23-Hydroxybetulinic acid attenuates 5-fluorouracil resistance of colorectal cancer by modulating M2 macrophage polarization via STAT6 signaling.

Macrophage polarization is closely associated with the inflammatory processes involved in the development and chemoresistance of colorectal cancer (CRC). M2 macrophages, the predominant subtype of tumor-associated macrophages (TAMs) in a wide variety of malignancies, have been demonstrated to promote the resistance of CRC to multiple chemotherapeutic drugs, such as 5-fluorouracil (5-FU). In our study, we investigated the potential of 23-Hydroxybetulinic Acid (23-HBA), a significant active component of Pulsatilla chinensis (P. chinensis), to inhibit the polarization of M2 macrophages induced by IL-4. Our results showed that 23-HBA reduced the expression of M2 specific marker CD206, while downregulating the mRNA levels of M2 related genes (CD206, Arg1, IL-10, and CCL2). Additionally, 23-HBA effectively attenuated the inhibitory effects of the conditioned medium from M2 macrophages on apoptosis in colorectal cancer SW480 cells. Mechanistically, 23-HBA prevented the phosphorylation and nuclear translocation of the STAT6 protein, resulting in the inhibition of IL-10 release in M2 macrophages. Moreover, it interfered with the activation of the IL-10/STAT3/Bcl-2 signaling pathway in SW480 cells, ultimately reducing M2 macrophage-induced resistance to 5-FU. Importantly, depleting STAT6 expression in macrophages abolished the suppressive effect of 23-HBA on M2 macrophage polarization, while also eliminating its ability to decrease M2 macrophage-induced 5-FU resistance in cancer cells. Furthermore, 23-HBA significantly diminished the proportion of M2 macrophages in the tumor tissues of colorectal cancer mice, simultaneously enhancing the anti-cancer efficacy of 5-FU. The findings presented in this study highlight the capacity of 23-HBA to inhibit M2 macrophage polarization, a process that contributes to reduced 5-FU resistance in colorectal cancer.

Development and validation of a multimodal model in predicting severe acute pancreatitis based on radiomics and deep learning.

OBJECTIVE: Aim to establish a multimodal model for predicting severe acute pancreatitis (SAP) using machine learning (ML) and deep learning (DL). METHODS: In this multicentre retrospective study, patients diagnosed with acute pancreatitis at admission were enrolled from January 2017 to December 2021. Clinical information within 24 h and CT scans within 72 h of admission were collected. First, we trained Model α based on clinical features selected by least absolute shrinkage and selection operator analysis. Second, radiomics features were extracted from 3D-CT scans and Model ß was developed on the features after dimensionality reduction using principal component analysis. Third, Model γ was trained on 2D-CT images. Lastly, a multimodal model, namely PrismSAP, was constructed based on aforementioned features in the training set. The predictive accuracy of PrismSAP was verified in the validation and internal test sets and further validated in the external test set. Model performance was evaluated using area under the curve (AUC), accuracy, sensitivity, specificity, recall, precision and F1-score. RESULTS: A total of 1,221 eligible patients were randomly split into a training set (n = 864), a validation set (n = 209) and an internal test set (n = 148). Data of 266 patients were for external testing. In the external test set, PrismSAP performed best with the highest AUC of 0.916 (0.873-0.960) among all models [Model α: 0.709 (0.618-0.800); Model ß: 0.749 (0.675-0.824); Model γ: 0.687 (0.592-0.782); MCTSI: 0.778 (0.698-0.857); RANSON: 0.642 (0.559-0.725); BISAP: 0.751 (0.668-0.833); SABP: 0.710 (0.621-0.798)]. CONCLUSION: The proposed multimodal model outperformed any single-modality models and traditional scoring systems.

Edwardsiella tarda Causing Septicemia in a Wild Crested Ibis (Nipponia nippon).

An adult Crested Ibis (Nipponia nippon) was found moribund in the Qinling area of China. Postmortem examination and histopathological analysis revealed lung inflammation and multi-organ hemorrhage. Bacterial isolation and whole-genome sequencing confirmed Edwardsiella tarda infection.

Two new benzophenones from the moss Pogonatum spinulosum.

Two new benzophenone derivatives (1 and 2), named Pogonatone C and pogonatone D, were isolated from the moss Pogonatum spinulosum. Their structures were elucidated by spectroscopic data analyses. The cytotoxicity of compounds for HepG2, HCT-116, A-549 and PANC-1 cells line was also evaluated by using the MTT method. Pogonatone C (1) displays high cytotoxicity on PANC-1 cell with IC50 value of 9.2 µM.

Efficacy of radiofrequency ablation following transarterial chemoembolisation combined with sorafenib for intermediate stage recurrent hepatocellular carcinoma: a retrospective, multicentre, cohort study.

Background: The evidence of radiofrequency ablation (RFA) following transarterial chemoembolisation (TACE) combined with sorafenib for intermediate-stage recurrent hepatocellular carcinoma (RHCC) is limited. Patient responses to this treatment vary because of the heterogeneous nature of RHCC, making it important to identify patients who are most likely to benefit from this combination therapy. The aim of this study was to evaluate the efficacy of RFA following TACE and sorafenib for the intermediate-stage RHCC. Methods: This retrospective, multicentre, cohort study included 363 patients with intermediate-stage RHCC underwent TACE combined with sorafenib (TACE-sorafenib group) or RFA following TACE and sorafenib (TACE-sorafenib + RFA group) between January 01, 2009 to December 31, 2015 from four institutions in China. Overall survival (OS), progression-free survival (PFS) and efficacy of patients were compared between the two groups by propensity score-matching (PSM). Findings: The 1-, 3-, and 5-year OS rates were 97.7%, 83.7%, 54.7% in TACE-sorafenib + RFA group, and 93.3%, 57.0%, 32.7% in TACE-sorafenib group. The 1-, 2-, and 3-year PFS rates were 85.3%, 58.0%, 26.9% in TACE-sorafenib + RFA group, and 55.3%, 30.7%, 15.3% in TACE-sorafenib group. Compared with the TACE-sorafenib group, the TACE-sorafenib + RFA group had significantly longer OS (HR, 0.54; 95%CI, 0.40-0.73; P < 0.001) and PFS (HR, 0.52; 95% CI, 0.41-0.66; P < 0.001). Subgroup analysis was conducted to precisely screen out the beneficial population from RFA treatment. Interpretation: Our findings suggest that addition of RFA following TACE and sorafenib combination was superior to TACE combined with sorafenib for intermediate-stage RHCC, resulting in longer OS and PFS. Patients who had good response to TACE and achieved downstaging successfully could not benefit from the RFA therapy. Funding: This research was funded by National Natural Science Foundation of China (No. 81627803), Chen Xiao-Ping Science and Technology Development Fund (CXPJJH1200009-06).

[High-flow nasal cannula oxygen therapy in prostate-targeted needle biopsy in high-risk patients with obstructive sleep apnea syndrome].

OBJECTIVE: To compare the effect of high-flow nasal cannula oxygen therapy (HFNC) from that of conventional nasal cannula oxygen therapy (CNC) on oxygenation during prostate-targeted needle biopsy under total intravenous anesthesia in high-risk patients with obstructive sleep apnea syndrome (OSAS). METHODS: We randomly assigned 64 high-risk OSAS patients to two groups of an equal number to receive HFNC and CNC, respectively, under total intravenous anesthesia. We recorded the incidence rates of SpO2<95% and the lowest SpO2 during surgery, the mean arterial pressure (MAP), heart rate (HR) and oxygen saturation (SpO2) upon entering the operation room (T0), at the beginning (T1) and the end of surgery (T2) and at 30 minutes postoperatively (T3), as well as arterial partial pressure of oxygen (PaO2) and arterial partial pressure of carbon dioxide (PaCO2) at T0 and T2, and the incidence rates of airway intervention and adverse events, followed by comparison of the parameters between the two groups. RESULTS: Both the lowest SpO2 and PaO2 were significantly increased in the HFNC group compared with those in the CNC group (P < 0.05) while no statistically significant difference was observed in PaCO2 between the two groups (P > 0.05). The intraoperative incidence rates of hypoxia, airway intervention, choking and body movement were remarkably lower in the HFNC than in the CNC group (P < 0.05), but there were no statistically significant differences in the operation time, anesthesia duration and propofol dosage between the two groups (P > 0.05). CONCLUSION: HFNC may provide more adequate oxygenation, improve airway management, and reduce the incidence of hypoxemia in high-risk OSAS patients during prostate biopsy under total intravenous anesthesia.

Development and Validation of Prognostic Nomograms for Hepatocellular Carcinoma After Hepatectomy Based on Inflammatory Markers.

Background: The value of lactate dehydrogenase (LDH) compared with other inflammation-based scores in predicting the outcomes of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients after curative resection remains unknown. This study aims to evaluate the predictive value of LDH and develop novel nomograms to predict postoperative recurrence and survival in these patients. Methods: This study retrospectively collected 1560 patients with HBV-related HCC who underwent curative resection from four institutions in China. In total, 924 patients were recruited from our center and randomly divided into the training cohort (n = 616) and internal validation (n = 308) cohorts. Additionally, 636 patients were selected from three other centers as the external validation cohort. The C index of inflammation-based scores was calculated and compared in the training cohort. Novel models were developed according to multivariable Cox regression analysis in the training cohort and validated in the internal and external validation cohorts. Results: LDH showed a higher C-index than other inflammation-based scores for recurrence survival (RFS, 0.60, 95% CI, 0.58-0.61) and overall survival (OS, 0.65, 95% CI, 0.63-0.68). The nomograms of RFS and OS were developed based on tumor diameter, macrovascular invasion, AFP, operative hemorrhage, tumor differentiation, tumor number and LDH and achieved a high C-index (0.78, 95% CI, 0.76-0.79 and 0.81, 95% CI, 0.79-0.83), which were remarkably higher than the C-indexes of the five conventional HCC staging systems (0.52-0.62 for RFS and 0.53-0.67 for OS). The nomograms were validated in the internal validation cohort (0.77 for RFS, 0.78 for OS) and external validation cohort (0.80 for RFS, 0.81 for OS) and performed well-fitted calibration curves. Conclusion: The two nomograms based on inflammatory markers achieved optimal prediction for RFS and OS of patients with HBV-related HCC after hepatectomy.

Knockdown of PSMC2 contributes to suppression of cholangiocarcinoma development by regulating CDK1.

Cholangiocarcinoma (CCA) has been well known as the second most common primary tumor of hepatobiliary system. PSMC2 (proteasome 26S subunit ATPase 2) is a key member of the 19S regulatory subunit of 26S proteasome, responsible for catalyzing the unfolding and translocation of substrates into the 20S proteasome, whose role in CCA is totally unknown. In this study, the results of immunohistochemistry analysis showed the upregulation of PSMC2 in CCA tissues compared with normal tissues, which was statistically analyzed to be associated with CCA tumor grade. Subsequently, the loss-of-function study suggested that knockdown of PSMC2 significantly suppressed cell proliferation, cell migration, promoted cell apoptosis and arrested cell cycle distribution in vitro. The decreased tumorigenicity of CCA cells with PSMC2 knockdown was confirmed in vivo by using mice xenograft model. In PSMC2 knockdown cells, pro-apoptotic protein Caspase3 was upregulated; anti-apoptotic proteins such as Bcl-2 and IGF-II were downregulated; among EMT markers, E-cadherin was upregulated while N-cadherin and Vimentin were downregulated, by which may PSMC2 regulates cell apoptosis and migration. Furthermore, through RNA-seq and verification by qPCR, western blotting and co-IP assays, CDK1 was identified as the potential downstream of PSMC2 mediated regulation of CCA. PSMC2 and CDK1 showed mutual regulation effects on expression level of each other. Knockdown of PSMC2 could aggregate the influence of CDK1 knockdown on cellular functions of CCA cells. In summary, our findings suggested that PSMC2 possesses oncogene-like functions in the development and progression of CCA through regulating CDK1, which may be used as an effective therapeutic target in CCA treatment.

The effect of the TP53 and RB1 mutations on the survival of hepatocellular carcinoma patients with different racial backgrounds.

BACKGROUND: Racial disparities in the survival of patients with hepatocellular carcinoma (HCC) exist. Gene mutations have a profound effect on carcinogenesis, are easily affected by environment and etiology factors, and may result in survival divergences among patients with different racial backgrounds. This report explores the effects of gene mutations on the survival of American Caucasians and Asian patients. METHODS: The sequencing and clinical data of 336 HCC patients were obtained from The Cancer Genome Atlas (TCGA) database. The sequencing data was subject to gene mutation profiling, and an analysis of immune cell infiltration was conducted. A multivariate analysis was performed to assess the independent effects of gene mutations on patients' overall survival (OS) and disease-free survival (DFS). RESULTS: Asian HCC patients had a significantly higher level of TP53 mutation frequency than Caucasian HCC patients (Asian vs. Caucasian, 39% vs. 23%; P=0.003). The TP53 mutation was associated with shorter OS [hazard ratio (HR), 2.33; 95% confidence interval (CI), 1.36-3.97; P=0.002] and DFS (HR, 2.2; 95% CI, 1.38-3.51; P<0.001) in Caucasian HCC patients, but had no effect on Asian HCC patients' survival. Compared to Asian HCC patients, Caucasian HCC patients with the TP53 mutation had a decreased proportion of infiltrating M2 macrophages and activating natural killer (NK) cells, and an increased proportion of follicular helper T cells. The RB1 mutation was associated with shorter OS (HR, 3.37; 95% CI, 1.73-6.57; P<0.001) in Asian HCC patients, and shorter DFS (HR, 2.11; 95% CI, 1.15-3.88; P=0.017) in Caucasian HCC patients. Asian HCC patients with the RB1 mutation had a decreased proportion of infiltrating CD8 T cells. CONCLUSIONS: The effects of the TP53 and RB1 mutations on survival differ among Asian and Caucasian HCC patients.

Identification of chondroitin polymerizing factor (CHPF) as tumor promotor in cholangiocarcinoma through regulating cell proliferation, cell apoptosis and cell migration.

Cholangiocarcinoma (CCA) is a variety of biliary epithelial tumors involving intrahepatic, perihilar and distal bile duct. It is the most common malignant bile duct tumor in the liver and the second most common primary liver cancer, whose molecular mechanism not fully understood. Specifically, the relationship between CCA and chondroitin polymerizing factor (CHPF) is still not clear. In this study, detection of clinical specimens was performed to preliminarily study the role of CHPF in CCA. CCA cells with CHPF knockdown were constructed for in vitro study, which was also used in the construction of mice xenograft model for investigating the role of CHPF in the development of CCA. The results demonstrated that CHPF was significantly upregulated in CCA tissues compared with normal tissues. High expression of CHPF was correlated with more advanced tumor grade. Moreover, knockdown of CHPF significantly inhibited cell proliferation, cell migration, promoted cell apoptosis and arrest cell cycle in G2 phase in vitro, as well as suppressed tumor growth in vivo. In conclusion, CHPF was identified as a tumor promotor in the development and metastasis of CCA, which may provide a novel therapeutic target for the targeted therapy against CCA.

The role of microglia in chronic pain and depression: innocent bystander or culprit?

Clinical evidence shows that chronic pain and depression often accompany each other, but the underlying pathogenesis of comorbid chronic pain and depression remains mostly undetermined. Biotechnology is gradually revealing the phenotype and function of microglia, with great progress regarding microglia's role in neurodegeneration, depression, chronic pain, and other conditions. This article summarizes the role of microglia in chronic pain, depression, and comorbidities, which is conducive to finding new targets to treat chronic pain and depression.

Deletion of PDK1 in oligodendrocyte lineage cells causes white matter abnormality and myelination defect in the central nervous system.

PDK1 (3-Phosphoinositide dependent protein kinase-1) is a member in the PI3K (phosphatidylinositol 3 kinase) pathway and is implicated in neurodevelopmental disease with microcephaly. Although the role of PDK1 in neurogenesis has been broadly studied, it remains unknown how PDK1 may regulate oligogenesis in the central nervous system (CNS). To address this question, we generated oligodendrocyte (OL) lineage cells specific PDK1 conditional knockout (cKO) mice. We find that PDK1 cKOs display abnormal white matter (WM), massive loss of mature OLs and severe defect in myelination in the CNS. In contrast, these mutants exhibit normal neuronal development and unchanged apoptosis in the CNS. We demonstrate that deletion of PDK1 severely impairs OL differentiation. We show that genetic or pharmacological inhibition of PDK1 causes deficit in the mammalian target of rapamycin (mTor) signaling and down-regulation of Sox10. Together, these results highlight a critical role of PDK1 in OL differentiation during postnatal CNS development.

Anemoside B4 prevents acute ulcerative colitis through inhibiting of TLR4/NF-κB/MAPK signaling pathway.

Anemoside B4 (B4) is a compound extracted from Pulsatilla chinensis(P. chinensis). Pharmacological studies have proved that it has certain anti-inflammatory activity. Acute ulcerative colitis (ulcerative colitis) is a non-specific inflammatory disease whose pathogenesis is not completely known, and there is no effective drugs. The purpose of this study was to investigate the protective effect of B4 on ulcerative colitis and its mechanism. In this study, the C57BL/6 mice model of ulcerative colitis was established by DSS [3% (w/v)] and treated with intraperitoneal injection of B4 and oral administration of mesalazine, respectively. During the experiment, the clinical symptoms of the mice were scored by the disease activity index (DAI). Histopathological changes were observed by HE staining. In addition, the effect of LPS on Raw264.7 cells was also studied. In vivo studies showed that B4 could prevent DSS-induced colitis mice from losing weight, shortening colon length and improving pathological changes of colon tissues. B4 significantly reduced levels of inflammatory cytokines IL-1ß, IL-6, and TNF-α in colon tissues. In vitro experiments, B4 was almost nontoxic to Raw264.7 cells and could protect the Raw264.7 cells induced by LPS. In terms of mechanism, B4 significantly inhibited the activation of the TLR4 signaling pathway induced by DSS and down-regulate the expression of key proteins in the TLR4/NF-κB/MAPK signaling pathway in Raw264.7 cells induced by LPS. These findings suggest that the inhibition of B4 on ulcerative colitis may be through the TLR4/NF-κB/MAPK pathway. Therefore, B4 may be used as a potential drug for the treatment of ulcerative colitis.

Comprehensive Proteomic Profiling of Patients' Tears Identifies Potential Biomarkers for the Traumatic Vegetative State.

The vegetative state is a complex condition with unclear mechanisms and limited diagnostic, prognostic, and therapeutic methods. In this study, we aimed to explore the proteomic profile of tears from patients in a traumatic vegetative state and identify potential diagnostic markers using tears-a body fluid that can be collected non-invasively. Using iTRAQ quantitative proteomic technology, in the discovery phase, tear samples collected from 16 patients in a traumatic vegetative state and 16 normal individuals were analyzed. Among 1080 identified tear proteins, 57 were upregulated and 15 were downregulated in the patients compared to the controls. Bioinformatics analysis revealed that the differentially-expressed proteins were mainly involved in the wound response and immune response signaling pathways. Furthermore, we verified the levels of 7 differentially-expressed proteins in tears from 50 traumatic vegetative state patients and 50 normal controls (including the samples used in the discovery phase) using ELISA. The results showed that this 7-protein panel had a high discrimination ability for traumatic vegetative state (area under the curve = 0.999). In summary, the altered tear proteomic profile identified in this study provides a basis for potential tear protein markers for diagnosis and prognosis of the traumatic vegetative state and also provides novel insights into the mechanisms of traumatic vegetative state.

Comparative effects of hawthorn (Crataegus pinnatifida Bunge) pectin and pectin hydrolyzates on the cholesterol homeostasis of hamsters fed high-cholesterol diets.

This study aims to compare the effects of feeding haw pectin (HP), haw pectin hydrolyzates (HPH), and haw pectin pentasaccharide (HPPS) on the cholesterol metabolism of hypercholesterolemic hamsters induced by high-cholesterol diets. The animals were fed a standard diet (SD), high-cholesterol diet (HCD), or HCD plus HP, HPH, or HPPS at a dose of 300mg/kg body weight for 4weeks. Results showed that HPPS was more effective than HP and HPH in decreasing the body weight gain (by 38.2%), liver weight (by 16.4%), and plasma and hepatic total cholesterol (TC; by 23.6% and 27.3%, respectively) of hamsters. In addition, the bile acid levels in the feces were significantly higher by 39.8% and 132.8% in the HPH and HPPS groups than in the HCD group. Such changes were not noted in the HP group. However, the HP group had higher cholesterol excretion capacities than the HPH and HPPS groups by inhibiting cholesterol absorption in the diet, with a 21.7% increase in TC excretion and a 31.1% decrease in TC absorption. Thus, HPPS could be a promising anti-atherogenic dietary ingredient for the development of functional food to improve cholesterol metabolism.

[Effects of norcantharidin on lipopolysaccharide-induced hepatocyte injury in vitro].

OBJECTIVE: To study the effects of norcantharidin (NCTD) on lipopolysaccharide (LPS)-induced hepatocyte injury and the expression of TNF-α and IL-6 in vitro. METHODS: Hepatocytes were isolated from male Sprague-Dawley rats by collagenase perfusion. LPS at concentration of 40 mg/L was used to induce injury to the cultured cells, and NCTD (0.5, 1.0, 2.5 µg/mL) was added at the same time. After 24 h of incubation, the cell proliferation rates were detected by MTT. LDH, TNF-α and IL-6 were measured by appropriate reagent kits.NF-κB DNA binding activity was measured. RESULTS: 40 mg/L LPS caused a 27% growth inhibition in primary hepatocytes. LDH leakage was 20- fold higher in NCTD-treated hepatocytes than in normal ones. TNF-α and IL-6 expression significantly increased. In cells treated with NCTD at doses of 0.5, 1.0 and 2.5 µg/mL, LDH leakage, TNF-α and IL-6 expression, and NF-κB DNA binding activity were attenuated in a dose dependent manner. CONCLUSION: NCTD protects hepatocytes from injury induced by LPS; the protection is associated with suppression of the inflammatory cytokine TNF-α and IL-6.