Peroxiredoxin I and II as novel therapeutic molecular targets in cervical cancer treatment through regulation of endoplasmic reticulum stress induced by bleomycin.

Cervical cancer, significantly affecting women worldwide, often involves treatment with bleomycin, an anticancer agent targeting breast, ovarian, and cervical cancers by generating reactive oxygen species (ROS) to induce cancer cell death. The Peroxiredoxin (PRDX) family, particularly PRDX1 and 2, plays a vital role in maintaining cellular balance by scavenging ROS, thus mitigating the damaging effects of bleomycin-induced mitochondrial and cellular oxidative stress. This process reduces endoplasmic reticulum (ER) stress and prevents cell apoptosis. However, reducing PRDX1 and 2 levels reverses their protective effect, increasing apoptosis. This research highlights the importance of PRDX1 and 2 in cervical cancer treatments with bleomycin, showing their potential to enhance treatment efficacy by managing ROS and ER stress and suggesting a therapeutic strategy for improving outcomes in cervical cancer treatment.

Hispidin Increases Cell Apoptosis and Ferroptosis in Prostate Cancer Cells Through Phosphatidylinositol-3-Kinase and Mitogen-activated Protein Kinase Signaling Pathway.

BACKGROUND/AIM: Chemotherapy is mainly used in the clinical treatment of prostate cancer. Different anticancer mechanisms can induce cell death in various cancers. Reactive oxygen species (ROS) play crucial roles in cell proliferation, differentiation, apoptosis, and signal transduction. It is widely accepted that ROS accumulation is closely related to chemical drug-induced cancer cell death. MATERIALS AND METHODS: We utilized the MTT assay to detect changes in cell proliferation. Additionally, colony formation and wound healing assay were conducted to investigate the effect of hispidin on cell colony formation and migration ability. Fluorescence microscopy was used to detect intracellular and mitochondrial ROS levels, while western blot was used for detection of cell apoptosis. RESULTS: Hispidin treatment significantly decreased viability of PC3 and DU145 cancer cells but exhibited no cytotoxicity in WPMY-1 cells. Furthermore, hispidin treatment inhibited cell migration and colony formation and triggered cellular and mitochondrial ROS accumulation, leading to mitochondrial dysfunction and mitochondrion-dependent apoptosis. Moreover, hispidin treatment induced ferroptosis in PC3 cells. Scavenging of ROS with N-acetyl cysteine significantly inhibited hispidin-induced apoptosis by altering the expression of apoptosis-related proteins, such as cleaved caspase-3, 9, Bax, and Bcl2. Furthermore, hispidin treatment dramatically up-regulated MAPK (involving p38, ERK, and JNK proteins) and NF-kB signaling pathways while down-regulating AKT phosphorylation. Hispidin treatment also inhibited ferroptosis signaling pathways (involving P53, Nrf-2, and HO-1 proteins) in PC3 cells. In addition, inhibiting these signaling pathways via treatment with specific inhibitors significantly reversed hispidin-induced apoptosis, cellular ROS levels, mitochondrial dysfunction, and ferroptosis. CONCLUSION: Hispidin may represent a potential candidate for treating prostate cancer.

Efficient Catalyst-Free One-Pot Synthesis of Polysaccharide-Polypeptide Hydrogels in Aqueous Solution.

The preparation of polysaccharide-peptide hydrogels usually involves multiple synthetic steps, thus reducing the effectiveness and practicality of these approaches. Inspired by recent discoveries in aqueous N-carboxyanhydride (NCA) ring-opening polymerization (ROP) and ring-opening polymerization-induced nanogelation, we present an aqueous one-pot strategy to prepare polysaccharide-polypeptide hydrogels. In this study, water-soluble polysaccharide carboxymethyl chitosan is used as the macromolecular initiator to prepare polysaccharide-polypeptide copolymers through the aqueous ROP of NCA. The catalyst-free approach afforded hydrogels with properties that could be controlled by adjusting the type and amount of NCA used, with the elastic modulus ranging from 50 Pa to 18000 Pa. The hydrogen bond-cross-linked hydrogel exhibited self-healing and injectable properties. Morphology characterization revealed that micelles were formed in the early stage of reaction, suggesting that the polymerization follows an aqueous ring-opening polymerization-induced self-assembly (ROPISA) mechanism and that aggregation of micelles during the reaction caused the gelation. Moreover, the hydrogels displayed high swelling ratios (>95% water content), and hemolysis and cytotoxicity experiments demonstrated that the hydrogels had excellent biocompatibility, indicating their potential in medical applications.

Establishment of Human Pituitary Neuroendocrine Tumor Derived Organoid and Its Pilot Application for Drug Screening.

CONTEXT: Precision medicine for pituitary neuroendocrine tumors (PitNETs) is limited by the lack of reliable research models. OBJECTIVE: To generate patient-derived organoids (PDOs), which could serve as a platform for personalized drug screening for PitNET patients. DESIGN: From July 2019 to May 2022, a total of 32 human PitNET specimens were collected for the establishment of organoids with an optimized culture protocol. SETTING: This study was conducted at Sun Yat-Sen University Cancer Center. PATIENTS: PitNET patients who were pathologically confirmed were enrolled in this study. INTERVENTIONS: Histological staining and whole-exome sequencing were utilized to confirm the pathologic and genomic features of PDOs. A drug response assay on PDOs was also performed. MAIN OUTCOME MEASURES: PDOs retained key genetic and morphological features of their parental tumors. RESULTS: PDOs were successfully established from various types of PitNET samples with an overall success rate of 87.5%. Clinical nonfunctioning PitNETs-derived organoids (22/23, 95.7%) showed a higher likelihood of successful generation compared to those from functioning PitNETs (6/9, 66.7%). Preservation of cellular structure, subtype-specific neuroendocrine profiles, mutational features, and tumor microenvironment heterogeneity from parental tumors was observed. A distinctive response profile in drug tests was observed among the organoids from patients with different subtypes of PitNETs. With the validation of key characteristics from parental tumors in histological, genomic, and microenvironment heterogeneity consistency assays, we demonstrated the predictive value of the PDOs in testing individual drugs. CONCLUSION: The established PDOs, retaining typical features of parental tumors, indicate a translational significance in innovating personalized treatment for refractory PitNETs.

Intestinal carcinogenicity screening of environmental pollutants using organoid-based cell transformation assay.

The high incidence of colorectal cancer (CRC) is closely associated with environmental pollutant exposure. To identify potential intestinal carcinogens, we developed a cell transformation assay (CTA) using mouse adult stem cell-derived intestinal organoids (mASC-IOs) and assessed the transformation potential on 14 representative chemicals, including Cd, iPb, Cr-VI, iAs-III, Zn, Cu, PFOS, BPA, MEHP, AOM, DMH, MNNG, aspirin, and metformin. We optimized the experimental protocol based on cytotoxicity, amplification, and colony formation of chemical-treated mASC-IOs. In addition, we assessed the accuracy of in vitro study and the human tumor relevance through characterizing interdependence between cell-cell and cell-matrix adhesions, tumorigenicity, pathological feature of subcutaneous tumors, and CRC-related molecular signatures. Remarkably, the results of cell transformation in 14 chemicals showed a strong concordance with epidemiological findings (8/10) and in vivo mouse studies (12/14). In addition, we found that the increase in anchorage-independent growth was positively correlated with the tumorigenicity of tested chemicals. Through analyzing the dose-response relationship of anchorage-independent growth by benchmark dose (BMD) modeling, the potent intestinal carcinogens were identified, with their carcinogenic potency ranked from high to low as AOM, Cd, MEHP, Cr-VI, iAs-III, and DMH. Importantly, the activity of chemical-transformed mASC-IOs was associated with the degree of cellular differentiation of subcutaneous tumors, altered transcription of oncogenic genes, and activated pathways related to CRC development, including Apc, Trp53, Kras, Pik3ca, Smad4 genes, as well as WNT and BMP signaling pathways. Taken together, we successfully developed a mASC-IO-based CTA, which might serve as a potential alternative for intestinal carcinogenicity screening of chemicals.

Deletion of myeloid-specific Orai1 calcium channel does not affect pancreatic tissue damage in experimental acute pancreatitis.

BACKGROUND: Store-operated Ca2+ entry (SOCE) mediated by ORAI1 channel plays a crucial role in acute pancreatitis (AP). Macrophage is an important regulator in amplifying pancreatic tissue damage, but little is known about the role of ORAI1 in macrophages. In this study, we examined the effects of macrophage-specific ORAI1 on pancreatic tissue damage in AP. METHOD: Myeloid-specific Orai1 deficient mice was generated by crossing a LysM-Cre mouse line with Orai1f/f mice. Bone marrow-derived macrophages (BMDMs) were isolated, cultured, and stimulated to induce M1 or M2 macrophage polarization. Intracellular Ca2+ signals were measured by time-lapse confocal microscope imaging, with a Ca2+ indicator (Fluo 4). Experimental AP was induced by hourly intraperitoneal injections of caerulein or retrograde biliopancreatic infusion of sodium taurocholate. Pancreatic tissue damage was assessed by histopathological scoring and immunostaining. Sepsis was induced by intraperitoneal injection of lipopolysaccharide; organ damage and serum pro-inflammatory cytokines were measured. RESULT: Myeloid-specific Orai1 deletion exhibited minimal effect on SOCE in M0 macrophages and promoted M2 macrophage polarization ex vivo. Myeloid-specific Orai1 deletion did not affect pancreatic tissue damage, nor neutrophil or macrophage infiltration in two models of AP. Similarly, myeloid-specific Orai1 deletion did not influence overall survival rate in a model of sepsis, nor lung, kidney, and liver damage; while serum pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1ß were higher in Orai1ΔLysM mice, but were largely reduced in mice with Orai1 inhibitor. CONCLUSION: Our data suggest that ORAI1 may not be a predominant SOCE channel in macrophages and play a limited role in mediating pancreatic tissue damage in AP.

An integrated approach to prioritizing ecological restoration of abandoned mine lands based on cost-benefit analysis.

How to increase the usable land area by adhering to environmentally friendly ecological restoration of mines with limited funds is a challenge that many cities are currently facing. Cost-benefit analysis (CBA) can provide efficient and effective restoration decisions for abandoned mine land (AML) ecological restoration with limited financial resources. Thus, this study proposes an integrated approach for coupling ecological benefits and restoration costs, including hotspots/coldspots analysis based on five ecosystem services (ESs), landscape connectivity analysis based on graph theory model, hidden costs, and project implementation costs to prioritize AML restoration. The study was conducted on 54 abandoned mine lands (AMLs) in Chaoyang city, the ecological security barrier of China's northern sand prevention belt (NSPB). The comprehensive analysis prioritized the restoration of AMLs into four levels, of which 9 mines were in priority I, where restoration was recommended as a priority, and 22 mines were in priority II, where restoration could be carried out within the affordability of funds. In addition, our model indicates areas with high ecological benefits, in which the ecological source area (7423.66 km2) and the ecosystem service hotspots area (2028.44 km2) are mostly distributed in the southwestern part of Chaoyang city, the two mountain ranges of Songling mountain and Nuruerhu mountain. This study provides scientific spatial guidance to ensure that the AMLs realizes effective restoration and management.

A centrosome-related gene signature for predicting the overall survival of uveal melanoma.

Background: Centrosome aberration (CA) plays a vital role in tumorigenesis and metastasis under pathophysiological conditions. The existence of CA was first reported in uveal melanoma (UVM) recently. Our study aimed to investigate the association of centrosome-related genes with UVM prognosis. Methods: The Cancer Genome Atlas (TCGA)-UVM and Gene Expression Omnibus series (GSE) 22138 were included in the study. Least absolute shrinkage and selection operator (LASSO) and Cox regression were combined to screen out key genes and construct a centrosome-related gene signature. Kaplan-Meier (KM) survival curves were used to evaluate the survival differences between the 2 groups. Gene enrichment, immune infiltration, and mutation profile were used to explore the underlying mechanism. Results: A centrosome-related gene signature was constructed: Risk score =-3.27071 × MAP6 - 5.03735 × CCDC40 - 2.68459 × PRKCD + 1.826349 × IGFBP4 + 11.66582 × RAB6C - 4.86899 × CCND3. The survival possibilities of the two groups were significantly different. The high-risk group showed cancer progression, inflammation, and immune restriction characteristics when compared with the low-risk group. BAP1 mutation was associated with high risk and SF3B1 mutation was associated with low risk according to the signature. Conclusions: Our study first investigated the role of centrosome-related genes in UVM overall survival (OS). We then constructed a centrosome-related gene signature for UVM, which provides new insights into the role of CA in UVM and identifies novel centrosome-related biomarkers.

Effects of Dietary Selenium Yeast Supplementation on Lactation Performance, Antioxidant Status, and Immune Responses in Lactating Donkeys.

Donkey milk is a traditional medicinal food with various biological activities. However, its production is very low, and lactating donkeys often experience oxidative stress, leading to a further decline in milk yield. In this study, we supplemented the diets of lactating donkeys with yeast selenium (SY) to investigate its effects on lactation performance, antioxidant status, and immune responses, and we expected to determine the optimum additive level of SY in the diet. For this study, 28 healthy lactating Dezhou donkeys with days in milk (DIM, 39.93 ± 7.02 d), estimated milk yield (EMY, 3.60 ± 0.84 kg/d), and parity (2.82 ± 0.48) were selected and randomly divided into 4 groups of 7 donkeys in each: Group SY-0 (control), Group SY-0.15, Group SY-0.3, and Group SY-0.5, with selenium supplementation of 0, 0.15, 0.3, and 0.5 mg of Se/kg DM (in form of SY) to the basal diet, respectively. The results showed a dose-dependent increase in milk yield, milk component yield, milk protein production efficiency, milk production efficiency, the activities of glutathione peroxidases (GSH-Px), catalase (CAT), and total antioxidant capacity (T-AOC), as well as the content of serum interleukin-10 (IL-10), white blood cells (WBC), lymphocytes (LYM), red blood cells (RBC), hematocrit, plasma selenium, and milk selenium. Conversely, it presented a dose-dependent decrease in the activity of nitric oxide synthase (iNOS) and the contents of malondialdehyde (MDA), reactive oxygen species (ROS), nitric oxide (NO), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and interferon-γ (IFN-γ). In conclusion, the results confirmed that dietary supplementation with SY can improve lactation performance, antioxidant status, and immune responses in lactating donkeys, and the recommended dose of SY was 0.3 mg/kg.

A 49-bp deletion of PmAP2L results in a double flower phenotype in Prunus mume.

The double flower is an important trait with substantial ornamental value. While mutations in PETALOSA TOE-type or AG (AGAMOUS) genes play a crucial role in enhancing petal number in ornamental plants, the complete mechanism underlying the formation of double flowers remains to be fully elucidated. Through the application of bulked segregant analysis (BSA), we identified a novel gene, APETALA2-like (PmAP2L), characterized by a 49-bp deletion in double-flowered Prunus mume. ß-Glucuronidase (GUS) staining and luciferase reporter assays confirmed that the 49-bp deletion in PmAP2L reduced its binding with Pmu-miRNA172a. Phylogenetic analysis and microsynteny analysis suggested that PmAP2L was not a PETALOSA TOE-type gene, and it might be a new gene controlling the formation of double flower in P. mume. Subsequently, overexpression of PmAP2L-D in tobacco led to a significant rise in the number of stamens and the conversion of stamens to petals. Furthermore, silencing of the homologue of RC5G0530900 in rose significantly reduced the number of petals. Using transient gene expression in P. mume flower buds, we determined the functional differences between PmAP2L-D and PmAP2-S in controlling flower development. Meanwhile, DNA-affinity purification sequencing (DAP-seq), yeast hybrid assays and luciferase reporter assays indicated that PmAP2L negatively regulated the floral organ identity genes by forming a repressor complex with PmTPL and PmHDA6/19. Overall, these findings indicate that the variation in PmAP2L is associated with differences in the regulation of genes responsible for floral organ identity, providing new insights into the double-flower trait and double-flower breeding in plants.

Effects of dietary energy level on antioxidant capability, immune function and rectal microbiota in late gestation donkeys.

Introduction: This study investigated the effects of dietary energy level on the antioxidant capability, immune function, and rectal microbiota in donkey jennets during the last 60 days of gestation. Methods: Fifteen pregnant DeZhou donkeys with age of 6.0 ± 0.1 years, body weight of 292 ± 33 kg, parity of 2.7 ± 0.1 parities and similar expected date of confinement (74 ± 4 days) were randomly allocated to three groups and feed three diets: high energy (10.92 MJ/kg, H), medium energy (10.49 MJ/kg, M), and low energy (9.94 MJ/kg, L). Results and Discussion: The serum activity of catalase (CAT), total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC) in group M was significantly higher, whereas the concentrations of malondialdehyde (MDA), interleukin 1 (IL-1), IL-2, and IL-6 were lower than those recorded for groups H and L (p ≤ 0.05). The dietary energy level significantly affected rectal microbial community structure in the jennet donkeys 35 days and 7 days before the parturition (p ≤ 0.05). The abundances of norank_f_norank_o_Coriobacteriales genus was significantly higher (p ≤ 0.05) in group H, and the abundances of norank_f_norank_o_Mollicutes_RF39 and the Candidatus_Saccharimonas were higher in group L (p ≤ 0.05). The abundance of Fibrobacter in group M was significantly increased (p ≤ 0.05). The abundance of norank_f_norank_o_Coriobacteriales was positively correlated with average daily gain (ADG) and tumor necrosis factor-α (TNF-α) concentrations (p ≤ 0.05). The abundance of norank_f_norank_o_Mollicutes_RF39 was positively correlated with IL-2 and IL-6 concentrations. The abundance of Candidatus_Saccharimonas was positively correlated with CAT, T-SOD and GSH-Px activities (p ≤ 0.05). The abundance of Fibrobacter was positively correlated with CAT and T-SOD activities (p ≤ 0.05), but negatively correlated with IL-2 concentration (p ≤ 0.05). In conclusion, an appropriate dietary with an energy content of 10.49 MJ/kg for jennet donkeys during late gestation increased the prenatal antioxidant capacity, reduced inflammatory cytokines, and promoted fetal growth, and these changes were related to diet-induced changes in rectal microbiota compositions.

Microbiomes in pancreatic cancer can be an accomplice or a weapon.

Recently, several investigations have linked the microbiome to pancreatic cancer progression. It is critical to reveal the role of different microbiomes in the occurrence, development, and treatment of pancreatic cancer. The current review summarizes the various microbiota types in pancreatic cancer while updating and supplementing the mechanisms of the representative gut, pancreatic, and oral microbiota, and their metabolites during its pathogenesis and therapeutic intervention. Several novel strategies have been introduced based on the tumor-associated microbiome to optimize the early diagnosis and prognosis of pancreatic cancer. The pros and cons involving different microbiomes in treating pancreatic cancer are discussed. The microbiome-related clinical trials for pancreatic cancer theranostics are outlined. This convergence of cutting-edge knowledge will provide feasible ideas for developing innovative therapies against pancreatic cancer.

Exploring the molecular mechanism of berberine for treating diabetic nephropathy based on network pharmacology.

BACKGROUND AND PURPOSE: Diabetic nephropathy (DN) is a prevalent complication of diabetes mellitus characterized by hyperglycemia, hyperlipidemia, albuminuria and edema. Increasing evidence indicated that berberine (BBR) could alleviate the occurrence and development of DN. However, the molecular mechanism underlying the beneficial effects of BBR in the treatment of DN remains unclear. METHODS: The online public databases were chosen to screen the relevant targets of BBR and DN and the screened overlapped targets were analyzed by GO enrichment analysis, KEGG enrichment analysis and protein-protein interaction network analysis. The interaction between BBR and the key proteinwas verified by molecular docking and cellularthermalshiftassay. Additionally, the expression of key proteins and related indicators of DN were verified by immunofluorescence and western blot in vitro and in vivo. RESULTS: We successfully identified 92 overlapped targets of BBR and DN based on network pharmacology. Notably, VEGFR2 was identified to be the main target of BBR. Meanwhile, we found that BBR exhibited a high binding affinity to VEGFR2 protein, as confirmed by molecular docking and CETSA. This binding led to interfering with the PI3K/AKT/mTOR signaling pathway. In addition, we found that BBR could inhibit the abnormal proliferation of mesangial cells and reduce the expression of downstream pathway protein in vitro and in vivo. Finally, BBR was found to effectively lower the level of blood glucose and improve kidney function in mice, highlighting its potential as a therapeutic agent for the treatment of DN. CONCLUSION: Berberine interfered the PI3K/AKT/mTOR signaling pathway via targeting VEGFR2 protein, further led to the inhibition of abnormal proliferation of mesangial cells and ultimately resulted in improved renal function.

PD-1 inhibitors combined with paclitaxel and cisplatin in first-line treatment of esophageal squamous cell carcinoma (ESCC): a network meta-analysis.

BACKGROUND: The combinations of PD-1 inhibitors with paclitaxel/cisplatinum (PD-1 + TP) and fluoropyrimidine/cisplatinum (PD-1 + FP) both have been shown to improve overall survival (OS) and progression-free survival (PFS) in patients with previously untreated, advanced esophageal squamous cell carcinoma (ESCC). However, there is no consensus on which chemotherapy regimen combined with PD-1 has better efficacy. To deal with this important issue in the first-line treatment of patients with ESCC, a network meta-analysis (NMA) was performed. METHODS: Data were collected from eligible studies searched in Medline, Web of Science, PubMed, the Cochrane Library and Embase. The pooled hazard ratio (HR) for the OS, and PFS, odds ratio (OR) for the objective response rate (ORR) and ≥ 3 grade treatment-related adverse events (≥ 3TRAEs) were estimated to evaluate the efficacy of PD-1 inhibitors combined with TP or FP. RESULTS: Five RCTs and one retrospective study involving 3685 patients and evaluating four treatments were included in this NMA. Compared to other treatments, PD-1 + TP was better. For the PFS, the HRs for PD-1 + TP compared to PD-1 + FP, TP and FP were 0.59 (0.44, 0.80), 0.56 (0.51, 0.61) and 0.45 (0.37, 0.56) respectively. For the OS, PD-1 + TP was also a better treatment compared to other treatments. The HRs were 0.74 (0.56, 0.96), 0.64 (0.57, 0.71), 0.53 (0.43, 0.67) respectively. For the ORR, there was no significant difference between PD-1 + TP and PD-1 + FP, and the ORs were 1.2 (0.69, 2.11). Compare with TP and FP, PD-1 + TP had an obvious advantage, ORs were 2.5 (2.04, 3.04) and 2.95 (1.91, 4.63). For ≥ 3TRAEs, PD-1 + TP compared to other treatments, ORs were 1.34 (0.74, 2.46) and 1.13 (0.92, 1.38) and 2.23 (1.35, 3.69). CONCLUSION: PD-1 + TP significantly improved both PFS and OS compared to PD-1 + FP. Taking into account both efficacy and safety, PD-1 + TP may be a superior first-line treatment option for ESCC.

Intestinal Microbiota Community and Blood Fatty Acid Profiles of Albas Cashmere Goats Fed with Flaxseed Oil and Whole Flaxseed.

The present study investigated the effects of flaxseed oil or flaxseed grain on the intestinal microbiota and blood fatty acid profiles of Albas cashmere goats. Sixty kid goats were allocated to three treatments and fed for 90 days with a control treatment, comprising a basal diet (CON, total-mixed ration with flaxseed meal), or experimental treatments, comprising a basal diet with added flaxseed oil (LNO) and a basal diet with added heated flaxseed grain (HLS). On day 90, two goats were randomly selected from each pen (eight goats per treatment) for euthanizing; then, five of the eight goats were randomly selected, and we collected their intestinal (duodenum, jejunum, ileum, cecum, and colon) digesta for analysis of the bacteria community. The results indicated that Firmicutes are the most predominant phylum in different segments of the intestinal digesta. Compared with the CON group, the relative abundance of duodenal Firmicutes, jejunal Saccharibacteria, and Verrucomicrobia significantly decreased in the LNO and HLS groups (p < 0.05), but there was no significant difference between the LNO and HLS groups. Compared with the CON and HLS groups, the RA of duodenal and jejunal Proteobacteria remarkably increased in the LNO group (p < 0.05), and there was no significant difference between the CON and HLS groups. Compared with the CON and LNO groups, the RA of Actinobacteria remarkably increased in the small intestine of the HLS group (p < 0.05), but there was no significant difference between the CON and LNO groups in the duodenum and ileum. The results of linear discriminant analysis (LDA) effect size (LEfSe) analysis showed that the HLS group was characterized by a higher RA of the [Eubacterium]_coprostanoligenes_group in the small intestine and the LNO group was represented by a higher RA of the Lachnospiraceae_NK3A20_group in the cecum and colon, while the CON group was represented by a higher RA of Solobacterium, Pseudoramibacter, and Acetitomaculum in the small intestine and a higher RA of norank_o__Bradymonadales, the Prevotellaceae_Ga6A1_group, and Ruminiclostridium_1 in the cecum and colon. In conclusion, the addition of flaxseed oil and grain rich in c18:3n3 to the diet could reduce the microbial diversity of the small intestinal segments and the microbial diversity and richness of the cecum and colon in Albas cashmere goats. And flaxseed grain is more efficient than flaxseed oil in protecting intestinal health and promoting the absorption of c18:3n3.

A multi-center, single-blinded, randomized, parallel-group, superiority study to compare the efficacy of manipulation under anesthesia versus intra-articular steroid injection in the treatment of patients with frozen shoulder and a diagnosis of rotator cuff injury or tear by MRI: study protocol for a randomized controlled trial.

BACKGROUND: Frozen shoulder (FS) is a common condition that can cause severe pain and limited range of motion in the shoulder joint. While intra-articular steroid injection has been shown to be an effective treatment for FS, manipulation under anesthesia (MUA) is an alternative treatment that has gained popularity in recent years. However, there is a lack of evidence regarding the effectiveness of MUA on FS patients with concomitant rotator cuff injury or tear. Though a few studies have shown that MUA is not associated with rotator cuff tears, and will not exacerbate the injury, more high-quality studies with bigger sample sizes are needed. Therefore, the aim of this multi-center, single-blinded, randomized, parallel-group, superiority study is to compare the efficacy of MUA versus intra-articular steroid injection in the treatment of FS patients with a diagnosis of rotator cuff injury or tear by MRI. METHODS: A parallel, single-blinded, multi-center randomized controlled trial of 320 patients will be conducted at three hospitals of China. Eligible patients with frozen shoulder and rotator cuff injury or tear diagnosed by MRI will be randomly assigned to, in equal proportions, the manipulation under anesthesia group and the intra-articular steroid injection group via a central randomization system, undergoing a corresponding operation on day one and a sequent physical exercise for 14 days. The primary outcome is the comprehensive efficacy evaluation (total effective rate) and the change of Constant-Murley Score. Outcome assessors and data analysts will be blinded, and participants will be asked not to reveal their allocation to assessors. DISCUSSION: This study aims to explore the superiority of manipulation under anesthesia in reducing pain and improving shoulder function in frozen shoulder patients accompanied with rotator cuff injury. To provide a scientific basis for the dissemination and application of manipulation under anesthesia, and a better knowledge for the role of MUA in the treatment of frozen shoulder accompanied with rotator cuff injury. TRIAL REGISTRATION: Chictr.org.cn ChiCTR2200067122 . Registered on 27 December 2022. ChiCTR is a primary registry of the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) network and includes all items from the WHO Trial Registration data set in Trial registration.

Nanomedicine-mediated regulated cell death in cancer immunotherapy.

Immunotherapy has attracted widespread attention in cancer treatment and has achieved considerable success in the clinical treatment of some tumors, but it has a low response rate in most tumors. To achieve sufficient activation of the immune response, significant efforts using nanotechnology have been made to enhance cancer immune response. In recent years, the induction of various regulated cell death (RCD) has emerged as a potential antitumor immuno-strategy, including processes related to apoptosis, autophagy, necroptosis, pyroptosis, ferroptosis, and cuproptosis. In particular, damage-associated molecular patterns (DAMPs) released from the damaged membrane of dying cells act as in situ adjuvants to trigger antigen-specific immune responses by the exposure of an increased antigenicity. Thus, RCD-based immunotherapy offers a new approach for enhancing cancer treatment efficacy. Furthermore, incorporation with multimodal auxiliary therapies in cell death-based immunotherapy can trigger stronger immune responses, resulting in more efficient therapeutic outcome. This review discusses different RCD modalities and summarizes recent nanotechnology-mediated RCDs in cancer immunotherapy.

Application of Surface Landmarks Combined with Image-Guided Sinus Location in the Retrosigmoid Approach and Their Clinic-Image Relationship Analysis.

Objectives During craniotomy for cerebellopontine angle (CPA) lesions, the exact exposure of the margin of the venous sinuses complex remains an essential but risky part of the procedure. Here, we revealed the exact position of the asterion and sinus complex by combining preoperative image information and intraoperative cranial landmarks, and analyzed their clinic-image relationship. Methods Ninety-four patients who underwent removal of vestibular schwannoma (VS) through retrosigmoid craniotomies were enrolled in the series. To determine the exact location of the sigmoid sinus and the transverse sinus and sigmoid sinus junction (TSSJ), we used preoperative images, such as computed tomography (CT) and/or magnetic resonance imaging (MRI) combined with intraoperative anatomical landmarks. The distance between the asterion and the sigmoid sinus was measured using MRI T1 sequences with gadolinium and/or the CT bone window. Results In 94 cases of retrosigmoid craniotomies, the asterion lay an average of 12.71 mm on the posterior to the body surface projection to the TSSJ. Intraoperative cranial surface landmarks were used in combination with preoperative image information to identify the distance from the asterion to the sigmoid sinus at the transverse sinus level, allowing for an appropriate initial burr hole (the margin of the TSSJ). Conclusion By combining intraoperative anatomical landmarks and preoperative image information, the margin of the TSSJ, in particular, the inferior margin of the transverse sinus, can be well and thoroughly identified in the retrosigmoid approach.

Exploring the Mechanism of Hepatotoxicity Induced by Dictamnus dasycarpus Based on Network Pharmacology, Molecular Docking and Experimental Pharmacology.

The root bark of Dictamnus dasycarpus Turcz is a traditional Chinese medicine, Dictamni Cortex (DC), which is mainly used in the clinical treatment of skin inflammation, eczema, rubella, rheumatism, and gynecological inflammation. Unexpectedly, there are some cases of liver injury after the administration of DC. However, the mechanism of hepatotoxicity remains ambiguous. The aim of this study was to explore the mechanism and substance bases of DC hepatotoxicity based on network pharmacology and molecular docking, verified through pharmacological experiments. Partial prototype components and metabolites in vivo of quinoline alkaloids from DC were selected as candidate compounds, whose targets were collected from databases. Network pharmacology was applied to study the potential hepatotoxic mechanism after correlating the targets of candidate compounds with the targets of hepatotoxicity. Molecular docking was simulated to uncover the molecular mechanism. Furthermore, the hepatotoxicity of the extract and its constituents from DC was evaluated in vivo and in vitro. We constructed the "potential toxic components-toxic target-toxic pathway" network. Our results showed that the targets of DC included CYP1A2 and GSR, participating in heterologous steroid metabolism, REDOX metabolism, drug metabolism, heterocyclic metabolic processes, the synthesis of steroid hormone, cytochrome P450 metabolism, chemical carcinogens and bile secretion pathways. In vitro and in vivo experiments displayed that DC could result in a decrease in GSH-Px and oxidative stress, simultaneously inhibiting the expression of CYP1A2 and inducing hepatotoxicity. These results further indicated the mechanism of hepatotoxicity induced by Dictamnus dasycarpus, providing a basic theory to explore and prevent hepatotoxicity in the clinical usage of Dictamnus dasycarpus.

PRDX1 negatively regulates bleomycin-induced pulmonary fibrosis via inhibiting the epithelial-mesenchymal transition and lung fibroblast proliferation in vitro and in vivo.

BACKGROUND: Pulmonary fibrosis is a major category of end-stage changes in lung diseases, characterized by lung epithelial cell damage, proliferation of fibroblasts, and accumulation of extracellular matrix. Peroxiredoxin 1 (PRDX1), a member of the peroxiredoxin protein family, participates in the regulation of the levels of reactive oxygen species in cells and various other physiological activities, as well as the occurrence and development of diseases by functioning as a chaperonin. METHODS: Experimental methods including MTT assay, morphological observation of fibrosis, wound healing assay, fluorescence microscopy, flow cytometry, ELISA, western blot, transcriptome sequencing, and histopathological analysis were used in this study. RESULTS: PRDX1 knockdown increased ROS levels in lung epithelial cells and promoted epithelial-mesenchymal transition (EMT) through the PI3K/Akt and JNK/Smad signalling pathways. PRDX1 knockout significantly increased TGF-ß secretion, ROS production, and cell migration in primary lung fibroblasts. PRDX1 deficiency also increased cell proliferation, cell cycle circulation, and fibrosis progression through the PI3K/Akt and JNK/Smad signalling pathways. BLM treatment induced more severe pulmonary fibrosis in PRDX1-knockout mice, mainly through the PI3K/Akt and JNK/Smad signalling pathways. CONCLUSIONS: Our findings strongly suggest that PRDX1 is a key molecule in BLM-induced lung fibrosis progression and acts through modulating EMT and lung fibroblast proliferation; therefore, it may be a therapeutic target for the treatment of BLM-induced lung fibrosis.