Macrophage-Derived Cathepsin S Remodels the Extracellular Matrix to Promote Liver Fibrogenesis.

BACKGROUND & AIMS: Liver fibrosis is an intrinsic wound-healing response to chronic injury and the major cause of liver-related morbidity and mortality worldwide. However, no effective diagnostic or therapeutic strategies are available, owing to its poorly characterized molecular etiology. We aimed to elucidate the mechanisms underlying liver fibrogenesis. METHODS: We performed a quantitative proteomic analysis of clinical fibrotic liver samples to identify dysregulated proteins. Further analyses were performed on the sera of 164 patients with liver fibrosis. Two fibrosis mouse models and several biochemical experiments were used to elucidate liver fibrogenesis. RESULTS: We identified cathepsin S (CTSS) up-regulation as a central node for extracellular matrix remodeling in the human fibrotic liver by proteomic screening. Increased serum CTSS levels efficiently predicted liver fibrosis, even at an early stage. Secreted CTSS cleaved collagen 18A1 at its C-terminus, releasing endostatin peptide, which directly bound to and activated hepatic stellate cells via integrin α5ß1 signaling, whereas genetic ablation of Ctss remarkably suppressed liver fibrogenesis via endostatin reduction in vivo. Further studies identified macrophages as the main source of hepatic CTSS, and splenectomy effectively attenuated macrophage infiltration and CTSS expression in the fibrotic liver. Pharmacologic inhibition of CTSS ameliorated liver fibrosis progression in the mouse models. CONCLUSIONS: CTSS functions as a novel profibrotic factor by remodeling extracellular matrix proteins and may represent a promising target for the diagnosis and treatment of liver fibrosis.

Nomogram for assistant diagnosing acute suppurative cholangitis: a case-control study.

BACKGROUND: Acute suppurative cholangitis (ASC) lacks sensitive and specific preoperative diagnostic criteria. Some researchers suggest treating ASC as severe cholangitis. This study aimed to explore the relationship between the Tokyo Guidelines 2018 (TG18) grading system for acute cholangitis (AC) and the diagnosis of acute suppurative cholangitis (ASC), searching for independent risk factors of ASC and develop a nomogram to discriminate ASC from acute nonsuppurative cholangitis (ANSC) accurately. METHODS: After applying the inclusion and exclusion criteria, 401 patients with acute cholangitis (AC) were retrospectively analyzed at Nanjing First Hospital between January 2015 and June 2023. SPSS version 27.0 and R studio software were used to analyze data obtained from medical records. The results were validated in a prospective cohort of 82 AC patients diagnosed at Nanjing First Hospital between July 2023 and February 2024. RESULTS: Among the 401 patients, 102 had suppurative bile (the ASC group; AC grade I: 40 [39.2%], AC grade II: 27 [26.5%], AC grade III: 35 [34.3%]), whereas 299 did not have (the ANSC group; AC grade I: 157 [52.5%], AC grade II: 92 [30.8%], AC grade III: 50 [16.7%]). The specificity of ASC for diagnosing moderate-to-severe cholangitis is 79.7%. Multivariate logistic regression analysis identified concurrent cholecystitis, CRP, PCT, TBA, and bile duct diameter as independent risk factors for suppurative bile, and all of these factors were included in the nomogram. The calibration curve exhibited consistency between the nomogram and the actual observation, and the area under the curve was 0.875 (95% confidence interval: 0.835-0.915), sensitivity was 86.6%, and specificity was 75.5%. CONCLUSION: Suppurative bile is a specific indicator for diagnosing moderate-to-severe cholangitis. However, diagnosing ASC with AC grade II and AC grade III has the risk of missed diagnosis as the sensitivity is only 60.8%. To improve the diagnostic rate of ASC, this study identified concurrent cholecystitis, CRP, PCT, TBA, and preoperative bile duct diameter as independent risk factors for ASC, and a nomogram was developed to help physicians recognize patients with ASC.

Prevalence of eye and adnexal disorders among elderly inmates in Taiwan prisons.

BACKGROUND: Prisoner health is a topic of significant importance; however, it has received limited attention in epidemiological studies, likely because of challenges in obtaining relevant data. Specifically, research on ocular disorders among elderly prisoners is lacking. Thus, the aim of this study was to evaluate the prevalence of disorders of the eye and adnexa among elderly prisoners in Taiwan. METHODS: We investigated the presence of eye and adnexal disorders in elderly prisoners in Taiwan using data from the Taiwan National Health Insurance Research Database. The ocular disorders were identified using the appropriate disease codes in the International Classification of Diseases, 9th revision Clinical Modification (codes 360-379). In addition, the most common types of eye and adnexal disorders among the prisoners were identified. RESULTS: A total of 2215 elderly prisoners (age ≥ 65 years; 2073 men and 142 women) were examined. The prevalence of eye and adnexal disorders among the prisoners was 18.87%. The elderly female prisoners exhibited a higher prevalence of eye and adnexal disorders than the elderly male prisoners. The most common disorders were disorders of the conjunctiva, cataract, and disorders of the lacrimal system. CONCLUSIONS: A considerable proportion of elderly prisoners have disorders of the eye and adnexa. The overall quality of life of elderly prisoners can be improved by addressing their visual health, which contributes to the fulfillment of their basic human rights.

Conventional versus high-voltage, long-term pulse Radiofrequency of ganglion impar in perineal pain with advanced rectal cancer: a Randomized, double-blind controlled trial.

STUDY OBJECTIVE: Advanced rectal cancer is a common cause of perineal pain and research on the use of radiofrequency therapy for the treatment of this pain is limited. In the present study, we aimed to compare the effectiveness and safety of conventional radiofrequency (CRF) and high-voltage long-term pulsed radiofrequency (H-PRF) of radiofrequency therapy in the management of perineal pain in advanced rectal cancer. DESIGN: Randomized, Double-Blind Controlled Trial. SETTING: Sichuan Cancer Hospital & Institute and Yanjiang District People's Hospital in Sichuan, China. PARTICIPANTS: A total of 72 patients with advanced rectal cancer experiencing perineal pain who were accepted for radiofrequency treatment. INTERVENTIONS: Patients were assigned randomly (1:1) assigned to either the group CRF or H-PRF in a double-blind trial. MEASUREMENTS AND MAIN RESULTS: The primary focus was on assessing perineal pain using numeric rating scales (NRS) scores at various time points. Secondary outcomes included the duration of maintaining a sitting position, depression scores, sleep quality, consumption of Oral Morphine Equivalent and Pregabalin, and the incidence of perineal numbness. A total of 57 patients (28 patients in the group CRF and 29 patients in the group H-PRF) were investigated. At all observation time points postoperatively, both groups of patients exhibited significant reductions in pain, enhancements in depression, improvements in sleep quality, and increased duration of sitting compared to their baseline measurements (P<0.05). During the 3 months and 6 months follow-up period, the group CRF exhibited significant reduction in pain, improvement in depression, sleep quality, and increased the time of keeping a sitting position compared with the group H-PRF (P<0.05). The consumption of oral morphine equivalent and Pregabalin as well as the incidence of perineal numbness were not significantly different between groups (P > 0.05). CONCLUSION: Our results demonstrate that application of CRF and H-PRF in ganglion impar to reduce perineal pain and improve the quality of life of patients with advanced rectal cancer is safe and effective. However, the long-term effect of CRF is better compared with that of H-PRF. TRIAL REGISTRATION: https://www.chictr.org.cn/ (ChiCTR2200061800) on 02/07/2022. This study adheres to CONSORT guidelines.

Pre-pregnancy obesity is not associated with poor outcomes in fresh transfer in vitro fertilization cycles: a retrospective study.

PURPOSE: The impact of body mass index (BMI) on in vitro fertilization (IVF) has been well acknowledged; however, the reported conclusions are still incongruent. This study aimed to investigate the effect of BMI on IVF embryos and fresh transfer clinical outcomes. METHODS: This retrospective cohort analysis included patients who underwent IVF/ICSI treatment and fresh embryo transfer from 2014 to March 2022. Patients were divided into the underweight group: BMI < 18.5 kg/m2; normal group: 18.5 ≤ BMI < 24 kg/m2; overweight group: 24 ≤ BMI < 28 kg/m2; and obesity group: BMI ≥ 28 kg/m2. A generalized linear model was used to analyze the impact of BMI on each IVF outcome used as a continuous variable. RESULTS: A total of 3465 IVF/ICSI cycles in the embryo part; and 1698 fresh embryo transplanted cycles from the clinical part were included. Available embryos rate (61.59% vs. 57.32%, p = 0.007) and blastocyst development rates (77.98% vs. 66.27%, p < 0.001) were higher in the obesity group compared to the normal BMI group. Also, the fertilization rate of IVF cycles in the obesity group was significantly decreased vs. normal BMI group (normal: 62.95% vs. 66.63% p = 0.006; abnormal: 5.43% vs. 7.04%, p = 0.037), while there was no difference in ICSI cycles. The clinical outcomes of overweight and obesity groups were comparable to the normal group. The gestational age of the obesity group was lower compared to the normal group (38.08 ± 1.95 vs. 38.95 ± 1.55, p = 0.011). The adjusted OR (AOR) of BMI for the preterm birth rate of singletons was 1.134 [(95% CI 1.037-1.240), p = 0.006]. BMI was significantly associated with live birth rate after excluded the PCOS patients [AOR: 1.042 (95% CI 1.007-1.078), p = 0.018]. In young age (≤ 35 years), clinical pregnancy rate and live birth rate were positively correlated with BMI, AOR was 1.038 [95% CI (1.001-1.076), p = 0.045] and 1.037 [95% CI (1.002-1.074) p = 0.038] respectively. CONCLUSION: Being overweight and obese was not associated with poor IVF outcomes but could affect blastocyst formation. ICSI could help to avoid low fertilization in obese patients. Also, obesity was associated with increased rates of premature singleton births.

Effect of sequential versus single-step culture medium on IVF treatments, including embryo and clinical outcomes: a prospective randomized study.

PURPOSE: Sequential media G5 series (Vitrolife) and single-step medium Continuous Single Culture Complete (CSC-C) (Irvine Scientific) are two different culture media. We want to examine difference between culturing effects of the two media. METHODS: To compare the fertilization and early embryo development, a prospective randomized controlled trial with sibling oocytes in infertile patients, aged ≤ 45 years with ≥ 8 oocytes (226 cycles) was conducted. Each half of the retrieved oocytes from the same patient were randomly allocated to two culture media separately. The remaining fresh cycles were randomly assigned to two culture media during the same period (179 cycles). We compared the clinical outcomes based on the total fresh ET cycles in this periods, in which the transferred embryos were only from one culture medium. RESULTS: Embryo outcomes: 226 cycles, included 176 IVF and 50 ICSI cycles, were analyzed, which correspond to 3518 inseminated or micro-injected oocytes. CLINICAL OUTCOMES: 71 (CSC-C) and 71 (G5 series) fresh ET cycles were compared. There were no significant differences in clinical outcomes and general fertilization rate. However, the fertilization rate was superior in the CSC-C when compared with G5 in ICSI cycles (76.51% vs. 67.25%, P = 0.008). In addition, the compacted embryo development rate was significantly higher in CSC-C on day 3. The cycles that had compacted embryos on day 3 demonstrated better outcomes both in embryos as well as clinically. CONCLUSIONS: CSC-C had higher fertilization rates than G5 series in ICSI cycles. In addition, the compaction rates of day 3 embryos were significantly higher in CSC-C.

Tailoring of spatial coherence in a multimode fiber by selectively exciting groups of eigenmodes.

Control of the properties of speckle patterns produced by mutual interference of light waves is important for various applications of multimode optical fibers. It has been shown previously that a high signal-to-noise ratio in a multimode fiber can be achieved by preferential excitation of lower order spatial eigenmodes in optical fiber communication. Here we demonstrate that signal spatial coherence can be tailored by changing relative contributions of the lower and higher order multimode fiber eigenmodes for the research of speckle formation and spatial coherence. It is found that higher order spatial eigenmodes are more conducive to the final speckle formation. The minimum speckle contrast occurs in the lower order spatial eigenmodes dominated regime. This work paves the way for control and manipulation of the spatial coherence of light in a multimode fiber varying from partially coherent or totally incoherent light.

Enhancement of cardiac lymphangiogenesis by transplantation of CD34+VEGFR-3+ endothelial progenitor cells and sustained release of VEGF-C.

Impairment of cardiac lymphatic vessels leads to cardiac lymphedema. Recent studies have suggested that stimulation of lymphangiogenesis may reduce cardiac lymphedema. However, effects of lymphatic endothelial progenitor cells (LEPCs) on cardiac lymphangiogenesis are poorly understood. Therefore, this study investigated effectiveness of LEPC transplantation and VEGF-C release with self-assembling peptide (SAP) on cardiac lymphangiogenesis after myocardial infarction (MI). CD34+VEGFR-3+ EPCs isolated from rat bone marrow differentiated into lymphatic endothelial cells after VEGF-C induction. VEGF-C also stimulated the cells to incorporate into the lymphatic capillary-like structures. The functionalized SAP could adhere with the cells and released VEGF-C sustainedly. In the condition of hypoxia and serum deprivation or abdominal pouch assay, the SAP hydrogel protected the cells from apoptosis and necrosis. At 4 weeks after intramyocardial transplantation of the cells and VEGF-C loaded with SAP hydrogel in rat MI models, cardiac lymphangiogenesis was increased, cardiac edema and reverse remodeling were reduced, and cardiac function was improved significantly. Delivery with SAP hydrogel favored survival of the engrafted cells. VEGF-C released from the hydrogel promoted differentiation and incorporation of the cells as well as growth of pre-existed lymphatic vessels. Cardiac lymphangiogenesis was beneficial for elimination of the inflammatory cells in the infarcted myocardium. Moreover, angiogenesis and myocardial regeneration were enhanced after reduction of lymphedema. These results demonstrate that the combined delivery of LEPCs and VEGF-C with the functionalized SAP promotes cardiac lymphangiogenesis and repair of the infarcted myocardium effectively. This study represents a novel therapy for relieving myocardial edema in cardiovascular diseases.

Induced Abortion, Birth Control Methods, and Breast Cancer Risk: A Case-Control Study in China.

BACKGROUND: The association between induced abortion and birth control methods (including oral contraceptives and intrauterine devices) and breast cancer may vary among countries, due to the different usage and frequency of birth control methods and induced abortion among countries. A better understanding of this association may help in determining safer birth control methods for Chinese women. METHODS: A case-control study was conducted with a total of 794 cases and 805 controls. Standardized questionnaires were used to collect information on demographic characteristics, exposure to induced abortion, birth control methods, and other risk factors for breast cancer. Multivariate logistic regression was conducted to explore the association between birth control methods and breast cancer. RESULTS: Multivariate logistic regression analyses showed that having a history of medical abortions, ≥3 surgical abortions, or both medical and surgical abortions was associated with an increased risk of breast cancer in post-menopausal women (odds ratio [OR] 2.48; 95% confidence interval [CI], 1.14-5.40). Pre-menopausal women who had used intra-uterine devices (IUDs) for more than 20 years tended to have a lower breast cancer risk than other age-matched pre-menopausal women (OR 0.41; 95% CI, 0.25-0.68). Both pre-menopausal and post-menopausal women who had <20 years exposure to IUDs and those who had used two or more birth control methods (with the exception of women who used IUDs for more than 20 years) tended to have much higher breast cancer risk. CONCLUSION: The relationship between induced abortion and birth control methods and breast cancer was complex, though being exposed to induced abortion and two or more birth control methods in one's lifetime appeared to be risk factors for breast cancer in Chinese women.

Degradation of phenol by coal-based carbon membrane integrating sulfate radicals-based advanced oxidation processes.

Phenol, as a representative organic pollutant in aquatic environments, has posed a serious threat to humans and ecosystem. In this work, a novel integration system combined coal-based carbon membrane with sulfate radicals-based advanced oxidation processes (SR-AOPs) was designed for degradation of phenol. The integrated system achieved 100% removal efficiency under the optimal condition (peroxydisulfate dosage is 0.2 g/L, at alkaline condition with 2 mL/min flow velocity). The quenching experiments revealed that the efficient removal of phenol by the integrated system were attributed to the co-existence of radical and nonradical mechanisms. This study proposes a green and efficient technique for the removal of phenol.

BMI, reproductive factors, and breast cancer molecular subtypes: A case-control study and meta-analysis.

BACKGROUND: The effects of body mass index (BMI) and reproductive factors may vary among breast cancer molecular subtypes, evidence of which is lacking in East Asia. METHODS: From 2002 to 2010, 1256 breast cancer patients and 1416 healthy women were recruited. Anthropometric and reproductive factors were collected from medical charts. Breast cancer subtype was defined by ER, PR, and HER2 status. Polytomous logistic regression was used to evaluate associations between risk factors and breast cancer subtypes, with subgroup analysis by menopausal status. A meta-analysis of relevant published studies in East Asia was also performed. RESULTS: In our case-control study, late menarche was negatively associated with luminal tumor risk (Ptrend = 0.03). Higher BMI was associated with risk of both luminal and triple-negative tumors (Ptrend<0.001). Late age at first live birth was associated with a 1.41- to 2.08-fold increased risk of all subtypes, while late menopause increased risk by 2.62-5.56 times. Heterogeneity of these associations was not detected for different menopausal statuses. The meta-analysis revealed a positive dose-response relationship between BMI and risk of both luminal and ER-PR- subtypes (Ptrend<0.05). Early menarche and nulliparity increased luminal tumor risk by 1.39 and 1.26 times, respectively. Non-breastfeeding also increased the risk of all subtypes. CONCLUSIONS: For East Asian women, overweight, late menopause, and lack of breastfeeding appear to increase risk of both luminal and ER-PR- tumors. Early menarche and nulliparity mainly impacted luminal tumor risk. These associations were not impacted by menopausal status.

Ectoine and 5-hydroxyectoine accumulation in the halophile Virgibacillus halodenitrificans PDB-F2 in response to salt stress.

The moderately halophilic bacterium Virgibacillus halodenitrificans PDB-F2 copes with salinity by synthesizing or taking up compatible solutes. The main compatible solutes in this strain were ectoine and hydroxyectoine, as determined by (1)H nuclear magnetic resonance spectroscopy ((1)H-NMR). A high-performance liquid chromatography (HPLC) analysis showed that ectoine was the major solute that was synthesized in response to elevated salinity, while hydroxyectoine was a minor solute. However, the hydroxyectoine/ectoine ratio increased from 0.04 at 3 % NaCl to 0.45 at 15 % NaCl in the late exponential growth phase. A cluster of ectoine biosynthesis genes was identified, including three genes in the order of ectA, ectB, and ectC. The hydroxyectoine biosynthesis gene ectD was not part of the ectABC gene cluster. Reverse transcription-quantitative polymerase chain reactions (RT-qPCR) showed that the expression of the ect genes was salinity dependent. The expression of ectABC reached a maximum at 12 % NaCl, while ectD expression increased up to 15 % NaCl. Ectoine and hydroxyectoine production was growth phase dependent. The hydroxyectoine/ectoine ratio increased from 0.018 in the early exponential phase to 0.11 in the stationary phase at 5 % NaCl. Hydroxyectoine biosynthesis started much later than ectoine biosynthesis after osmotic shock, and the temporal expression of the ect genes differed under these conditions, with the ectABC genes being expressed first, followed by ectD gene. Increased culture salinity triggered ectoine or hydroxyectoine uptake when they were added to the medium. Hydroxyectoine was accumulated preferentially when both ectoine and hydroxyectoine were provided exogenously.

Functional Characterization of Soybean Glyma04g39610 as a Brassinosteroid Receptor Gene and Evolutionary Analysis of Soybean Brassinosteroid Receptors.

Brassinosteroids (BR) play important roles in plant growth and development. Although BR receptors have been intensively studied in Arabidopsis, the BR receptors in soybean remain largely unknown. Here, in addition to the known receptor gene Glyma06g15270 (GmBRI1a), we identified five putative BR receptor genes in the soybean genome: GmBRI1b, GmBRL1a, GmBRL1b, GmBRL2a, and GmBRL2b. Analysis of their expression patterns by quantitative real-time PCR showed that they are ubiquitously expressed in primary roots, lateral roots, stems, leaves, and hypocotyls. We used rapid amplification of cDNA ends (RACE) to clone GmBRI1b (Glyma04g39160), and found that the predicted amino acid sequence of GmBRI1b showed high similarity to those of AtBRI1 and pea PsBRI1. Structural modeling of the ectodomain also demonstrated similarities between the BR receptors of soybean and Arabidopsis. GFP-fusion experiments verified that GmBRI1b localizes to the cell membrane. We also explored GmBRI1b function in Arabidopsis through complementation experiments. Ectopic over-expression of GmBRI1b in Arabidopsis BR receptor loss-of-function mutant (bri1-5 bak1-1D) restored hypocotyl growth in etiolated seedlings; increased the growth of stems, leaves, and siliques in light; and rescued the developmental defects in leaves of the bri1-6 mutant, and complemented the responses of BR biosynthesis-related genes in the bri1-5 bak1-D mutant grown in light. Bioinformatics analysis demonstrated that the six BR receptor genes in soybean resulted from three gene duplication events during evolution. Phylogenetic analysis classified the BR receptors in dicots and monocots into three subclades. Estimation of the synonymous (Ks) and the nonsynonymous substitution rate (Ka) and selection pressure (Ka/Ks) revealed that the Ka/Ks of BR receptor genes from dicots and monocots were less than 1.0, indicating that BR receptor genes in plants experienced purifying selection during evolution.

Evolving renorrhaphy technique for retroperitoneal laparoscopic partial nephrectomy: single-surgeon series.

OBJECTIVES: To evaluate renorrhaphy techniques and to analyze surgical outcomes in retroperitoneal laparoscopic partial nephrectomy. METHODS: A retrospective study from January 2008 to December 2011 analyzed 526 patients with renal tumors in whom renorrhaphy was changed from one layer, interrupted, figure-of-eight (n = 228) suture to two layers, continuous, unknotted (n = 298) suture. All procedures were carried out by the same laparoscopic surgeon (XZ). Patient demographics, tumor characteristics, operative outcomes and perioperative renal function were compared. RESULTS: Median follow up for one layer, interrupted, figure-of-eight suture and two layers, continuous, unknotted suture was 31 and 28 months, respectively. The two layers, continuous, unknotted suture group had shorter warm ischemia time (P = 0.021), faster removal of Jackson-Pratt drains (P = 0.029) and shorter hospital stay (P = 0.037) than the one layer, interrupted, figure-of-eight suture group. There was a trend towards a better preservation of glomerular filtration rates in the two layers, continuous, unknotted suture group (P = 0.045). In a multivariable model, the two layers, continuous, unknotted suture technique was a statistically significant independent predictor of warm ischemia time (P = 0.01), hospital stay (P = 0.001) and estimated glomerular filtration rates (P = 0.043). CONCLUSIONS: Two layers, continuous, unknotted suture renorrhaphy allows better outcomes than one layer, interrupted, figure-of-eight suture renorrhaphy in retroperitoneal laparoscopic partial nephrectomy. A longer clinical follow-up evaluation is warranted.

Nicotine regulates abnormal macrophage polarization and trophoblast invasion associated with preterm labor via the α7nAChR/SIRT1 axis.

INTRODUCTION: Preterm birth (PTB) frequently results from the syndrome of preterm labor (PTL). PTL is linked to an atypical maternal inflammatory response, as well as intrauterine inflammation and/or infection. In this study, we explored the mechanisms involved in nicotine-mediated abnormal macrophage polarization and trophoblast invasion associated with PTL. METHODS: First, THP-1-M0 macrophages were generated by treating the human monocytic leukemia cell line (THP-1) with phorbol 12-myristate 13-acetate for a duration of 24 h. Afterward, nicotine treatment was administered, followed by coculturing with the HTR-8/SVneo trophoblast cell line (HTR-8) at a ratio of 1:1. Next, we transfected sh-α7nAChR and treated THP-1-M0 macrophages and HTR-8 cells with nicotine. In addition, we transfected THP-1-M0 macrophages with sh-NC or sh-SIRT1 or subjected them to 4 nM nicotinamide adenine dinucleotide (NAD) metabolic inhibitor FK866 treatment. Moreover, HTR-8 cells were treated with nicotine, after which THP-1-M0 macrophages were cocultured with HTR-8 cells. Finally, we constructed an in vivo RU486-induced PTL rat model to verify the effect of nicotine and the mechanisms involved. RESULTS: We found that nicotine affected polarization and α7nAChR expression in HTR-8 cocultured THP-1-M0 macrophages. Knocking down α7nAChR blocked the effect of nicotine on the proliferation and invasion of HTR-8 cells. Furthermore, nicotine activated the α7nAChR/SIRT1 axis to regulate THP-1-M0 macrophage polarization through the cholinergic anti-inflammatory pathway. Additionally, NAD metabolism mediated the role of the α7nAChR/SIRT1 axis in nicotine-induced polarization of HTR-8 cocultured THP-1-M0 macrophages. In vivo experiments demonstrated that nicotine alleviated inflammation in PTL rats, which involved the α7nAChR/SIRT1 axis. CONCLUSION: Nicotine regulated abnormal macrophage polarization and trophoblast invasion associated with PTL via the α7nAChR/SIRT1 axis.

Growth differentiation factor 11 alleviates oxidative stress-induced senescence of endothelial progenitor cells via activating autophagy.

BACKGROUND: Stem cell transplantation has been regarded as a promising therapeutic strategy for myocardial regeneration after myocardial infarction (MI). However, the survival and differentiation of the transplanted stem cells in the hostile ischaemic and inflammatory microenvironment are poor. Recent studies have focused on enhancing the survival and differentiation of the stem cells, while strategies to suppress the senescence of the transplanted stem cells is unknown. Therefore, we investigated the effect of growth differentiation factor 11 (GDF11) on attenuating oxidative stress-induced senescence in the engrafted endothelial progenitor cells (EPCs). METHODS: Rat models of oxidative stress were established by hydrogen peroxide conditioning. Oxidative stress-induced senescence was assessed through senescence-associated ß-galactosidase expression and lipofuscin accumulation. The effects of GDF11 treatment on senescence and autophagy of EPCs were evaluated 345, while improvement of myocardial regeneration, neovascularization and cardiac function were examined following transplantation of the self-assembling peptide (SAP) loaded EPCs and GDF11 in the rat MI models. RESULTS: Following hydrogen peroxide conditioning, the level of ROS in EPCs decreased significantly upon treatment with GDF11. This resulted in reduction in the senescent cells and lipofuscin particles, as well as the damaged mitochondria and rough endoplasmic reticula. Concurrently, there was a significant increase in LC3-II expression, LC3-positive puncta and the presence of autophagic ultrastructures were increased significantly. The formulated SAP effectively adhered to EPCs and sustained the release of GDF11. Transplantation of SAP-loaded EPCs and GDF11 into the ischaemic abdominal pouch or myocardium resulted in a decreased number of the senescent EPCs. At four weeks after transplantation into the myocardium, neovascularization and myocardial regeneration were enhanced, reverse myocardial remodeling was attenuated, and cardiac function was improved effectively. CONCLUSIONS: This study provides novel evidence suggesting that oxidative stress could induce senescence of the transplanted EPCs in the ischemic myocardium. GDF11 demonstrates the ability to mitigate oxidative stress-induced senescence in the transplanted EPCs within the myocardium by activating autophagy.

Alkaloids from Zanthoxylum nitidum and their anti-proliferative activity against A549 cells by regulating the EGFR/AKT/mTOR pathway.

Zanthoxylum nitidum is frequently used as a traditional Chinese medicine and food supplement. Our previous study revealed that its constituent compounds were able to inhibit cancer cell proliferation. In our continuous exploration of bioactive compounds in Z. nitidum, we isolated ten alkaloids (1-10), including one new natural compound (1), and nine known alkaloids (2-10), from an ethanolic extract of the whole plant. The chemical structures were elucidated based on a combination of comprehensive NMR and HRESIMS analyses. Compounds 5, 8 and 10 exhibited significant antiproliferative effects against A549 cancer cell lines. We further elucidated the underlying molecular mechanisms of the antiproliferative activity of compound 8 in A549 human lung cancer cells. Compound 8 was found to induce cell cycle arrest in the G0/G1 phase via p53 activation and CDK4/6 suppression. Compound 8 also effectively inhibited cell migration through the modulation of the epithelial-mesenchymal transition (EMT), as indicated by the expression of biomarkers, such as N-cadherin downregulation and E-cadherin upregulation. Compound 8 significantly suppressed the activation of the EGFR/AKT/mTOR signalling pathway in A549 cells. These results indicate that alkaloid 8 from Z. nitidum has potential to be a lead antiproliferative compound in cancer cells.

Increased Long-Term Risk of Dementia in Patients With Carbon Monoxide Poisoning: A Systematic Review and Meta-Analysis of Cohort Studies.

OBJECTIVE: To assess whether carbon monoxide (CO) poisoning increases the incidence of dementia. METHODS: We searched the Cochrane Library, PubMed, and EMBASE from inception to 14 August 2022. Two authors independently selected studies, assessed the quality of included studies, and extracted data. Any disagreement was resolved by discussion with a third author. Only cohort study with an enough follow-up period was included for systematic reviews and meta-analysis. RESULTS: Thirty-three full texts were initially searched, but only three studies met our inclusion criteria, and they were comprised of 134,563 participants who were initially free of dementia. The follow-up period ranged from 9 to 12 years. We found that CO poisoning increased the risk of dementia incidence (adjusted hazard ratio 2.61, 95% confidence interval 1.56 to 4.36, p=0.0003). Subgroup analysis showed that the increased dementia risk was significant in males but not in females, and the highest risk was in young age group, followed by in middle age group, but not in the old one. CONCLUSION: Overall the evidence from prospective cohort studies supported a link between CO exposure and an increased dementia risk, although all the included studies were limited to Taiwanese population.

Evaluation of AJCC staging system and proposal of a novel stage grouping system in retroperitoneal liposarcoma: the Fudan Zhongshan experience.

Background: Overall survival (OS) varies significantly among individuals with heterogeneous retroperitoneal liposarcoma (RPLS), even among those with the same clinical stage. Improved staging of RPLS is a critical unmet need, given the disappointing results of external validations of the 8th American Joint Committee on Cancer (AJCC) TNM staging system. Methods: The cohort study included 220 consecutive patients who underwent surgical resection for primary RPLS at the largest sarcoma centre of Fudan University in China from September 2009 to August 2021, combined with 277 adult patients with RPLS in the SEER database from 1975 to 2020. Data analysis was performed from December 2021 to December 2022. Patients were retrospectively restaged according to the 8th and 7th editions of the TNM staging system as well as the new TNM (nTNM) staging system. The primary endpoint was overall survival (OS). Comparative analysis of postoperative survival was performed using the Kaplan-Meier method, and differences between subgroups were tested using the log-rank test. The OS prediction nomogram was generated based on baseline variables and tumour characteristics. Harrell's consistency index (C-index), area under the curve (AUC) of receiver operating characteristic curves (ROC), and calibration curves were used to evaluate the performance of the nomogram. Results: A total of 497 patients were enrolled in the study, including 282 (56.7%) male patients. The median follow-up was 51 months (interquartile range, IQR, 23-83), and the OS rates at 1, 3, and 5 years were 87.9%, 75.3%, and 64.9%, respectively. According to the staging distribution of the AJCC 7th edition, 6 patients were stage IA (1.2%), 189 patients were stage IB (38%), 12 patients were stage IIA (2.4%), 150 patients were stage IIB (30.1%), 131 patients were stage III (26.3%), and 9 patients were stage IV (1.8%). With the 8th edition staging, this distribution changed: 6 patients (1.2%) were stage IA, 189 patients (38%) were stage IB, 12 patients (2.4%) were stage II, 24 patients (4.8%) were stage IIIA, 257 patients (51.7%) were stage IIIB, and 9 patients (1.8%) were stage IV. 182 patients (36.6%) were reclassified according to the nTNM staging system with the new T stage classification. The C-index and log-rank score improved after implementation of nTNM implementation. The nTNM system was associated with improved identification of high-risk patients compared with the AJCC 7th and 8th TNM. The FNCLCC stage proved to be highly prognostic with significant intergroup differences in OS. The calibration curve shows a high degree of agreement between the actual OS rate and the nomogram estimated OS rate. Conclusion: Compared with 8th AJCC TNM, 7th AJCC TNM staging system showed a more homogeneous staging distribution and a slight improvement in the prognostic accuracy of RPLS. The revised T-stage and nTNM systems showed better risk stratification performance. The FNCLCC stage was found to have high prognostic value, further emphasising histological grade is the least negligible prognostic factor in predicting patient survival. The constructed nomogram model enables individualized prognostic analysis and helps to develop risk-adapted therapy for RPLS patients.

Diabetes mellitus is a risk factor for incident chronic kidney disease: A nationwide cohort study.

Objective: Diabetes mellitus and chronic kidney disease are multifactorial conditions with multiple etiologies that share similar pathophysiologies. This nationwide cohort study examined the impact of diabetes mellitus on the follow-up development of chronic kidney disease. Methods: By retrieving the Longitudinal Health Insurance Database 2005, 5121 patients with diabetes mellitus were included in this study and 5121 patients without diabetes mellitus, who were matched according to sex, age, and Charlson comorbidity index made up the control group. The adjusted hazard ratios for chronic kidney disease were calculated using Cox proportional hazards regression analysis. Kaplan-Meier analysis was used to estimate the cumulative incidence of chronic kidney disease rate in the diabetes mellitus and control groups. Results: After adjusting for sex, age, and Charlson comorbidity index score, the diabetes mellitus group had a 1.380 times higher (95% CI: 1.277-1.492) risk of developing chronic kidney disease than the control group. Further stratified analysis showed that patients with diabetes mellitus had a significantly higher risk of developing chronic kidney disease regardless of their sex, age, and Charlson comorbidity index score, compared to those without diabetes mellitus. Conclusions: There is a possibility that diabetes mellitus serves as an independent risk factor for chronic kidney disease development. Early screening and monitoring of diabetes mellitus appear to be of great importance in the prevention of chronic kidney disease.