ED-71 Improves Bone Mass in Ovariectomized Rats by Inhibiting Osteoclastogenesis Through EphrinB2-EphB4-RANKL/OPG Axis.

Purpose: Estrogen deficiency is the main reason of postmenopausal osteoporosis. Eldecalcitol (ED-71) is a new active vitamin D analogue clinically used in the treatment of postmenopausal osteoporosis. We aimed to investigate whether EphrinB2-EphB4 and RANKL/RANK/OPG signaling cooperate in mediating the process of osteoporosis by ED-71. Methods: In vivo, the ovariectomized (OVX) rats were administered orally with 30 ng/kg ED-71 once a day for 8 weeks. HE staining, Masson staining and Immunofluorescence staining were used to evaluate bone mass, bone formation, osteoclastogenesis associated factors and the expression of EphrinB2, EphB4, RANKL and OPG. In vitro, H2O2 stimulation was used to simulate the cell environment in osteoporosis. Immunofluorescence, quantitative real time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) and Western Blot were applied to detect the expression of EphrinB2, EphB4, RANKL and OPG. In osteoblasts, EphB4 was knocked down by EphB4 small-interfering RNA (siRNA) transfection. LY294002 (PI3K inhibitor) or ARQ092 (AKT inhibitor) was used to block PI3K/AKT pathway. An indirect co-culture system of osteoblasts and osteoclasts was established. The mRNA and protein expression of osteoclastogenes is associated factors were tested by qRT-PCR and Western Blot. Results: ED-71 increased bone mass and decreased the number of osteoclasts in OVX rats. Moreover, ED-71 promoted the expression of EphrinB2, EphB4, and decreased the RANKL/OPG ratio in osteoblasts. Osteoclastogenesis was restrained when osteoclasts were indirectly co-cultured with ED-71-treated osteoblasts. After silencing of EphB4 expression in osteoblasts, ED-71 inhibited the expression of P-PI3K and P-AKT and increased the ratio of RANKL/OPG. This reversed the inhibitory effect of ED-71 on osteoclastogenes. Therefore, in ED-71-inhibited osteoclastogenes, EphB4 is a key factor affecting the secretion of RANKL and OPG by osteoblasts. EphB4 suppressed the RANKL/OPG ratio through activating PI3K/AKT signaling in osteoblasts. Conclusion: ED-71 inhibits osteoclastogenesis through EphrinB2-EphB4-RANKL/OPG axis, improving bone mass in ovariectomized rats. PI3K/AKT pathway is involved this process.

The Fabrication of a Customized Surgical Template for a Miniscrew Placement Using a Fully Digitized Process.

This report presents a clinical case involving the application of a computer-aided design and manufacturing (CAD-CAM) guide to insert miniscrew anchorage at the zygomatic alveolar ridge. A 24-year-old male adult came in with overcrowded teeth and a protruding facial profile, particularly severe overcrowding in the upper teeth and moderate overcrowding in the lower teeth. The orthodontic treatment plan involved extracting four first premolars and adding a mini-implant in the upper jaw to enhance anchorage. A miniscrew was placed in the patient's left zygomatic alveolar ridge using a guide and in the right zygomatic alveolar ridge based on experience. The use of a mini-implant guide improves the accuracy of mini-implant positioning and angulation in the infrazygomatic crest zone, reduces the risk of tooth root damage, and enhances mini-implant stability.

ZAP facilitates NLRP3 inflammasome activation via promoting the oligomerization of NLRP3.

The NOD-like receptor family protein 3 (NLRP3) inflammasome is a crucial complex for the host to establish inflammatory immune responses and plays vital roles in a series of disorders, including Alzheimer's disease and acute peritonitis. However, its regulatory mechanism remains largely unclear. Zinc finger antiviral protein (ZAP), also known as zinc finger CCCH-type antiviral protein 1 (ZC3HAV1), promotes viral RNA degradation and plays vital roles in host antiviral immune responses. However, the role of ZAP in inflammation, especially in NLRP3 activation, is unclear. Here, we show that ZAP interacts with NLRP3 and promotes NLRP3 oligomerization, thus facilitating NLRP3 inflammasome activation in peritoneal macrophages of C57BL/6 mice. The shorter isoform of ZAP (ZAPS) appears to play a greater role than the full-length isoform (ZAPL) in HEK293T cells. Congruously, Zap-deficient C57BL/6 mice may be less susceptible to alum-induced peritonitis and lipopolysaccharide-induced sepsis in vivo. Therefore, we propose that ZAP is a positive regulator of NLRP3 activation and a potential therapeutic target for NLRP3-related inflammatory disorders.

AKR1C2 genetic variants mediate tobacco carcinogens metabolism involving bladder cancer susceptibility.

Tobacco carcinogens metabolism-related genes (TCMGs) could generate reactive metabolites of tobacco carcinogens, which subsequently contributed to multiple diseases. However, the association between genetic variants in TCMGs and bladder cancer susceptibility remains unclear. In this study, we derived TCMGs from metabolic pathways of polycyclic aromatic hydrocarbons and tobacco-specific nitrosamines, and then explored genetic associations between TCMGs and bladder cancer risk in two populations: a Chinese population of 580 cases and 1101 controls, and a European population of 5930 cases and 5468 controls, along with interaction and joint analyses. Expression patterns of TCMGs were sourced from Nanjing Bladder Cancer (NJBC) study and publicly available datasets. Among 43 TCMGs, we observed that rs7087341 T > A in AKR1C2 was associated with a reduced risk of bladder cancer in the Chinese population [odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.72-0.97, P = 1.86 × 10-2]. Notably, AKR1C2 rs7087341 showed an interaction effect with cigarette smoking on bladder cancer risk (Pinteraction = 5.04 × 10-3), with smokers carrying the T allele increasing the risk up to an OR of 3.96 (Ptrend < 0.001). Genetically, rs7087341 showed an allele-specific transcriptional regulation as located at DNA-sensitive regions of AKR1C2 highlighted by histone markers. Mechanistically, rs7087341 A allele decreased AKR1C2 expression, which was highly expressed in bladder tumors that enhanced metabolism of tobacco carcinogens, and thereby increased DNA adducts and reactive oxygen species formation during bladder tumorigenesis. These findings provided new insights into the genetic mechanisms underlying bladder cancer.

Endoscopic Balloon Dilatation of the Eustachian Tube via the Soft Palate Approach in Miniature Pigs.

The eustachian tube (ET) is one of the most complex organs in the human body, and its dysfunction may lead to a variety of diseases. In recent years, an increasing number of scholars have opted to conduct ET-related studies using large experimental animals such as miniature pigs or sheep, yielding promising results. Typically, conventional endoscopic procedures are performed through the nasal approach for large experimental animals. However, due to the elongated and narrow nasal cavity in these animals, transnasal surgeries are challenging. To address this issue, we explored an ET surgery approach via the soft palate. The animal was placed in a supine position. After endotracheal intubation under general anesthesia, a mouth opener was used to fully expose the upper palate. Local infiltration with diluted adrenal fluid was performed for anesthesia of the area. A sickle knife was then used to make a longitudinal soft palate incision at the junction of the soft and hard palates. After hemostasis, an endoscope was inserted into the nasopharynx cavity, allowing the visualization of the pharyngeal opening of the ET on the posterior lateral wall of the nasal cavity. Subsequently, a specialized pusher was used to insert a balloon into ET. The balloon was inflated, maintained at 10 bar for 2 min, and then removed. The incision in the soft palate was then sutured to ensure proper alignment. The soft palate healed well after the operation. This surgical approach is suitable for ET-related procedures in large experimental animals (e.g., miniature pigs, sheep, and dogs). The surgical procedure is simple, with a short surgical time, and wound healing is rapid. Under endoscopy, the pharyngeal opening of the ET is visible, and it is thus a good choice for procedures such as balloon dilation of the ET.

UPLC/Q-TOF-MS-based metabolomics and molecular docking analysis of Bifidobacterium adolescentis exposure to levofloxacin.

Antibiotic-associated diarrhea is a common adverse reaction caused by the widespread use of antibiotics. The decrease in probiotics is one of the reasons why antibiotics cause drug-induced diarrhea. However, few studies have addressed the intrinsic mechanism of antibiotics inhibiting probiotics. To investigate the underlying mechanism of levofloxacin against Bifidobacterium adolescentis, we used a metabolomics mass spectrometry-based approach and molecular docking analysis for a levofloxacin-induced B. adolescentis injury model. The results showed that levofloxacin reduced the survival rate of B. adolescentis and decreased the number of B. adolescentis. The untargeted metabolomics analysis identified 27 potential biomarkers, and many of these metabolites are involved in energy metabolism, amino acid metabolism and the lipid metabolism pathway. Molecular docking showed that levofloxacin can bind with aminoacyl-tRNA synthetase and lactic acid dehydrogenase. This result provides a novel insight into the mechanism of the adverse reactions of levofloxacin.

The anti-colorectal cancer effect and metabolites of Agrimonia pilosa Ledeb.

ETHNOPHARMACOLOGICAL RELEVANCE: Agrimonia pilosa Ledeb. (Rosaceae, A. pilosa) has been used in traditional medicine in China, Japan, Korea, and other Asian countries for treatment of acute and chronic enteritis and diarrhea. Secondary metabolites have been isolated and tested for biological activities. It remains unclear in terms of its potential components of anti-colorectal cancer properties. AIM OF THE STUDY: The study aimed to how extracts from A. pilosa and their components influenced tumor microenvironment and the colorectal tumor growth in vivo on AOM/DSS induced colorectal cancer mice, the metabolites of A. pilosa was also been studied. MATERIALS AND METHODS: Different methods have been used to extract different parts of A. pilosa. And the anti-proliferation effect of these extracts on colon cancer cells have been tested. The components of A. pilosa and its metabolites in vivo were analyzed by UPLC-QTOF-MS/MS. The anti-colorectal cancer (CRC) effects of A. pilosa and its components in vivo were studied on AOM/DSS induced CRC mice. The effects of constituents of A. pilosa on the composition of immune cells in tumor microenvironment (TME) were analyzed by flow cytometry. 16 S rDNA technology was used to analyze the effect of administration on the composition of intestinal microflora. Pathological section staining was used to compare the morphological changes and molecular expression of intestinal tissue in different groups. RESULTS: The constituent exists in root of A. pilosa showed the strongest anti-proliferation ability on colon cancer cells in vitro. The extract from the root of A. pilosa could attenuate the occurrence of colorectal tumors induced by AOM/DSS in a concentration-dependent manner. Administration of the extract from the root of A. pilosa could affect the proportion of γδT cells, tumor associated macrophages and myeloid derived suppressor cells in TME, increasing the proportion of anti-tumor immune cells and decrease the immunosuppressive cells in the TME to promote the anti-tumor immune response. The administration of the extract adjusted the composition of gut microbiota and its components Agrimoniin and Agrimonolide-6-o-glucoside showed the strongest anti-CRC effect in vivo with adjusting the gut microbiota differently. CONCLUSIONS: The extract from root of A. pilosa showed anti-colorectal cancer effects in vivo and in vitro, affecting the composition of gut microbiota and the anti-tumor immune response. Within all components of A. pilosa, Agrimoniin and Agrimonolide-6-o-glucoside showed remarkable anti-CRC efficiency in vivo and in vitro. Besides, the metabolites of extract from root of A. pilosa in gastrointestinal tract mainly composed of two parts: Agrimonolide-related metabolites and Urolithins. The extract from root of A. pilosa could contribute to potential drugs for assisting clinical anti-colon cancer therapy.

The deubiquitinase cofactor UAF1 interacts with USP1 and plays an essential role in spermiogenesis.

Spermiogenesis defines the final phase of male germ cell differentiation. While multiple deubiquitinating enzymes have been linked to spermiogenesis, the impacts of deubiquitination on spermiogenesis remain poorly characterized. Here, we investigated the function of UAF1 in mouse spermiogenesis. We selectively deleted Uaf1 in premeiotic germ cells using the Stra8-Cre knock-in mouse strain (Uaf1 sKO), and found that Uaf1 is essential for spermiogenesis and male fertility. Further, UAF1 interacts and colocalizes with USP1 in the testes. Conditional knockout of Uaf1 in testes results in disturbed protein levels and localization of USP1, suggesting that UAF1 regulates spermiogenesis through the function of the deubiquitinating enzyme USP1. Using tandem mass tag-based proteomics, we identified that conditional knockout of Uaf1 in the testes results in reduced levels of proteins that are essential for spermiogenesis. Thus, we conclude that the UAF1/USP1 deubiquitinase complex is essential for normal spermiogenesis by regulating the levels of spermiogenesis-related proteins.

WRKY transcription factors modulate flowering time and response to environmental changes.

WRKY transcription factors (TFs), originating in green algae, regulate flowering time and responses to environmental changes in plants. However, the molecular mechanisms underlying the role of WRKY TFs in the correlation between flowering time and environmental changes remain unclear. Therefore, this review summarizes the association of WRKY TFs with flowering pathways to accelerate or delay flowering. WRKY TFs are implicated in phytohormone pathways, such as ethylene, auxin, and abscisic acid pathways, to modulate flowering time. WRKY TFs can modulate salt tolerance by regulating flowering time. WRKY TFs exhibit functional divergence in modulating environmental changes and flowering time. In summary, WRKY TFs are involved in complex pathways and modulate response to environmental changes, thus regulating flowering time.

Relationships among anxiety, depression, and health-related quality of life in adult epilepsy: A network analysis.

OBJECTIVE: Comorbid depression and anxiety in patients with epilepsy (PWE) are common and frequently under-treated, thus, causing poor health-related quality of life (HRQoL). However, little is known regarding the interconnections between anxious/depressive symptoms and the dimensions of HRQoL. Therefore, we conducted a network analysis to explore these relationships in detail among Chinese adult PWE. METHODS: A cohort of adult PWE was consecutively recruited from the First Affiliated Hospital of Chongqing Medical University. HRQoL, depression, and anxiety were measured with Quality of Life in Epilepsy Inventory-31, Neurological Disorders Depression Inventory for Epilepsy, and Generalized Anxiety Disorder 7-Item Scale, respectively. A regularized partial correlation network was constructed to investigate the interconnections between symptoms of anxiety/depression and the dimensions of HRQoL. We calculated expected influence (EI) and bridge expected influence (BEI) values to identify the most influential nodes. RESULTS: A total of 396 PWE were enrolled in this study, 78.1% of whom had focal onset epilepsy. The prevalence of anxiety and depression was 30.3% and 28.8%, respectively. The symptoms "frustrated" and "uncontrollable worry" had the highest EI values, whereas "emotional well-being", "seizure worry", "difficulty finding pleasure", and "nervousness or anxiety" had the highest BEI values. CONCLUSION: This study provides new insights into the relationships among anxiety, depression, and HRQoL. Critical central symptoms and bridge symptoms identified in the network might help to quickly identify PWE comorbid anxiety and depression in busy outpatient settings, thereby enabling early intervention and enhancing quality of life.

Construction of ecological network in Qujing city based on MSPA and MCR models.

With the rapid advancement of urbanization and industrialization, ecological patches within cities and towns are fragmented and ecological corridors are cut off, regional ecological security is threatened and sustainable development is hindered. Building an ecological network that conforms to regional realities can connect fragmented patches, protect biodiversity and regional characteristics, and provide scientific reference for regional ecological protection and ecological network planning. By taking Qilin District, the main urban area of Qujing City as an example, and using geospatial data as the main data source, based on morphological spatial pattern analysis (MSPA) and minimum cumulative resistance (MCR), this study identified ecological source areas, extracted ecological corridors, and build & optimize ecological networks. (1) All landscape types are identified based on MSPA, the proportion of core area was the highest among all landscape types, which was 80.69%, combined with the connectivity evaluation, 14 important ecological source areas were selected. (2) 91 potential ecological corridors were extracted through MCR and gravity models, there were 16 important ones. (3) The network connectivity analysis method is used to calculate the α, ß, and γ indexes of the ecological network before optimization, which were 2.36, 6.5, and 2.53, while after optimization, α, ß and γ indices were 3.8, 9.5 and 3.5, respectively. The combined application of MSPA-MCR model and ecological network connectivity analysis evaluation is conducive to improving the structure and functionality of ecological network.

Classical swine fever virus non-structural protein 5B hijacks host METTL14-mediated m6A modification to counteract host antiviral immune response.

Classical Swine Fever (CSF), caused by the Classical Swine Fever Virus (CSFV), inflicts significant economic losses on the global pig industry. A key factor in the challenge of eradicating this virus is its ability to evade the host's innate immune response, leading to persistent infections. In our study, we elucidate the molecular mechanism through which CSFV exploits m6A modifications to circumvent host immune surveillance, thus facilitating its proliferation. We initially discovered that m6A modifications were elevated both in vivo and in vitro upon CSFV infection, particularly noting an increase in the expression of the methyltransferase METTL14. CSFV non-structural protein 5B was found to hijack HRD1, the E3 ubiquitin ligase for METTL14, preventing METTL14 degradation. MeRIP-seq analysis further revealed that METTL14 specifically targeted and methylated TLRs, notably TLR4. METTL14-mediated regulation of TLR4 degradation, facilitated by YTHDF2, led to the accelerated mRNA decay of TLR4. Consequently, TLR4-mediated NF-κB signaling, a crucial component of the innate immune response, is suppressed by CSFV. Collectively, these data effectively highlight the viral evasion tactics, shedding light on potential antiviral strategies targeting METTL14 to curb CSFV infection.

Effect of transcutaneous electrical acupoint stimulation based on the theory of "qi ascending and descending movement" on autonomic nervous system and gastrointestinal function in patients after general anesthesia laparoscopic cholecystectomy. / 基于"气机升降"ç†è®ºç»çš®ç©´ä½ç”µåˆºæ¿€å¯¹å ¨éº»è ¹è ”é•œèƒ†å›Šåˆ‡é™¤æœ¯åŽæ‚£è€ è‡ªä¸»ç¥žç»å’Œèƒƒè‚ åŠŸèƒ½çš„å½±å“.

OBJECTIVES: To observe the therapeutic effect of transcutaneous electrical acupoint stimulation (TEAS) based on the theory of "qi ascending and descending movement" in patients after general anesthesia laparoscopic cholecystectomy, so as to explore the impact of TEAS on the autonomic nervous system and gastrointestinal function of patients. METHODS: A total of 204 patients scheduled to undergo general anesthesia laparoscopic cholecystectomy were selected and randomly divided into control, double acupoints and multiple acupoints groups, with 68 cases in each group. For patients in the multiple acupoints group, TEAS was applied at Zusanli (ST36), Tiantu (CV22), Danzhong (CV17), Zhongwan (CV12), Taichong (LR3), and Neiguan (PC6) 30 min before anesthesia induction until the end of the surgery. In the double acupoints group, TEAS was applied only at ST36 and PC6. No electrical stimulation was applied in the control group. The postoperative bloating, bowel sound recovery time, first farting time, first defecation time, length of hospital stay, nausea and vomiting were compared among the three groups. Heart rate variability was monitored by twelve-lead electrocardiogram to evaluate the autonomic nervous function of the patients, including the low frequency power/high frequency power ratio (LF/HF), the standard deviation of all sinus RR intervals (SDNN), and the root mean square of difference between successive normal RR intervals (RMSSD). RESULTS: At 6 h and 24 h after surgery, the symptoms of bloating, nausea and vomiting in the multiple acupoints group and double acupoints group were significantly improved compared to the control group (P<0.05), and the multiple acupoints group was superior to the double acupoints group (P<0.05). Compared with the control group, the bowel sound recovery time, first farting time, first defecation time, and length of hospital stay were significantly shorter (P<0.05) in the multiple acupoints group and double acupoints group, and the multiple acupoints group was superior to the double acupoints group (P<0.05). At 1 d and 2 d after surgery, compared with the control group, LF/HF was decreased (P<0.05) while SDNN and RMSSD were increased (P<0.05) in the multiple acupoints group and double acupoints group, and there was a significant difference between the two groups (P<0.05). CONCLUSIONS: TEAS treatment based on the theory of "qi ascending and descending movement" can relieve gastrointestinal dysfunction, reduce early postoperative sympathetic nerve excitement and maintain parasympathetic nerve tension in patients after general anesthesia laparoscopic cholecystectomy, thereby promoting gastrointestinal function recovery.

Multichannel bridges and NSC synergize to enhance axon regeneration, myelination, synaptic reconnection, and recovery after SCI.

Regeneration in the injured spinal cord is limited by physical and chemical barriers. Acute implantation of a multichannel poly(lactide-co-glycolide) (PLG) bridge mechanically stabilizes the injury, modulates inflammation, and provides a permissive environment for rapid cellularization and robust axonal regrowth through this otherwise inhibitory milieu. However, without additional intervention, regenerated axons remain largely unmyelinated (<10%), limiting functional repair. While transplanted human neural stem cells (hNSC) myelinate axons after spinal cord injury (SCI), hNSC fate is highly influenced by the SCI inflammatory microenvironment, also limiting functional repair. Accordingly, we investigated the combination of PLG scaffold bridges with hNSC to improve histological and functional outcome after SCI. In vitro, hNSC culture on a PLG scaffold increased oligodendroglial lineage selection after inflammatory challenge. In vivo, acute PLG bridge implantation followed by chronic hNSC transplantation demonstrated a robust capacity of donor human cells to migrate into PLG bridge channels along regenerating axons and integrate into the host spinal cord as myelinating oligodendrocytes and synaptically integrated neurons. Axons that regenerated through the PLG bridge formed synaptic circuits that connected the ipsilateral forelimb muscle to contralateral motor cortex. hNSC transplantation significantly enhanced the total number of regenerating and myelinated axons identified within the PLG bridge. Finally, the combination of acute bridge implantation and hNSC transplantation exhibited robust improvement in locomotor recovery. These data identify a successful strategy to enhance neurorepair through a temporally layered approach using acute bridge implantation and chronic cell transplantation to spare tissue, promote regeneration, and maximize the function of new axonal connections.

The transcription factor bZIP44 cooperates with MYB10 and MYB72 to regulate the response of Arabidopsis thaliana to iron deficiency stress.

Nicotianamine (NA) plays a crucial role in transporting metal ions, including iron (Fe), in plants; therefore, NICOTIANAMINE SYNTHASE (NAS) genes, which control NA synthesis, are tightly regulated at the transcriptional level. However, the transcriptional regulatory mechanisms of NAS genes require further investigations. In this study, we determined the role of bZIP44 in mediating plant response to Fe deficiency stress by conducting transformation experiments and assays. bZIP44 positively regulated the response of Arabidopsis to Fe deficiency stress by interacting with MYB10 and MYB72 to enhance their abilities to bind at NAS2 and NAS4 promoters, thereby increasing NAS2 and NAS4 transcriptional levels and promote NA synthesis. In summary, the transcription activities of bZIP44, MYB10, and MYB72 were induced in response to Fe deficiency stress, which enhanced the interaction between bZIP44 and MYB10 or MYB72 proteins, synergistically activated the transcriptional activity of NAS2 and NAS4, promoted NA synthesis, and improved Fe transport, thereby enhancing plant tolerance to Fe deficiency stress.

A Novel Approach Utilizing Domain Adversarial Neural Networks for the Detection and Classification of Selective Sweeps.

The identification and classification of selective sweeps are of great significance for improving the understanding of biological evolution and exploring opportunities for precision medicine and genetic improvement. Here, a domain adaptation sweep detection and classification (DASDC) method is presented to balance the alignment of two domains and the classification performance through a domain-adversarial neural network and its adversarial learning modules. DASDC effectively addresses the issue of mismatch between training data and real genomic data in deep learning models, leading to a significant improvement in its generalization capability, prediction robustness, and accuracy. The DASDC method demonstrates improved identification performance compared to existing methods and excels in classification performance, particularly in scenarios where there is a mismatch between application data and training data. The successful implementation of DASDC in real data of three distinct species highlights its potential as a useful tool for identifying crucial functional genes and investigating adaptive evolutionary mechanisms, particularly with the increasing availability of genomic data.

Astaxanthin Inhibits STING Carbonylation and Enhances Antiviral Responses.

STING-mediated DNA sensing pathway plays a crucial role in the innate antiviral immune responses. Clarifying its regulatory mechanism and searching STING agonists has potential clinical implications. Although multiple STING agonists have been developed to target cancer, there are few for the treatment of infectious diseases. Astaxanthin, a natural and powerful antioxidant, serves many biological functions and as a potential candidate drug for many diseases. However, how astaxanthin combats viruses and whether astaxanthin regulates the cyclic GMP-AMP synthase-STING pathway remains unclear. In this study, we showed that astaxanthin markedly inhibited HSV-1-induced lipid peroxidation and inflammatory responses and enhanced the induction of type I IFN in C57BL/6J mice and mouse primary peritoneal macrophages. Mechanistically, astaxanthin inhibited HSV-1 infection and oxidative stress-induced STING carbonylation and consequently promoted STING translocation to the Golgi apparatus and oligomerization, which activated STING-dependent host defenses. Thus, our study reveals that astaxanthin displays a strong antiviral activity by targeting STING, suggesting that astaxanthin might be a promising STING agonist and a therapeutic target for viral infectious diseases.

Perturbations in gut and respiratory microbiota in COVID-19 and influenza patients: a systematic review and meta-analysis.

Objectives: Coronavirus disease-19 (COVID-19)/influenza poses unprecedented challenges to the global economy and healthcare services. Numerous studies have described alterations in the microbiome of COVID-19/influenza patients, but further investigation is needed to understand the relationship between the microbiome and these diseases. Herein, through systematic comparison between COVID-19 patients, long COVID-19 patients, influenza patients, no COVID-19/influenza controls and no COVID-19/influenza patients, we conducted a comprehensive review to describe the microbial change of respiratory tract/digestive tract in COVID-19/influenza patients. Methods: We systematically reviewed relevant literature by searching the PubMed, Embase, and Cochrane Library databases from inception to August 12, 2023. We conducted a comprehensive review to explore microbial alterations in patients with COVID-19/influenza. In addition, the data on α-diversity were summarized and analyzed by meta-analysis. Results: A total of 134 studies comparing COVID-19 patients with controls and 18 studies comparing influenza patients with controls were included. The Shannon indices of the gut and respiratory tract microbiome were slightly decreased in COVID-19/influenza patients compared to no COVID-19/influenza controls. Meanwhile, COVID-19 patients with more severe symptoms also exhibited a lower Shannon index versus COVID-19 patients with milder symptoms. The intestinal microbiome of COVID-19 patients was characterized by elevated opportunistic pathogens along with reduced short-chain fatty acid (SCFAs)-producing microbiota. Moreover, Enterobacteriaceae (including Escherichia and Enterococcus) and Lactococcus, were enriched in the gut and respiratory tract of COVID-19 patients. Conversely, Haemophilus and Neisseria showed reduced abundance in the respiratory tract of both COVID-19 and influenza patients. Conclusion: In this systematic review, we identified the microbiome in COVID-19/influenza patients in comparison with controls. The microbial changes in influenza and COVID-19 are partly similar.

Global and Regional Burden and Trend of Neoplasms Attributable to Alcohol Consumption in the Past 3 Decades.

OBJECTIVES: To provide valuable insights for targeted cancer screening among high-risk patients, we analyzed the global and regional burden of neoplasms resulting from alcohol consumption between 1990 and 2019. METHODS: The information used in this study was collected from the Global Burden of Disease 2019 dataset. Initially, the database was used to extract details of mortality rates, disability-adjusted life years (DALYs), and the number of individuals affected by alcohol-related neoplasms (ARNs). Subsequently, the data were compared by cancer type, sex, age, region, and sociodemographic index. Furthermore, the study involved the calculation and comparison of estimated annual percentage changes in age-standardized DALYs rates (ASDRs) and mortality rates. RESULTS: The impact of alcohol on the burden of cancer varied by type of cancer, sex, age, and geographical location. Notably, males exhibited significantly higher ASDRs compared with females. Specifically, in 2019, alcohol emerged as the primary contributor to the number of DALYs associated with esophageal cancer, followed by liver cancer and colorectal cancer in men. Patients aged 50+ years exhibited a heightened rate of DALYs associated with ARNs. From 1990 to 2019, ASDRs among individuals with ARNs did not exhibit a decline in low-middle and low sociodemographic index regions. CONCLUSIONS: Alcohol consumption represents a significant risk factor for the burden of cancer, particularly within the realm of digestive system malignancies. Consequently, targeted cancer screening efforts should be directed toward the population that engages in alcohol drinking, with a particular focus on men aged 50 years and older, residing in economically disadvantaged areas.

S-nitrosothiol homeostasis maintained by ADH5 facilitates STING-dependent host defense against pathogens.

Oxidative (or respiratory) burst confers host defense against pathogens by generating reactive species, including reactive nitrogen species (RNS). The microbial infection-induced excessive RNS damages many biological molecules via S-nitrosothiol (SNO) accumulation. However, the mechanism by which the host enables innate immunity activation during oxidative burst remains largely unknown. Here, we demonstrate that S-nitrosoglutathione (GSNO), the main endogenous SNO, attenuates innate immune responses against herpes simplex virus-1 (HSV-1) and Listeria monocytogenes infections. Mechanistically, GSNO induces the S-nitrosylation of stimulator of interferon genes (STING) at Cys257, inhibiting its binding to the second messenger cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). Alcohol dehydrogenase 5 (ADH5), the key enzyme that metabolizes GSNO to decrease cellular SNOs, facilitates STING activation by inhibiting S-nitrosylation. Concordantly, Adh5 deficiency show defective STING-dependent immune responses upon microbial challenge and facilitates viral replication. Thus, cellular oxidative burst-induced RNS attenuates the STING-mediated innate immune responses to microbial infection, while ADH5 licenses STING activation by maintaining cellular SNO homeostasis.