Genus_Ruminococcus and order_Burkholderiales affect osteoporosis by regulating the microbiota-gut-bone axis.

Background: This study aimed to clarify the relationship between the gut microbiota and osteoporosis combining Mendelian randomization (MR) analysis with animal experiments. Methods: We conducted an analysis on the relationship between differential bacteria and osteoporosis using open-access genome-wide association study (GWAS) data on gut microbe and osteoporosis obtained from public databases. The analysis was performed using two-sample MR analysis, and the causal relationship was examined through inverse variance weighting (IVW), MR Egger, weighted median, and weighted mode methods. Bilateral oophorectomy was employed to replicate the mouse osteoporosis model, which was assessed by micro computed tomography (CT), pathological tests, and bone transformation indexes. Additionally, 16S rDNA sequencing was conducted on fecal samples, while SIgA and indexes of IL-6, IL-1ß, and TNF-α inflammatory factors were examined in colon samples. Through immunofluorescence and histopathology, expression levels of tight junction proteins, such as claudin-1, ZO-1, and occludin, were assessed, and conduct correlation analysis on differential bacteria and related environmental factors were performed. Results: A positive correlation was observed between g_Ruminococcus1 and the risk of osteoporosis, while O_Burkholderiales showed a negative correlation with the risk of osteoporosis. Furthermore, there was no evidence of heterogeneity or pleiotropy. The successful replication of the mouse osteoporosis model was assessed, and it was found that the abundance of the O_Burkholderiales was significantly reduced, while the abundance of g_Ruminococcus was significantly increased in the ovariectomized (OVX)-mice. The intestinal SIgA level of OVX mice decreased, the expression level of inflammatory factors increased, barrier damage occurred, and the content of LPS in the colon and serum significantly increased. The abundance level of O_Burkholderiales is strongly positively correlated with bone formation factors, gut barrier indicators, bone density, bone volume fraction, and trabecular bone quantity, whereas it was strongly negatively correlated with bone resorption factors and intestinal inflammatory factors, The abundance level of g_Ruminococcus shows a strong negative correlation with bone formation factors, gut barrier indicators, and bone volume fraction, and a strong positive correlation with bone resorption factors and intestinal inflammatory factors. Conclusion: O_Burkholderiales and g_Ruminococcus may regulate the development of osteoporosis through the microbiota-gut-bone axis.

Elevation of Serum Prostate-Specific Antigen Levels in Males With Pulmonary Embolism.

Hypoxemia is a clinical characteristic of pulmonary embolism (PE). Hypoxemia is associated with variations in serum prostate-specific antigen (PSA) levels. Thus, the present study aimed to determine serum PSA levels in patients with PE, which may be helpful in improving clinical evaluation in screening for prostate diseases in those with PE. Clinical data from 61 consecutive male patients with PE and 113 age-matched healthy male controls were retrospectively analyzed. The pulmonary artery obstruction index (PAOI) was used to evaluate the pulmonary embolic burden. Compared with healthy controls, serum total PSA (tPSA) levels were significantly increased (P = .003), and free PSA (fPSA)/tPSA ratio was significantly decreased in patients with PE (P < .001). There was no significantly difference in serum fPSA levels between patients with PE and healthy controls (P = .253). A significant positive association was observed between serum tPSA levels and PAOI in patients with PE (ß = .270, P = .036). Multivariable linear regression analysis revealed that serum tPSA levels were independently associated with PAOI in patients with PE (ß = .347, P = .003). Serum tPSA levels were higher in male patients with PE than those in healthy controls, but fPSA was not affected. These findings highlight that PE may elevate serum tPSA levels, and that measures of tPSA should be interpreted with caution in screening for prostate diseases in patients with PE.

Urokinase in the treatment of tuberculous pleurisy: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy of urokinase (UK) treatment for tuberculous pleural effusion (TPE). METHODS: We searched Chinese biomedical literature database, WanFang data, CNKI, PubMed, EMbase, Web of Science and The Cochrane Library for the randomized controlled trials (RCTs) of urokinase treatment for tuberculous pleurisy from January 2000 to February 2023. Pleural tuberculosis, urokinase and randomized controlled trial were used as keywords. The eligible studies were meta-analyzed by using Revman 5.4.1: risk of bias was assessed, mean difference (MD) and 95% CI were used for continuous variables, pooled studies were conducted using random-effects or fixed-effects models, forest plots were drawn to analyze efficacy, and funnel plots were drawn to discuss publication bias. RESULTS: Twenty-nine RCTs were included. The meta-analyzed results showed that, on the basis of routine anti-tuberculosis, comparison between the treatment group treated with urokinase and the control group treated with antituberculosis alone, the time of pleural effusion absorption [MD-5.82, 95%CI (- 7.77, - 3.87); P<0.00001] and the residual pleural thickness [MD-1.31, 95%CI (- 1.70, - 0.91); P<0.00001], pleural effusion drainage volume [MD 822.81, 95%CI (666.46,977.96); P<0.00001], FVC%pred [MD 7.95, 95%CI (4.51,11.40); P<0.00001], FEV1%pred [MD 12.67, 95%CI (10.09,15.24); P<0.00001] were significantly different. CONCLUSION: The clinical effect of urokinase is better than that of antituberculous therapy alone: it can increase total pleural effusion, decrease residual pleural thickness, improve the pulmonary function, and shorten the time of pleural effusion absorption.

Novel GSH-responsive prodrugs derived from indole-chalcone and camptothecin trigger apoptosis and autophagy in colon cancer.

Antineoplastic agents that target tubulin have shown efficacy as chemotherapeutic drugs, yet they are often constrained by multidrug resistance (MDR) and unwanted side effects. A multi-targeted strategy demonstrates great potency in reducing toxicity and enhancing efficacy and provides an alternative way for attenuating MDR. In this study, a series of dual-targeted anti-cancer agents based on indole-chalcone derivatives and the camptothecin (CPT) scaffold were synthesized. Among them, 14-1 demonstrated superior anti-proliferative activity than its precursor 13-1, CPT or their physical mixtures against tested cancer cells, including multidrug-resistant variants, while exhibited moderate cytotoxicity toward human normal cells. Mechanistic studies revealed that 14-1 acted as a glutathione-responsive prodrug, inducing apoptosis by substantially enhancing intracellular uptake of CPT, inhibiting tubulin polymerization, increasing the accumulation of intracellular reactive oxygen species, and initiating a mitochondrion-dependent apoptotic pathway. Moreover, 14-1 notably induced autophagy and suppressed topoisomerase I activity to further promote apoptosis. Importantly, 14-1 displayed potent inhibitory effect on tumor growth in paclitaxel (PTX)-resistant colorectal cancer (HCT-116/PTX) xenograft models without inducing obvious toxicity compared with CPT- or combo-treated group. These results suggest that 14-1 holds promise as a novel candidate for anti-cancer therapy, particularly in PTX-resistant cancers.

Borneol exerts its antipruritic effects by inhibiting TRPA1 and activating TRPM8.

ETHNOPHARMACOLOGICAL RELEVANCE: Borneol is a long-established traditional Chinese medicine that has been found to be effective in treating pain and itchy skin. However, whether borneol has a therapeutic effect on chronic itch and its related mechanisms remain unclear. AIM OF THE STUDY: To investigate the antipruritic effect of borneol and its molecular mechanism. MATERIALS AND METHODS: DrugBAN framework and molecular docking were applied to predict the targets of borneol, and the calcium imaging or patch-clamp recording analysis were used to detect the effects of borneol on TRPA1, TRPM8 or TRPV3 channels in HEK293T cells. In addition, various mouse models of acute itch and chronic itch were established to evaluate the antipruritic effects of borneol on C57BL/6J mice. Then, the borneol-induced pruritic relief was further investigated in Trpa1-/-, Trpm8-/-, or Trpa1-/-/Trpm8-/- mice. The effects of borneol on the activation of TRPM8 and the inhibition of TRPA1 were also measured in dorsal root ganglia neurons of wild-type (WT), Trpm8-/- and Trpv1-/- mice. Lastly, a randomized, double-blind study of adult patients was conducted to evaluate the clinical antipruritic effect of borneol. RESULTS: TRPA1, TRPV3 and TRPM8 are the potential targets of borneol according to the results of DrugBAN algorithm and molecular docking. Calcium imaging and patch-clamp recording analysis demonstrated that borneol activates TRPM8 channel-induced cell excitability and inhibits TRPA1 channel-mediated cell excitability in transfected HEK293T cells. Animal behavior analysis showed that borneol can significantly reduce acute and chronic itch behavior in C57BL/6J mice, but this effect was eliminated in Trpa1-/-, Trpm8-/- mice, or at least in Trpa1-/-/Trpm8-/- mice. Borneol elicits TRPM8 channel induced [Ca2+]i responses but inhibits AITC or SADBE-induced activation of TRPA1 channels in dorsal root ganglia neurons of WT and Trpv1-/- mice, respectively. Furthermore, the clinical results indicated that borneol could reduce itching symptoms in patients and its efficacy is similar to that of menthol. CONCLUSION: Borneol has therapeutic effects on multiple pruritus models in mice and patients with chronic itch, and the mechanism may be through inhibiting TRPA1 and activating TRPM8.

Establishment of pseudorabies virus latency and reactivation model in mice dorsal root ganglia culture.

Pseudorabies virus (PRV) belongs to the alpha herpesvirus family and is responsible for Aujeszky's disease in pigs. Similar to other alpha herpesviruses, PRV establishes a lifelong latent infection in trigeminal ganglion. These latently infected pigs serve as a reservoir for recurrent infections when reactivation is triggered, making the eradication of PRV a challenging task. However, the molecular mechanism underlying PRV latency and reactivation in neurons is still poorly understood due to limitations in the in vitro model. To establish a pseudorabies virus latency and reactivation model in primary neuron cultures, we isolated dorsal root ganglion (DRG) from newborn Kunming mice using a method named epineurium-pulling for DRG collection (EPDC) and cultured primary neurons in vitro. A dual-colour recombinant PRV BAC mRuby-VP16 was constructed and 0.5 multiplicity of infection (MOI) was found as an appropriate dose in the presence of aciclovir to establish latency. Reactivation was induced using UV-inactivated herpesviruses or a series of chemical inhibitors. Interestingly, we found that not only UV-PRV, but also UV-HSV-1 and UV-BHoV-5 were able to induce rapid PRV reactivation. The efficiency of reactivation for LY294002, forskolin, etoposide, dexamethasone, and acetylcholine was found to be dependent on their concentration. In conclusion, we developed a valuable model of PRV latency and reactivation, which provides a basis for future mechanism research.

Comprehensive bioinformatics analysis of the solute carrier family and preliminary exploration of SLC25A29 in lung adenocarcinoma.

According to the latest epidemiological investigation, lung adenocarcinoma (LUAD) is one of the most fatal cancer among both men and women. Despite continuous advancements in treatment approaches in recent years, the prognosis for LUAD remains relatively poor. Given the crucial role of the solute carrier (SLC) family in maintaining cellular energy metabolism stability, we conducted a comprehensive analysis of the association between SLC genes and LUAD prognosis. In the present study, we identified 71 genes among the SLC family members, of which 32 were downregulated and 39 were upregulated in LUAD samples. Based on these differentially expressed genes, a prognostic risk scoring model was established that was composed of five genes (SLC16A7, SLC16A4, SLC16A3, SLC12A8, and SLC25A15) and clinical characteristics; this model could effectively predict the survival and prognosis of patients in the cohort. Notably, SLC2A1, SLC25A29, and SLC27A4 were identified as key genes associated with survival and tumor stage. Further analysis revealed that SLC25A29 was underexpressed in LUAD tissue and regulated the phenotype of endothelial cells. Endothelial cell proliferation and migration increased and apoptosis decreased with a decrease in SLC25A29 expression. Investigation of the upstream regulatory mechanisms of SLC25A29 revealed that SLC25A29 expression gradually decreased as the lactate concentration increased. This phenomenon suggested that the expression of SLC25A29 may be related to lactylation modification. ChIP-qPCR experiments confirmed the critical regulatory role played by H3K14la and H3K18la modifications in the promoter region of SLC25A29. In conclusion, this study confirmed the role of SLC family genes in LUAD prognosis and revealed the role of SLC25A29 in regulating endothelial cell phenotypes. These study results provided important clues to further understand LUAD pathogenesis and develop appropriate therapeutic strategies.

Preliminary Experience with Continuous Submucosal Anastomosis in Small-Diameter Hepaticojejunostomy during Single-Port Laparoscopic Choledochal Cyst Surgery in Children.

PURPOSE: Hepaticojejunostomy anastomosis (HJA) is the most challenging aspect in single-port laparoscopic choledochal cystectomy and Roux-en-Y hepaticojejunostomy (SPCH) in children, especially in small-diameter anastomoses (diameters less than 5 mm), which are more susceptible to anastomotic stricture. We developed the continuous submucosal technique for HJA (CS-HJA) to lessen postoperative complications. The purpose of this study is to introduce our preliminary experiences with CS-HJA. METHODS: We retrospectively analyzed all available clinical data of children who underwent SPCH surgery between March 2020 and October 2022. We operated with CS-HJA on 10 children who were diagnosed with small-diameter hepaticojejunostomy (diameter less than 5 mm). Data collection mainly included demographic information, imaging data, perioperative details, and postoperative outcomes. Ten patients were included in this study. The average patient age was 55.2 months; the age range was 3 to 120 months, and the average weight was 11.6 kg; male-female ratio was 1:9. The choledocho had fusiform dilatation in five cases and cystic dilatation in five cases. There was no dilatation of the left and right hepatic ducts or intrahepatic bile ducts in all patients. All patients had no dilatation of the left and right hepatic ducts or intrahepatic bile ducts. All patients underwent a single-port laparoscopic bile-intestinal anastomosis using a submucosal jejunal anastomosis technique. Analysis of the duration of the bile-intestinal anastomosis, the length of the child's stay in the hospital after surgery, the intraoperative complications, and the postoperative complications was performed. RESULTS: All the 10 patients underwent successful SPCH by CS-HJA technique. The average length of time for hepaticojejunostomy ranged from 22 to 40 minutes, and the postoperative hospital stay was 5.2 to 9.2 days. There were no instances of bile leakage following the operation. At 17 to 30 months of follow-up, there was no abdominal pain or jaundice, and the reexamination of transaminases, bilirubin, and amylase were normal. Ultrasonography showed no bile duct stricture or dilated bile ducts, and the incision is elegant, and the families of the patients were satisfied. CONCLUSION: In SPCH surgery in children, the CS-HJA technique is safe and feasible for small-diameter hepaticojejunostomy.

Developing a nomogram for predicting surgical intervention in pediatric intussusception after hydrostatic reduction.

Purpose: The aim of this study was to develop and validate a nomogram for predicting surgical intervention in pediatric intussusception after hydrostatic reduction. Methods: Children with intussusception who had treated with sonographically guided saline hydrostatic reduction as an initial treatment were enrolled in this study. The enrolled patients were randomly selected for training and validation sets, and the split ratio was 7:3. The medical records of enrolled patients were retrospectively reviewed. The patients were divided into a surgery and a non-surgery group according to the results of the nonsurgical reduction. A model for predicting the risk of surgical treatment was virtualized by the nomogram using logistic regression analysis. Results: The training set consisted of 139 patients and the validation set included 74. After logistic regression analysis using training set, duration of symptoms, bloody stools, white blood cells (WBCs), creatine kinase isoenzyme (CK-MB), long-axis diameter, poor prognostic signs by ultrasound and mental state were identified as the independent predictors of surgical intervention for intussusception. A model that incorporated the above independent predictors was developed and presented as a nomogram. The C-index of the nomogram in the validation set was 0.948 (95% CI, 0.888-1.000). The calibration curve demonstrated a good agreement between prediction and observation. The decision curve analysis (DCA) curve showed that the model achieved a net benefit across all threshold probabilities. Conclusion: Based on the predictors of duration of symptoms, bloody stools, WBCs, CK-MB, long-axis diameter, poor prognostic signs by ultrasound and mental state, we developed a nomogram for predicting surgical intervention after hydrostatic reduction. This nomogram could be applied directly to facilitate pre-surgery decision for pediatric intussusception.

Probabilistic double hierarchy linguistic Maclaurin symmetric mean-MultiCriteria Border Approximation area Comparison method for multi-criteria group decision making and its application in a selection of traditional Chinese medicine prescriptions.

Traditional Chinese medicine (TCM) has gradually played an indispensable role in people's health maintenance, especially in the treatment of chronic diseases. However, there is always uncertainty and hesitation in the judgment and understanding of diseases by doctors, which affects the status recognition and optimal diagnosis and treatment decision-making of patients. In order to overcome the above problems, we lead into probabilistic double hierarchy linguistic term set (PDHLTS) to accurately describe language information in traditional Chinese medicine and make decisions. In this paper, a multi-criteria group decision making (MCGDM) model is constructed based on the MSM-MCBAC (Maclaurin symmetric mean-MultiCriteria Border Approximation area Comparison) method in the PDHL environment. Firstly, a PDHL weighted Maclaurin symmetric mean (PDHLWMSM) operator is proposed to aggregate the evaluation matrices of multiple experts. Then, combined with the BWM and maximizing deviation method, a comprehensive weight determination method is put forward to calculate the weights of criteria. Furthermore, we propose PDHL MSM-MCBAC method based on the Multi-Attributive Border Approximation area Comparison (MABAC) method and the PDHLWMSM operator. Finally, an example of a selection of TCM prescriptions is used and some comparative analyses are made to verify the effectiveness and superiority of this paper.

Host-Guest Symmetry and Charge Matching in Glycine-Templated Metal Sulfate-Oxalates Obtained by a Solvent-Free Method.

Two metal sulfate-oxalates, (Hgly)2·Zn(SO4)(C2O4) (1) and Hgly·In(SO4)(C2O4)(gly) (2), were prepared under solvent-free conditions, where gly = glycine. They have similar layered structures despite the fact that aliovalent metal ions are used as structural nodes. Notably, glycine molecules play dual roles as a protonated cation and a zwitterionic ligand in compound 2. The two compounds display moderate second-harmonic-generation (SHG) responses, confirming their noncentrosymmetric structures. Theoretical calculations were performed to reveal the origin of their SHG responses.

The clinicopathological characteristics of gastric cancer and precancerous conditions in gastric DLBCL and MALT lymphoma patients: a multi-center retrospective study.

OBJECTIVE: The objective of this study is to explore the clinicopathological characteristics of gastric cancer and precancerous conditions in patients with primary gastric lymphoma. METHODS: We analyzed 474 cases of primary gastric lymphoma, mainly DLBCL and MALT, from three clinical centres retrospectively, and compared the clinicopathological parameters of primary gastric lymphoma patients complicated with gastric cancer, precancerous conditions, or with no complications. RESULTS: A total of 5.1% of the patients with primary gastric lymphoma were diagnosed with gastric cancer, including metachronous gastric adenocarcinoma (3.2%) and synchronous gastric adenocarcinoma (1.9%). Of the patients with gastric lymphoma, 14.6% had precancerous conditions including atrophy (14.6%), intestinal metaplasia (8.9%), and low-grade intraepithelial neoplasia (1.9%). Primary gastric lymphoma patients with an ulcerative type (p = 0.009) and Lugano classification stage IIE + IV (p < 0.001) lymphoma had a higher risk of complicating with gastric cancers or precancerous conditions. The rate of infection of Helicobacter pylori (Hp) was 68.4% in patients with primary gastric lymphoma, which was higher in patients with MALT lymphoma (p < 0.001), Lugano classification stage I + II (p < 0.001), and patients complicated with precancerous conditions and gastric cancer (p < 0.001), especially gastric cancer of the intestinal type (p = 0.04). Gastric cancer (95.8%) and precancerous conditions (91.3%) occurred mostly in Hp-infected primary gastric lymphoma patients, with a minor subset of Hp-eradicated patients. Primary gastric lymphoma patients had a higher detection rate of early gastric cancer (25.0%) and a five-year survival rate (40.0%) than the general Chinese population. CONCLUSIONS: Patients with primary gastric lymphoma have a high risk of developing gastric cancer and precancerous conditions, and this risk may be related to Helicobacter pylori infection. Follow-up of primary gastric lymphoma provides an opportunity for the detection of early gastric cancer.Key messages5.1% of the patients with primary gastric lymphoma were diagnosed with gastric cancer.14.6% of the patients with gastric lymphoma had premalignant lesions including atrophy (14.6%), intestinal metaplasia (8.9%), and low-grade intraepithelial neoplasia (1.9%).Primary gastric lymphoma patients complicating with gastric cancer had a higher infection rate of Helicobacter pylori (100.0%), a detection rate of early gastric cancer (25.0%) and a five-year survival rate (40.0%) than the general Chinese population.

TRPA1 is involved in the inhibitory effect of Ke-teng-zi on allergic contact dermatitis via MAPK and JAK/STAT3 signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: The seeds of Entada phaseoloides (Linn.) Merr. commonly named "Ke-teng-zi" is a traditional Chinese folk medicine and reported to treat dermatitis, spasm, and headache. However, the exact effect and the mechanism of Ke-teng-zi on the treatment of dermatitis is unclear. AIM OF THE STUDY: To elucidate the antipruritic effect and molecular mechanisms of Ke-teng-zi on the treatment of allergic contact dermatitis (ACD). MATERIALS AND METHODS: The main components of the n-butanol fraction of 70% ethanol extract from Ke-teng-zi (abbreviated as KB) were analyzed by HPLC. The chloroquine (CQ)-induced acute itch and squaraine dibutyl ester (SADBE)-induced ACD chronic itch in mice was established, and the TNF-α/IFN-γ stimulated Human keratinocytes (HaCaT) were used to evaluate the antipruritic and anti-inflammatory effects of KB. Behavioral tests, lesion scoring, and histology were also examined. The expression levels of molecules in MAPK and JAK/STAT3 pathways, the mRNA levels of chemokines and cytokines in both the skin of ACD mice and the HaCaT cells were detected by western blot and qPCR. Furthermore, whole-cell patch-clamp recordings in TRPA1-tranfected HEK293T cells were used to elucidate the effect of KB on TRPA1 channels. TRPA1 siRNA was used to evaluate the role of TRPA1 in the anti-inflammatory effect of KB in keratinocytes. RESULTS: The main compounds in KB could bind to the active sites of TRPA1 mainly through hydrogen bond and hydrophobic bond interactions. KB could inhibit the scratching behavior in CQ-induced acute itch, and the inhibitory effect of KB was blocked by TRPA1 inhibitor HC-030031. In addition, KB significantly decreased the scratching bouts of ACD mice, reduced the skin lesion scores, mast cells degranulation, and epidermal thickening, inhibited the production of inflammatory chemokines/cytokines and CGRP, and down-regulated the levels of p-ERK1/2, p-p38, and p-STAT3, compared to the ACD mice. Moreover, continuous application of KB induced the desensitization of TRPA1 channels. Also, KB inhibited the expression of p-ERK1/2, p-p38, and p-STAT3, and down-regulated the expression of inflammatory chemokines and cytokines in vitro, which were reversed by the TRPA1 siRNA. CONCLUSIONS: KB alleviated the pruritus and skin inflammation in ACD mice through TRPA1 channels desensitization and down-regulation of intracellular MAPK and JAK/STAT3 signaling pathways. Our results suggested that Ke-teng-zi is a potential drug for the treatment of inflammatory skin diseases such as ACD.

Anti-inflammatory and osteoprotective effects of Shi-Wei-Ru-Xiang pills on collagen-induced arthritis in rats via inhibiting MAPK and STAT3 pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Shi-Wei-Ru-Xiang pills (SW) as a tradition Tibetan medicine has been clinically proved effective in rheumatoid arthritis (RA) treatment. However, the underlying mechanism of SW remains unclear. AIM OF THE STUDY: This study aimed to investigate the anti-arthritic effect of SW and its possible mechanisms of action. MATERIALS AND METHODS: A CIA rat model in vivo, and IL-1ß-stimulated synoviocytes or chondrocytes and a co-culture system (IL-1ß-stimulated synoviocytes/chondrocytes) in vitro were used to evaluate the effects of SW on the treatment of RA. Arthritic score, paw swelling rate, hematoxylin-eosin (HE) staining, and Safranin-O-Fast green (S-O) staining were used to evaluate the anti-arthritic activity of SW in CIA rats. TUNEL assay or flow cytometry were performed to measure chondrocytes apoptosis in vivo and invitro. The effects of SW on the expression and production of pro-inflammatory cytokines were assessed by qRT-PCR and Elisa. The inhibitory effects of SW on the phosphorylation of p38, Erk1/2, and STAT3 were analyzed by Western blot. RESULTS: SW treatment significantly alleviated paw swelling, severity of arthritic and cartilage destruction in CIA rats. Moreover, SW decreased the expression of mRNAs of proinflammatory cytokines including TNF-α, IL-1ß and IL-6 in the synovium, suppressed the production of these pro-inflammatory cytokines in serum and hind paws, downregulated the protein expression of p-p38, p-Erk1/2 and p-STAT3, and protected the chondrocytes apoptosis in CIA rats. Consistent with the results in vivo, SW also inhibited the activation of MAPK and STAT3 pathways, suppressed the expression of pro-inflammatory cytokines in IL-1ß-stimulated synoviocytes, and attenuated chondrocytes apoptosis in IL-1ß-stimulated chondrocytes. In the co-culture system, SW pre-treatment in IL-1ß-stimulated synoviocytes exhibited inhibition of chondrocytes apoptosis, which was associated with attenuation of inflammation in synoviocytes. CONCLUSION: These results suggested that the underlying mechanisms by which SW exerts its anti-arthritis effect may be related to the reduction of proinflammatory cytokine levels, inhibition of p38, Erk1/2 and STAT3 phosphorylation, and attenuating of chondrocyte apoptosis.

Release of hepatitis B virions is positively regulated by glucose-regulated protein 78 through direct interaction with preS1.

In this study, we investigated the mechanism of hepatitis B virus (HBV)-enveloped particle release. Specifically, we used preS1 as a bait protein to screen host proteins using mass spectroscopy, with the results of immunofluorescence, western blot, co-immunoprecipitation, isothermal titration calorimetry, and pull-down assays identifying glucose-regulated protein (GRP)78 as a specific target for preS1 binding. We employed transcriptome sequencing, enzyme-linked immunosorbent assays, and particle gel assays to investigate the mechanism of GRP78-mediated positive regulation of HBV-enveloped particle release. Additionally, we performed phage-display, surface plasmon resonance, and molecular-docking assays to assess peptides inhibiting enveloped-particle release. We found that HBV upregulated GRP78 expression in liver cell lines and the serum of patients with chronic hepatitis B. Furthermore, GRP78 promoted the release of HBV-enveloped particles in vitro and in vivo within an HBV transgenic mouse model. Moreover, we identified interactions of preS1 peptides with GRP78 via hydrogen bonding and hydrophobic interactions, which effectively inhibited its interaction with HBV-enveloped particles and their subsequent release. These findings provide novel insights regarding HBV virion release, and demonstrated that GRP78 interacted with preS1 to positively regulate the release of HBV-enveloped particles, suggesting GRP78 as a potential therapeutic target for inhibiting HBV infection.

AEN Suppresses the Replication of Porcine Epidemic Diarrhea Virus by Inducing the Expression of Type I IFN and ISGs in MARC-145 Cells.

Apoptosis-enhancing nuclease (AEN), which shares close evolutionary relationships with the interferon-stimulated gene 20 protein (ISG20) homologs in humans, is a member of the DEDDh exonuclease family. Numerous studies on various pathogens have identified the essential roles of ISG20 in inhibiting virus replication. However, the fundamental functions of AEN during viral infection remain largely unknown. This study discovered that AEN expression was significantly upregulated in MARC-145 cells infected with Porcine epidemic diarrhea virus (PEDV) strain 85-7. In contrast, the amount of AEN protein decreased as viral replication increased. It was found that PEDV nsp1 and nsp5 mediated the decrease in AEN production, suggesting that an increase in AEN was not conducive to virus replication. By comparing AEN and its exonuclease-inactive mutant AEN-4A, we determined that the antiviral activity of AEN was independent of its exonuclease function. qPCR analyses revealed that AEN and AEN-4A could induce a significant increase in the transcription levels of IFN-α, IFN-ß, and ISGs (OASL, IFI44, IFIT2, ISG15, Mx1, Mx2), and that AEN-4A has a higher induction ability. Overexpression of AEN and AEN-4A in MARC-145 cells targeting IFN-ß knockdown or IFN-deficient Vero cells showed reduced or a complete loss of antiviral activity of both, suggesting that AEN may activate the type I IFN immune response and promote the expression of ISGs, thereby inhibiting PEDV replication. Taken together, our data prove the novel mechanism of AEN-mediated virus restriction.

Problem Characteristics and Dynamic Search Balance-Based Artificial Bee Colony for the Optimization of Two-Tiered WSN Lifetime with Relay Nodes Deployment.

Lifetime optimization is one of the key issues among the many challenges of wireless sensor networks. The introduction of a small number of high-performance relay nodes can effectively improve the quality of the network services. However, how to deploy these nodes reasonably to fully enhance the network lifetime becomes a very difficult problem. In this study, a modified and enhanced Artificial Bee Colony is proposed to maximize the lifetime of a two-tiered wireless sensor network by optimal deployment of relay nodes. First, the dimension of the problem is introduced into the candidate search equation and the local search is adjusted according to the fitness of the problem and number of iterations, which helps to balance the exploration and exploitation ability of the algorithm. Second, in order to prevent the algorithm from falling into local convergence, a dynamic search balance strategy is proposed instead of the scout bee phase in the original Artificial Bee Colony. Then, a feasible solution formation method is proposed to ensure that the relay nodes can form the upper-layer backbone of the network. Finally, we employ this algorithm on a test dataset obtained from the literature. The simulation results show that the proposed algorithm for two-tiered wireless sensor network lifetime optimization can obtain higher and stable average network lifetime and more reasonable relay node deployment compared to other classical and state-of-the-art algorithms, verifying the competitive performance of the proposed algorithm.

Elevated monocyte to high-density lipoprotein cholesterol ratio correlates with clinical severity in acute inflammatory demyelinating polyradiculoneuropathy patients.

While monocyte to high-density lipoprotein cholesterol ratio (MHR) has been reported to be associated with nervous system lesions, the role of MHR has not been determined in patients with Guillain-Barré Syndrome (GBS). The purpose of our study was to explore the role of MHR in patients with GBS. A total of 52 GBS patients were involved in the study retrospectively, including patients with acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor axonal neuropathy (AMAN), and acute motor sensory axonal neuropathy (AMSAN). We used Hughes Functional Grading Scale (HFGS) score to evaluate functional status in GBS patients. Among patients with different subtypes of GBS, MHR was significantly elevated in those with demyelination compared to patients without demyelination (p < 0.001); AIDP patients had an increased MHR compared with AMAN or AMSAN patients (p = 0.001; p = 0.013). There was a positive correlation between MHR and HFGS score (r = 0.463, p = 0.006) in AIDP patients, but not in AMAN or AMSAN. Multiple linear regression analysis revealed that MHR was independently associated with HFGS score (beta = 0.405, p = 0.013) in AIDP patients. Our study suggests that MHR as an inflammatory marker is elevated in patients with AIDP compared to AMAN or AMSAN patients, while MHR has a positive correlation with clinical severity in AIDP patients, suggesting that MHR may provide an additional information to reflect the pathophysiology of AIDP.

Bacteria-mediated cancer therapy: A versatile bio-sapper with translational potential.

Bacteria are important symbionts for humans, which sustain substantial influences on our health. Interestingly, some bastrains have been identified to have therapeutic applications, notably for antitumor activity. Thereby, oncologists have developed various therapeutic models and investigated the potential antitumor mechanisms for bacteria-mediated cancer therapy (BCT). Even though BCT has a long history and exhibits remarkable therapeutic efficacy in pre-clinical animal models, its clinical translation still lags and requires further breakthroughs. This review aims to focus on the established strains of therapeutic bacteria and their antitumor mechanisms, including the stimulation of host immune responses, direct cytotoxicity, the interference on cellular signal transduction, extracellular matrix remodeling, neoangiogenesis, and metabolism, as well as vehicles for drug delivery and gene therapy. Moreover, a brief discussion is proposed regarding the important future directions for this fantastic research field of BCT at the end of this review.

Application of information-intelligence technologies in pharmacy intravenous admixture services in a Chinese third-class a hospital.

BACKGROUND: Pharmacy intravenous admixture service (PIVAS) center has emerged as an important department of hospital as it can improve occupational protection and ensure the safety and effectiveness of intravenous infusions. However, medication errors were considered to be a significant challenge in PIVAS, so information-intelligence technologies were introduced to optimize the management of PIVAS. Our article summarized the application of information-intelligence technologies in PIVAS of a large third-class A hospital in China, and provided an example for PIVAS in other hospitals at home and abroad. METHODS: Prescription-reviewing rules containing intravenous medications and infusion solution guideline were recorded in the database of prescription-cheking system. Drugs information were recorded in the PIVAS management system with special identification and warning labels to reduce intravenous infusion errors. Automatic labeling device was used to label the infusion bags, and the quality control program database of intelligent compounding robot for cytotoxic drugs was established ingeniously. Automatic sorting devices were applied for the third batch of finished infusion admixtures, and intelligent logistics robots were used to transport the infusion to the ward. RESULTS: After establishing and implementing of prescription-reviewing rules in the prescription-cheking system database, the number of prescriptions checked by pharmacists increased from 18 to 43 per minute. The success rate of intervention with irrational medical orders increased from 85.89% to 99.06% (P < 0.05). By introducing various intelligent devices, automatic labeling significantly enhanced work efficiency and reduced the error rate (P < 0.001). Furthermore, the use of intelligent intravenous compounding robots significantly reduced the risk of errors (P < 0.001). CONCLUSIONS: The application of information-intelligence technologies in PIVAS can improve work efficiency and reduce error risk. However, some intelligent devices have failed to achieve the expected effect in practical use, and further improvements are needed to meet the demands of PIVAS in the future.