus rhamnosus GG, Escherichia coli Nissle 1917 and VSL#3 was orally administered to neonatal mice on a daily basis either for 1 week in advance or for 3 days starting from the day of RSV infection. We showed that administration of the probiotics protected against RSV-induced lung pathology by suppressing RSV infection and exerting an antiviral response via alveolar macrophage (AM)-derived IFN-ß. Furthermore, administration of the probiotics reversed gut dysbiosis and significantly increased the abundance of short-chain fatty acid (SCFA)-producing bacteria in RSV-infected mice, which consequently led to elevated serum SCFA levels. Moreover, administration of the probiotics restored lung microbiota in RSV-infected mice. We demonstrated that the increased production of IFN-ß in AMs was attributed to the increased acetate in circulation and the levels of Corynebacterium and Lactobacillus in lungs. In conclusion, we reveal that probiotics protect against RSV infection in neonatal mice through a microbiota-AM axis, suggesting that the probiotics may be a promising candidate to prevent and treat RSV infection, and deserve more research and development in future.

[Modified Dihuang Decoction improves ovarian reserve in mice by regulating Bcl-2-related mitochondrial apoptosis pathway].

The present study investigated the effect of Modified Dihuang Decoction in improving ovarian reserve in mice through the Bcl-2-related mitochondrial apoptosis pathway. Forty-eight adult female BALB/c mice were randomly divided into the following six groups with eight mice in each group: a blank group, a model group, a femoston group(three cycles of treatment with 0.13 mg·kg~(-1) estradiol tablets for 2 days and 1.43 mg·kg~(-1) estradiol and dydrogesterone tablets for 3 days), and high(64.74 g·kg~(-1))-, medium(43.16 g·kg~(-1))-, and low-dose(21.58 g·kg~(-1)) Modified Dihuang Decoction groups. Mice in other groups except the blank group received a single intraperitoneal injection of 12 mg·kg~(-1) cyclophosphamide and 1.2 mg·kg~(-1) busulfan to induce a model of diminished ovarian reserve(DOR), while those in the blank group received an equal volume of normal saline. Mice were treated with corresponding drugs for 15 d from the 36 th day, once per day, and the mice in the blank group and the model group were treated with an equal volume of normal saline. The general condition and oestrous cycle were observed. The serum hormone levels were detected with the enzyme-linked immunosorbent assay(ELISA). The morphological changes of ovaries were observed by HE staining. Western blot was used to detect the protein expression of cysteinyl aspartate specific proteinase-9(caspase-9), cleaved caspase-3, Bcl-2 associated X protein(Bax), Bcl-2, superoxide dismutase-2(SOD-2), and glutathione peroxidase-1(GPx-1). The mRNA expression of Bax and Bcl-2 was detected by real-time fluorescence-based quantitative polymerase chain reaction(real-time PCR). The results showed that compared with the blank group, the model group showed body weight loss, disordered oestrous cycle, elevated serum levels of follicle-stimulating hormone(FSH) and luteinizing hormone(LH), reduced serum levels of estradiol(E_2), anti-mullerian hormone(AMH), and inhibin B(INHB), the declining number of ovarian follicles and granulosa layers, increased number of atretic follicles, up-regulated protein expression of caspase-9, cleaved caspase-3, and Bax and Bax mRNA expression in ovaries, and down-regulated protein expression of Bcl-2, SOD-2 and GPx-1, and Bcl-2 mRNA expression. Compared with the model group, the Modified Dihuang Decoction groups displayed restored body weight and oestrous cycle, decreased serum levels of FSH and LH, elevated serum levels of E_2, AMH, and INHB, increased number of ovarian follicles, thickened granulosa layers, and declining number of atretic follicles. Additionally, the protein expression of caspase-9, cleaved caspase-3, and Bax, and Bax mRNA expression was down-regulated, and the protein expression of Bcl-2, SOD-2, and GPx-1, and Bcl-2 mRNA expression was up-regulated. The results suggest that Modified Dihuang Decoction can regulate endocrine hormone, promote follicle growth and improve ovarian reserve by enhancing ovarian anti-oxidant capacity, inhibiting the Bcl-2-related mitochondrial apoptosis pathway, and further inhibiting cell apoptosis.

Elevated monocytic myeloid-derived suppressor cells positively correlate with infection frequency in children with RRTIs.

In children with recurrent respiratory tract infections (RRTIs), the percentages and numbers of monocytic myeloid-derived suppressor cells (MDSCs) were elevated. The elevated MDSCs positively correlate with respiratory tract infection frequency in RRTIs children. The elevated MDSCs can inhibit CD8+ T-cells proliferation in RRTIs children.