Casual effects of gut microbiota on risk of infections: a two-sample Mendelian randomization study.

Background: The correlation between gut microbiota and infections has garnered significant attention in previous studies; nevertheless, our understanding of the causal relationships and mechanisms between specific microbial species and infections remains limited. Methods: This study aimed to employ Mendelian randomization (MR) using single-nucleotide polymorphisms (SNPs) and genome-wide association study (GWAS) data of European ancestry to explore the genetic-level relationships between distinct types of gut microbiota and susceptibility to infections. Our analysis encompassed three prevalent infections: intestinal infections, pneumonia, and urinary tract infections, while concurrently examining various types of gut microbiota. Results: We identified 18 protective gut microbiotas alongside 13 associated with increased infection risk. Particularly noteworthy are certain microbial communities capable of producing butyrate, such as the Ruminococcaceae and Lachnospiraceae families, which exhibited both favorable and unfavorable effects. Additionally, we observed a few certain communities linked to infection susceptibility, including ErysipelotrichaceaeUCG003 (OR = 0.13, 95% CI: 0.054-0.33, p = 1.24E-05), Collinsella (OR = 3.25, 95% CI: 2.00-5.27, p = 1.87E-06), and NB1n (OR = 1.24, 95% CI: 1.09-1.40, p = 1.12E-03). Conclusion: This study reveals complex relationships between gut microbiota and various infections. Our findings could potentially offer new avenues for exploring prevention and treatment strategies for infectious diseases.

Relationship Between Infiltration of CD163+ TAMs, FoxP3+ Tregs, or CD66b+ TANs and Cell Differentiation in Colorectal Cancer Tissues.

BACKGROUND/AIMS: There are many studies on immune cell infiltration in colorectal cancer, including FoxP3+-regulatory T cells, CD66b+ tumorassociated neutrophils, and CD163+ tumor-associated macrophages. These studies mainly focus on the relationship between cell infiltration and tumor progression, prognosis, and so on, while the relationship between tumor cell differentiation and cell infiltration is poorly understood. We aimed to explore the relationship between cell infiltration and tumor cell differentiation. MATERIALS AND METHODS: The tissue microarray and immunohistochemistry were used to determine the infiltration of FoxP3+-regulatory T cells, CD66b+ tumor-associated neutrophils, and CD163+ tumor-associated macrophages in 673 colorectal cancer samples from the Second Affiliated Hospital, Wenzhou Medical University (2001-2009). Kruskal-Wallis test was used to assess the positive cell infiltration in colorectal cancer tissues with tumor cells of varying degrees of differentiation. RESULTS: The number of CD163+ tumor-associated macrophages, FoxP3+-regulatory T cells, and CD66b+ tumor-associated neutrophils in colorectal cancer tissues was different, and the level of CD163+ tumor-associated macrophages was the highest while the level of FoxP3+-regulatory T cells was the least. There were significant differences in the cell infiltration of colorectal cancer tissue cells with different levels of differentiation (P < .05). The highest infiltration of CD163+ tumor-associated macrophages (154.07 ± 6.95) and FoxP3+-regulatory T cells (20.14 ± 2.07) were in the poorly differentiated colorectal cancer tissues, while the higher infiltration of CD66b+ tumor-associated neutrophils was in the moderately or well-differentiated colorectal cancer tissues (36.70 ± 1.10 and 36.09 ± 1.06, respectively). CONCLUSION: Infiltration of CD163+ tumor-associated macrophages, FoxP3+-regulatory T cells, and CD66b+ tumor-associated neutrophils in colorectal cancer tissues may be related to the differentiation of tumor cells.

A Novel Pyroptosis-Associated Gene Signature to Predict Prognosis in Patients with Colorectal Cancer.

Background: Pyroptosis is a form of cell death characterized by cell swelling and plasma membrane bubbling in association with inflammatory and immune responses. To date, the association between pyroptosis and colorectal cancer remains unclear. We aimed to establish a novel pyroptosis-associated model for the prognosis of colorectal cancer. Methods: Pyroptosis-related genes were extracted using Gene Set Enrichment Analysis. A least absolute shrinkage and selection operator regression model was constructed to identify a pyroptosis-related gene signature using the Cancer Genome Atlas and Gene Expression Omnibus databases. Then, Kyoto Encyclopedia of Genes and Genomes and Gene Ontology and GSEA were performed to better understand the potential mechanisms and the functional pathways associated with pyroptosis involved in colorectal cancer. The relationship between the pyroptosis-related signature and immune infiltration was investigated using Cell-Type Identification by Estimating Relative Subsets of RNA Transcripts and MCPcounter. Results: A 12 pyroptosis-related gene signature was identified. Then, patients were classified into high- and low-risk groups. Kaplan-Meier and receiver operating characteristic analyses confirmed that the high-risk groups showed worse overall survival, progression-free survival, or relapse-free survival probability. Functional enrichment analysis showed that pyroptosis was associated with extracellular matrix-related pathways. Furthermore, the pyroptosis risk score was associated with immune infiltration. The low-risk group exhibited a higher percentage of plasma cells, CD4 T cells, activated dendritic cells, and activated mast cells. M2 macrophages and M0 macrophages were positively related to the risk score. Conclusion: Our research yielded a novel pyroptosis-related prognostic signature for colorectal cancer that was related to immune cell infiltration, and it provided an immunological perspective for developing personalized therapies.

AWGS2019 vs EWGSOP2 for diagnosing sarcopenia to predict long-term prognosis in Chinese patients with gastric cancer after radical gastrectomy.

BACKGROUND: Sarcopenia is a nutrition-related disease and has a profound effect on the long-term overall survival (OS) of patients with gastric cancer. Its diagnostic criterion is critical to clinical diagnosis and treatment. However, previous research reported widely differing sarcopenia prevalence due to different criteria. AWGS2019 and EWGSOP2 are the two latest and widely adopted criteria. AIM: To compare the effects of AWGS2019 and EWGSOP2 on the long-term OS of Chinese gastric cancer patient after radical gastrectomy. METHODS: An observational study was conducted from July 2014 to January 2017, which included 648 consecutive gastric cancer patients who underwent radical gastrectomy. The sarcopenia elements (skeletal muscle index, handgrip strength, and gait speed) were measured within 1 mo or 7 d before surgery. The patients were followed at fixed intervals to gain the outcomes. Multivariate Cox regression analysis was performed to determine the association between sarcopenia and the long-term OS of these patients according to the two criteria separately. The predictive performance of the models with AWGS2019 and EWGSOP2 were evaluated by the concordance index (C-index) and area under the time-dependent receiver operating characteristic curve (AUC). The Akaike information criterion (AIC) was applied to compare model fits. RESULTS: The prevalence of sarcopenia was 20.5% and 11.3% according to AWGS2019 and EWGSOP2, respectively. Sarcopenia was an independent risk factor for the long-term OS no matter based on AWGS2019 or EWGSOP2, but AWGS2019-sarcopenia in multivariate model had a higher hazard ratio (HR) [2.150 (1.547-2.988)] than EWGSOP2-sarcopenia [HR 1.599 (1.092-2.339)]. Meanwhile, the model with AWGS2019-sarcopenia [C-index 0.773 (0.742-0.804); AIC 2193.7; time-dependent AUC 0.812 (0.756-0.867) for 1-year OS, 0.815 (0.778-0.852) for 3-year OS, and 0.809 (0.759-0.859) for 5-year OS] had better predictive power and model fits than the model with EWGSOP2-sarcopenia [C-index 0.762 (0.729-0.795); AIC 2215.2; time-dependent AUC 0.797 (0.741-0.854) for 1-year OS, 0.804 (0.767-0.842) for 3-year OS, and 0.799 (0.748-0.850) for 5-year OS]. CONCLUSION: Sarcopenia is an independent risk factor for the long-term OS in Chinese gastric cancer patients undergoing radical gastrectomy. The prediction model with AWGS2019-sarcopenia has better predictive power and model fits than the prediction model with EWGSOP2-sarcopenia. AWGS2019 may be more appropriate for diagnosing sarcopenia in these Chinese patients than EWGSOP2.

Identification of Candidate Genes Associated with Postherpetic Neuralgia Susceptibility.

BACKGROUND: Postherpetic neuralgia (PHN) is one of the most common complications of herpes zoster (HZ). Heritable factors have been found to play a role in various clinical pain symptoms. However, the effect of gene variability on the susceptibility of PHN remains poorly understood. OBJECTIVES: The aim of this study was to evaluate whether genetic variation in pain pathway genes was associated with PHN susceptibility in the Chinese population. STUDY DESIGN: Case-control study. SETTING: Department of Anesthesiology and Pain Medicine in a university hospital. METHODS: Seventy patients with PHN and 111 patients with HZ without developing PHN were enrolled. All patients received standardized antiviral agents and analgesics as needed during the acute phase of HZ. Twenty-four candidate genetic polymorphisms in 12 genes (IL1B, SCN9A, KCNK9, TRPV1, P2RX7, HTR1A, HTR2A, ADRB1, ADRB2, BDNF, COMT, and OPRM1) were genotyped in all patients. Multivariable logistic regression analyses were used to identify genetic variations associated with PHN susceptibility while controlling for potential confounders. RESULTS: Our results suggested that only variation in P2RX7 gene was associated with PHN susceptibility. The P2RX7 rs7958311 AG heterozygous genotype carriers had a decreased risk for PHN in the overdominant model (odds ratio [OR], 0.40; 95% confidence interval [CI], 0.21-0.77; P = 0.005), and codominant model (OR, 0.44; 95% CI, 0.20-0.98; P = 0.045). The P2RX7 rs7958311 GG homozygote genotype was associated with an increased risk for PHN under a recessive model (OR, 2.15; 95% CI, 1.01-4.56; P = 0.046). There were no significant associations between the other 23 single-nucleotide polymorphisms and PHN susceptibility. LIMITATIONS: Lack of validation cohort to verify the findings. CONCLUSIONS: In the present study in the Chinese population, we found purinergic receptor P2X7 rs7958311 may contribute to PHN development after HZ. Future larger independent cohorts are warranted to replicate these initial findings. KEY WORDS: Herpes zoster, postherpetic neuralgia, polymorphisms.

Single nucleotide polymorphisms associated with postoperative inadequate analgesia after single-port VATS in Chinese population.

BACKGROUND: Postoperative inadequate analgesia following video-assisted thoracoscopic surgery (VATS) is a common and significant clinical problem. While genetic polymorphisms may play role in the variability of postoperative analgesia effect, few studies have evaluated the associations between genetic mutations and inadequate analgesia after single-port VATS. METHODS: Twenty-eight single nucleotide polymorphisms (SNPs) among 18 selected genes involved in pain perception and modulation were genotyped in 198 Chinese patients undergoing single-port VATS. The primary outcome was the occurrence of inadequate analgesia in the first night and morning after surgery which was defined by a comprehensive postoperative evaluation. Multivariable logistic regression analyses were used to identify the association between genetic variations and postoperative inadequate analgesia. RESULTS: The prevalence of postoperative inadequate analgesia was 45.5% in the present study. After controlling for age and education level, association with inadequate analgesia was observed in four SNPs among three genes encoding voltage-gated sodium channels. Patients with the minor allele of rs33985936 (SCN11A), rs6795970 (SCN10A), and 3312G > T (SCN9A) have an increased risk of suffering from inadequate analgesia. While the patients carrying the minor allele of rs11709492 (SCN11A) have lower risk experiencing inadequate analgesia. CONCLUSIONS: We identified that SNPs in SCN9A, SCN10A, and SCN11A play a role in the postoperative inadequate analgesia after single-port VATS. Although future larger and long-term follow up studies are warranted to confirm our findings, the results of the current study may be utilized as predictors for forecasting postoperative analgesic effect for patients receiving this type of surgery. TRIAL REGISTRATION: This study was retrospectively registered in the ClinicalTrials.gov Registry (NCT03916120) on April 16, 2019.

Moderate-severe postoperative pain in patients undergoing video-assisted thoracoscopic surgery: A retrospective study.

Moderate-severe pain after surgical procedures is associated with decreased quality of life and increased costs. This study aimed to identify the incidence and predictive factors of moderate-severe postoperative pain within 48 hours following video-assisted thoracoscopic surgery (VATS) in a tertiary hospital. A retrospective cohort analysis was performed using medical records of adult patients who underwent VATS between January 2015 and December 2016. Logistic regression was performed to identify predictive factors for moderate-severe pain (visual analogue scale, VAS ≥ 4) within 24 hours and within 48 hours postoperatively. Of the 1164 participants, the incidence of moderate-severe pain was 12.7% within the first 24 hours and 15.6% within the first 48 hours after surgery. In multivariable analysis, the independent risk factors related to moderate-severe pain within 24 hours after surgery were younger age, increased body mass index, preoperative pain within 1 month and history of smoking. The risk factors for moderate-severe acute pain within 48 hours were almost the same, except that the number of chest tubes were also included. Moderate-severe postoperative pain following VATS is not rare, and presence of several risk factors deserves more aggressive pain management strategies perioperatively.

Postoperative analgesic effect of hydromorphone in patients undergoing single-port video-assisted thoracoscopic surgery: a randomized controlled trial.

Objective: To study the general efficacy of hydromorphone as a systemic analgesic in postoperative pain management following single-port video-assisted thoracoscopic surgery (VATS) and to explore the optimal administration regimen. Methods: A prospective, randomized, double-blind study was designed and conducted in a tertiary hospital. In total, 157 valid patients undergoing single-port VATS were randomly allocated into three groups. A total of 53 patients received morphine bolus only for postoperative analgesia (Group Mb); 51 patients received a hydromorphone background infusion plus bolus (Group Hb + i), and 53 patients received a hydromorphone bolus only (Group Hb). The primary outcomes were patient-reported static and dynamic pain levels; the secondary outcomes included side effects, sleep quality, and recovery indexes. Results: Patients in Group Hb + i experienced lower pain intensity (approximately 10 out of 100 on the visual analog scale) in both static pain and dynamic pain in the days following surgery (P<0.01), better sleep quality during the first night only (P=0.002), and a higher satisfaction level than those in the other two groups (P=0.006). A comparison of these variables in Group Mb and Group Hb resulted in no significant differences. Lastly, side effects and recovery indexes remained the same among bolus-only groups and bolus-plus-background-infusion groups. Conclusion: There is no advantage to administering hydromorphone over morphine using bolus only mode. Within 24 h after surgery, a background infusion should be considered as a part of a standard protocol for patient-controlled intravenous analgesia. At 24 h after surgery, the background infusion should be adjusted in accordance with patient preferences and pain intensity.

Involvement of the PI3K/Akt/NF-κB Signaling Pathway in the Attenuation of Severe Acute Pancreatitis-Associated Acute Lung Injury by Sedum sarmentosum Bunge Extract.

Sedum sarmentosum Bunge possesses excellent anti-inflammatory properties and was used in the treatment of inflammatory diseases. The aim of the present study was to investigate the efficiency of Sedum sarmentosum Bunge extract (SSBE) on severe acute pancreatitis-associated (SAP-associated) acute lung injury (ALI) in rats and to explore the underlying mechanisms. Here, we used a sodium taurocholate-induced SAP rat model to determine the role of SSBE in ALI. During the course of pancreatitis, the expressions of phosphorylated phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt) and nuclear factor-kappa B (NF-κB) p65 in the lungs were upregulated. Meanwhile, a parallel increase in the levels of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the lungs was observed after the induction of SAP. Treatment with SSBE significantly reduced the expression of p-Akt and p-p65 in the lungs and attenuated the severity of SAP-associated ALI compared to the SAP group at 12 h and 24 h. In summary, this study showed that SSBE has beneficial effects on SAP-associated ALI, probably through the PI3-K/Akt signaling pathways by suppressing the NF-κB activities.

Downregulation of paraoxonase 3 contributes to aggressive human hepatocellular carcinoma progression and associates with poor prognosis.

Paraoxonase (PON) enzymes possess antioxidant properties and protect against cardiovascular diseases. As a member of PON family, PON3 is primarily synthesized in the liver and poorly investigated. This study aimed to examine the expression of PON3 in human hepatocellular carcinoma (HCC) and investigate the clinical significance and biological function of PON3 in HCC patients. We first analyzed PON3 expression in 50 paired HCC samples (HCC tissues vs matched para-cancerous tissues) and 160 clinical HCC specimens by using immunohistochemistry (IHC). Our results showed that the expression of PON3 was downregulated in HCC and significantly associated with tumor-node-metastasis (TNM) stage, tumor size, and tumor number. Kaplan-Meier survival and Cox regression analyses showed that PON3 was an independent prognostic factor for overall survival (OS) and time to recurrence (TTR). Finally, we aimed to reveal the biological function of PON3 in HCC growth and metastasis, and our results showed that overexpression of PON3 potently inhibited growth and metastasis of HCC. Collectively, our study demonstrated that PON3 exhibited tumor-suppressive effects toward HCC and it might serve as a novel prognostic marker in HCC.

Inhibition of Macrophage Migration Inhibitory Factor Protects against Inflammation and Matrix Deposition in Kidney Tissues after Injury.

Background. Macrophage migration inhibitory factor (MIF) is an important immunoregulatory cytokine involved in inflammation, which may be one important reason resulting in matrix deposition in renal tissues after injury. However, the underlying mechanisms have not yet been elucidated. Methods and Results. We uncovered a crucial role of MIF in inflammation and collagen deposition in vivo and in vitro. In rats, ureteral obstruction induced tubular injury, matrix accumulation, and inflammatory cell infiltration. Additionally, enhanced MIF levels in the obstructed kidneys were closely related to the increasing numbers of CD68-positive macrophages. These obstruction-induced injuries can be relieved by recanalization, consequently resulting in downregulated expression of MIF and its receptor CD74. Similarly, ischemia reperfusion induced renal injury, and it was accompanied by elevated MIF levels and macrophages infiltration. In cultured tubular epithelial cells (TECs), aristolochic acid (AA) promoted matrix production and increased MIF expression, as well as the release of macrophage-related factors. Inhibition of MIF with an antagonist ISO-1 resulted in the abolishment of these genotypes in AA-treated TECs. Conclusion. MIF plays an important role in macrophage-related inflammation and matrix deposition in kidney tissues following injury. MIF as a specific inhibitor may have therapeutic potential for patients with inflammatory and fibrotic kidney diseases.

Hedgehog Signaling in Pancreatic Fibrosis and Cancer.

The hedgehog signaling pathway was first discovered in the 1980s. It is a stem cell-related pathway that plays a crucial role in embryonic development, tissue regeneration, and organogenesis. Aberrant activation of hedgehog signaling leads to pathological consequences, including a variety of human tumors such as pancreatic cancer. Multiple lines of evidence indicate that blockade of this pathway with several small-molecule inhibitors can inhibit the development of pancreatic neoplasm. In addition, activated hedgehog signaling has been reported to be involved in fibrogenesis in many tissues, including the pancreas. Therefore, new therapeutic targets based on hedgehog signaling have attracted a great deal of attention to alleviate pancreatic diseases. In this review, we briefly discuss the recent advances in hedgehog signaling in pancreatic fibrogenesis and carcinogenesis and highlight new insights on their potential relationship with respect to the development of novel targeted therapies.

Activation of autophagy through calcium-dependent AMPK/mTOR and PKCθ pathway causes activation of rat hepatic stellate cells under hypoxic stress.

The activation of hepatic stellate cells (HSCs) is a prominent event in liver fibrogenesis. However, how HSCs are activated in the hypoxic microenvironment remains unclear. Here, we found that hypoxia increased autophagy in rat HSCs. Moreover, hypoxia induced an elevation of the intracellular calcium concentration ([Ca(2+)]i), which was abolished by the cytosolic Ca(2+) chelator or the phospholipase C (PLC)-specific inhibitor. Furthermore, hypoxia-induced autophagy involved the calcium-dependent activation of the 5'-adenosine monophosphate-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) and protein kinase C-theta (PKCθ) pathways. In addition, hypoxia-mediated activation of HSCs depended on autophagy. Our results suggest that autophagy induction via the calcium-dependent AMPK-mTOR and PKCθ pathways might lead to the activation of HSCs during hypoxic stress.

Reduced Pancreatic Exocrine Function and Organellar Disarray in a Canine Model of Acute Pancreatitis.

The aim of the present study was to investigate the pancreatic exocrine function in a canine model and to analyze the changes in organelles of pancreatic acinar cells during the early stage of acute pancreatitis (AP). AP was induced by retrograde injection of 5% sodium taurocholate (0.5 ml/kg) into the main pancreatic duct of dogs. The induction of AP resulted in serum hyperamylasemia and a marked reduction of amylase activity in the pancreatic fluid (PF). The pancreatic exocrine function was markedly decreased in subjects with AP compared with the control group. After the induction of AP, histological examination showed acinar cell edema, cytoplasmic vacuolization, fibroblasts infiltration, and inflammatory cell infiltration in the interstitium. Electron micrographs after the induction of AP revealed that most of the rough endoplasmic reticulum (RER) were dilated and that some of the ribosomes were no longer located on the RER. The mitochondria were swollen, with shortened and broken cristae. The present study demonstrated, in a canine model, a reduced volume of PF secretion with decreased enzyme secretion during the early stage of AP. Injury of mitochondria and dilatation and degranulation of RER may be responsible for the reduced exocrine function in AP. Furthermore, the present model and results may be useful for researching novel therapeutic measures in AP.

Luteolin decreases invasiveness, deactivates STAT3 signaling, and reverses interleukin-6 induced epithelial-mesenchymal transition and matrix metalloproteinase secretion of pancreatic cancer cells.

Luteolin, a flavone, has been shown to exhibit anticancer properties. Here, we investigated whether luteolin affects epithelial-mesenchymal transition (EMT) and invasiveness of pancreatic cancer cell lines and their underlying mechanism. Pancreatic cancer cell lines PANC-1 and SW1990 were used in our study, and their EMT characters, matrix metalloproteinase (MMP) expression level, invasiveness, and signal transducer and activator of transcription 3 (STAT3) activity were determined after luteolin treatment. We also treated pancreatic cancer cells with interleukin-6 (IL-6) to see whether IL-6-induced activation of STAT3, EMT, and MMP secretion was affected by luteolin. We found that luteolin inhibits EMT and MMP2, MMP7, and MMP9 expression in a dose-dependent manner, similar to STAT3 signaling. Through Transwell assay, we found that invasiveness of pancreatic cancer cells was inhibited by luteolin. EMT characters and MMP secretion increase with STAT3 activity after IL-6 treatment and these effects, caused by IL-6, were inhibited by luteolin. We concluded that luteolin inhibits invasiveness of pancreatic cancer cells, and we speculated that luteolin inhibits EMT and MMP secretion likely through deactivation of STAT3 signaling. Luteolin has potential antitumor effects and merits further investigation.