Long-Term Triclocarban Exposure Induced Enterotoxicity by Triggering Intestinal AhR-Mediated Inflammation and Disrupting Microbial Community in Mice.

Exposure to triclocarban (TCC), a commonly used antibacterial agent, has been shown to induce significant intestine injuries and colonic inflammation in mice. However, the detailed mechanisms by which TCC exposure triggered enterotoxicity remain largely unclear. Herein, intestinal toxicity effects of long-term and chronic TCC exposure were investigated using a combination of histopathological assessments, metagenomics, targeted metabolomics, and biological assays. Mechanically, TCC exposure caused induction of intestinal aryl hydrocarbon receptor (AhR) and its transcriptional target cytochrome P4501A1 (Cyp1a1) leading to dysfunction of the gut barrier and disruption of the gut microbial community. A large number of lipopolysaccharides (LPS) are released from the gut lumen into blood circulation owing to the markedly increased permeability and gut leakage. Consequently, toll-like receptor-4 (TLR4) and NF-κB signaling pathways were activated by high levels of LPS. Simultaneously, classic macrophage phenotypes were switched by TCC, shown with marked upregulation of macrophage M1 and downregulation of macrophage M2 that was accompanied by striking upregulation of proinflammatory factors such as Il-1ß, Il-6, Il-17, and Tnf-α in the intestinal lamina propria. These findings provide new evidence for the TCC-induced enterotoxicity.

Identification and Genome Characterization of a Novel Virus within the Genus Totivirus from Chinese Bayberry (Myrica rubra).

Chinese bayberry (Myrica rubra) is an economically significant fruit tree native to eastern Asia and widely planted in south-central China. However, studies about the viruses infecting M. rubra remain largely lacking. In the present study, we employed the metatranscriptomic method to identify viruses in M. rubra leaves exhibiting yellowing and irregular margin symptoms collected in Fuzhou, a city located in China's Fujian province in the year 2022. As a consequence, a novel member of the genus Totivirus was identified and tentatively named "Myrica rubra associated totivirus 1" (MRaTV1). The genome sequencing of MRaTV1 was determined by overlapping reverse transcription polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE). The two deduced proteins encoded by MRaTV1 have the highest amino acid (aa) sequence identity to the coat protein (CP) and RNA-dependent RNA polymerase (RdRP) of Panax notoginseng virus A (PNVA), a member of the genus Totivirus within the family Totiviridae, at 49.7% and 61.7%, respectively. According to the results of the phylogenetic tree and the species demarcation criteria of the International Committee on Taxonomy of Viruses (ICTV) for the genus Totivirus, MRaTV1 is considered a new member of the genus Totivirus.

Biomanufacture of L-homoserine lactone building block: A strategy for preparing γ-substituted L-amino acids by modular reaction.

A strain high-performance of esterase producing bacteria was screened from soil, which could selectively hydrolyze D-homoserine lactone from its racemate to achieve the resolution of L- homoserine lactone with more than 99% e.e. in 48% yield. L-homoserine lactone building block was then converted to L-α-amino-γ-bromobutyronic acid chiral blocks, which reacted with various nucleophilic reagent modules could to be applied to prepare L-γ- substituted α-amino acids such as L-selenomethionine, L-methionine, L-glufosinate and L-selenocystine. Its advantages included high selectivity of biocatalytic resolution reactions, high optical purity of products, racemic recycle of D-substrates and modular reaction, which simplified the production process of these products and highlighted the power of biological manufacturing.

MRI advances in the imaging diagnosis of tuberculous meningitis: opportunities and innovations.

Tuberculous meningitis (TBM) is not only one of the most fatal forms of tuberculosis, but also a major public health concern worldwide, presenting grave clinical challenges due to its nonspecific symptoms and the urgent need for timely intervention. The severity and the rapid progression of TBM underscore the necessity of early and accurate diagnosis to prevent irreversible neurological deficits and reduce mortality rates. Traditional diagnostic methods, reliant primarily on clinical findings and cerebrospinal fluid analysis, often falter in delivering timely and conclusive results. Moreover, such methods struggle to distinguish TBM from other forms of neuroinfections, making it critical to seek advanced diagnostic solutions. Against this backdrop, magnetic resonance imaging (MRI) has emerged as an indispensable modality in diagnostics, owing to its unique advantages. This review provides an overview of the advancements in MRI technology, specifically emphasizing its crucial applications in the early detection and identification of complex pathological changes in TBM. The integration of artificial intelligence (AI) has further enhanced the transformative impact of MRI on TBM diagnostic imaging. When these cutting-edge technologies synergize with deep learning algorithms, they substantially improve diagnostic precision and efficiency. Currently, the field of TBM imaging diagnosis is undergoing a phase of technological amalgamation. The melding of MRI and AI technologies unquestionably signals new opportunities in this specialized area.

Dietary Isoquercetin Ameliorates Bone Loss via Restoration of the Gut Microbiota and Lipopolysaccharide-Triggered Inflammatory Status in Ovariectomy Mice.

Osteoporosis is one of the skeletal degenerative diseases accompanied by bone loss and microstructure disruption. Given that the gut-bone signaling axis highly contributes to bone health, here, dietary isoquercetin (IQ) was shown to effectively improve postmenopausal osteoporosis (PMO) in an ovariectomy (OVX) mouse model through the modulation of the gut-bone cross-talk. An in vivo study showed that OVX induced striking disruption of the microbial community, subsequently causing gut leakage and gut barrier dysfunction. As a result, lipopolysaccharide (LPS)-triggered inflammatory cytokines released from the intestine to bone marrow were determined to be associated with bone loss in OVX mice. Long-term dietary IQ effectively improved microbial community and gut barrier function in the OVX mice and thus markedly improved bone loss and host inflammatory status by repressing the NF-κB signaling pathway. An in vitro study further revealed that IQ treatments dose-dependently inhibited LPS-induced inflammation and partly promoted the proliferation and differentiation of osteoblasts. These results provide new evidence that dietary IQ has the potential for osteoporosis treatment.

Ovarian toxicity of e-cigarette liquids: Effects of components and high and low nicotine concentration e-cigarette liquid in vitro.

INTRODUCTION: Electronic cigarette use has become increasingly popular, with potential consequences for reproductive health. We aimed to investigate the effects of different components of e-liquid on the ovary and compare the impact of low nicotine concentration e-liquids (LN e-liquids) and high nicotine concentration e-liquids (HN e-liquids) on ovarian toxicity. METHODS: A total of 378 rat ovaries were divided into seven groups, including control (no intervention), nicotine (0.05 mg/mL), flavoring (0.25 µL/mL), propylene glycol (PG) (2.5 µL/mL), vegetable glycerin (VG) (2.0 µL/mL), LN e-liquid (0.05 mg nicotine + 0.25 µL flavoring + 2.5 µL PG + 2.0 µL VG + 0.25 µL distilled water/mL medium) and HN e-liquid groups (0.05 mg nicotine + 0.05 µL flavoring + 0.5 µL PG + 0.4 µL VG + 0.05 µL distilled water/mL medium). After three hours of in vitro culture, ovarian morphology, oxidation levels [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA)], and apoptosis levels [factor related apoptosis (Fas), Cyt-c, Caspase-9, Caspase-3] were analyzed. RESULTS: Our findings indicate that nicotine has limited impact on the ovary, while flavoring, PG, and VG all cause ovarian damage including morphological damage, disruption of oxidative balance and promotion of apoptosis, with VG having the most significant effect. Moreover, LN e-liquids may lead to more severe ovarian damage than HN e-liquids at an equal intake of total nicotine. CONCLUSIONS: Our study highlights that in e-liquid formula, nicotine has a limited effect on the ovaries, but flavoring, PG, and VG all cause damage to the ovaries, with VG the most damaging. At a consistent level of total nicotine intake, e-liquids with low nicotine concentrations cause more damage to the ovaries than those with high nicotine concentrations. These findings contribute to a better understanding of the impact of e-liquids on ovarian health and have important implications for public health policy.

Real-world treatment patterns and survival for locally advanced esophageal squamous cell carcinoma.

The "real world" treatment mode and clinical efficacy of locally advanced esophageal squamous cell carcinoma (LAESCC) are unclear. Meanwhile, the role of immunotherapy in the clinical practice is also puzzling. We conducted the research to investigate the statue of "real world" LAESCC. The clinical data of patients with locally advanced esophageal squamous cell carcinoma which met the criteria from January 2010 to December 2019 have been retrospectively analyzed, and the distribution of clinical treatment patterns has been analyzed. They cover such aspects as dfferences in survival time and further analysis of the differences in overall survival (OS) and progression-free survival (PFS) between patients who received immunotherapy and those who did not receive immunotherapy. What is more, Cox risk regression model has also been used to evaluate the risk factors affecting the prognosis of LAESCC. The cases of a total of 5328 newly diagnosed patients with esophageal cancer were collected, and a total of 363 patients were included in the study, with a median age of (46.2 ± 7.8) years old; 84 (23.1%) and 279 (76.9%) patients received 1L and ≥ 2L, respectively; Concurrent chemoradiotherapy (74.1%) and paclitaxel combined with platinum-based chemotherapy (14.3%) were the main first-line treatment options; fluorouracil combined with cisplatin regimen-based chemotherapy (63.8%) was the main treatment option for ≥ 2L, of which 69 patients (25.3%) received immunization treatment; OS of patients with 1 line of therapy and ≥ 2L were (22.4 ± 7.2) months and (38.7 ± 8.5) months, respectively, and the comparison between groups was statistically significant (P < .05); among 69 patients with ≥ 2L who received immunotherapy, PFS and The OS was (14.6 ± 6.9) and (45.3 ± 9.7) respectively, and the comparison between the groups was statistically significant (all P < .05). Cox multivariate analysis has shown that clinical stage, immunotherapy, concurrent chemoradiotherapy, and ≥ 2L are the main factors affecting OS. and immunotherapy, concurrent chemoradiotherapy, and ≥ 2L are independent factors affecting PFS. Concurrent chemoradiotherapy is currently one of the standard treatments for LAESCC, and most patients are still willing to receive second-line or above treatments. Adding immunotherapy to standard treatment modalities may further optimize clinical treatment modalities and improve patient outcomes.

Therapeutic effects of isoquercetin on ovariectomy-induced osteoporosis in mice.

Bone marrow mesenchymal stem cells (BMSCs) are non-hematopoietic multipotent stem cells capable of differentiating into mature cells. Isoquercetin, an extract from natural sources, has shown promise as a potential treatment for osteoporosis. To investigate the therapeutic effects of isoquercetin on osteoporosis, bone marrow mesenchymal stem cells (BMSCs) were cultured in vitro, and osteogenesis or adipogenesis was induced in the presence of isoquercetin for 14 days. We evaluated cell viability, osteogenic and adipogenic differentiation, as well as mRNA expression levels of Runx2, Alpl, and OCN in osteoblasts, and mRNA expression levels of Pparγ, Fabp4, and Cebpα in adipocytes. The results showed that isoquercetin dose-dependently increased cell viability and promoted osteogenic differentiation, as evidenced by Alizarin Red and alkaline phosphatase staining and mRNA expression levels of Runx2, Alpl, and OCN in osteoblasts (P < 0.05). In contrast, isoquercetin inhibited adipogenic differentiation and decreased the mRNA expression levels of Pparγ, Fabp4, and Cebpα in adipocytes (P < 0.05). In vivo, isoquercetin treatment increased bone quantity and density in an osteoporosis model mice group, as determined by µCT scanning and immunohistochemistry (P < 0.05). These findings suggest that isoquercetin may have therapeutic potential for osteoporosis by promoting the proliferation and differentiation of BMSCs towards osteoblasts while inhibiting adipogenic differentiation.

Triclocarban exposure aggravates dextran sulfate sodium-induced colitis by deteriorating the gut barrier function and microbial community in mice.

Triclocarban (TCC) is an antibacterial component widely used in personal care products with potential toxicity possessing public health issues. Unfortunately, enterotoxicity mechanisms of TCC exposure remain largely unknown. Using a combination of 16S rRNA gene sequencing, metabolomics, histopathological and biological examinations, this study systematically explored the deteriorating effects of TCC exposure on a dextran sulfate sodium (DSS)-induced colitis mouse model. We found that TCC exposure at different doses significantly aggravated colitis phenotypes including shortened colon length and altered colonic histopathology. Mechanically, TCC exposure further disrupted intestinal barrier function, manifested by significant downregulation of the number of goblet cells, mucus layer thickness and expression of junction proteins (MUC-2, ZO-1, E-cadherin and Occludin). The gut microbiota composition and its metabolites such as short-chain fatty acids (SCFAs) and tryptophan metabolites were also markedly altered in DSS-induced colitis mice. Consequently, TCC exposure markedly exacerbated colonic inflammatory status of DSS-treated mice by activating NF-κB pathway. These findings provided new evidence that TCC could be an environmental hazards for development of IBD or even colon cancer.

Prognostic nutritional index predicts the prognosis of patients with advanced esophageal cancer treated with immune checkpoint inhibitors: a retrospective cohort study.

Background: Immune checkpoint inhibitors (ICIs) play an important role in the treatment of esophageal cancer (EC). However, their efficacy is variable, and there are still no effective and convenient biomarkers to identify and assess their efficacy. In recent years, programmed cell death-ligand 1 (PD-L1) expression, tumor mutation burden (TMB) and other commonly used biomarkers still cannot meet clinical needs. PNI is easy to obtain and its predictive value for the prognosis of immunotherapy has been confirmed in many cancer species, but the relationship between PNI and the efficacy of immunotherapy for esophageal cancer is still unclear. Therefore, this study aims to explore the predictive value of PNI in advanced esophageal cancer treated with ICIs. Methods: The clinicopathological features of 78 patients with advanced EC who received immunotherapy in the 900th Hospital of the Joint Logistics Team from September 2018 to May 2022 were retrospectively analyzed. The laboratory test results within 10 days prior to the start of ICI treatment were recorded, including absolute lymphocyte count and albumin (ALB) level. Meanwhile, the effects of pre-treatment prognostic nutritional index (PNI) and body mass index (BMI) on the overall survival (OS) and progression-free survival (PFS) in patients with advanced EC were analyzed. Results: The median age of the enrolled patients was 58 years, and 38 patients (48.7%) received second-or-later-line therapy. The median progression-free survival (mPFS) and median overall survival (mOS) were 7.4 months and 13 months, respectively. The mPFS and mOS were 8.8 months and 15 months, respectively, in the high baseline PNI subgroup, which were significantly higher than those in the low baseline PNI subgroup (4.7 and 8.2 months, respectively; both P<0.05). Multivariate regression analysis showed that low baseline PNI was an independent predictor of poor PFS [hazard studio (HR) =0.35, 95% CI: 0.14-0.85, P=0.020) and poor OS (HR =0.41, 95% CI: 0.17-0.99, P=0.047) and treatment line was an independent predictor of PFS. Baseline BMI was not significantly associated with prognosis. Conclusions: PNI is a simple and effective biomarker for predicting the prognosis of immunotherapy in patients with advanced EC, although further prospective studies are warranted.

A Novel Prenylflavonoid Icariside I Ameliorates Estrogen Deficiency-Induced Osteoporosis via Simultaneous Regulation of Osteoblast and Osteoclast Differentiation.

Regulation of osteoblast-mediated bone formation and osteoclast-mediated bone resorption is crucial for bone health. Currently, most clinical drugs for osteoporosis treatment such as bisphosphonates are commonly used to inhibit bone resorption but unable to promote bone formation. In this study, we discovered for the first time that icariside I (GH01), a novel prenylflavonoid isolated from Epimedium, can effectively ameliorate estrogen deficiency-induced osteoporosis with enhancement of trabecular and cortical bone in an ovariectomy (OVX) mouse model. Mechanistically, our in vitro results showed that GH01 repressed osteoclast differentiation and resorption through inhibition of RANKL-induced TRAF6-MAPK-p38-NFATc1 cascade. Simultaneously, we also found that GH01 dose-dependently promoted osteoblast differentiation and formation by inhibiting adipogenesis and accelerating energy metabolism of osteoblasts. In addition, both in vitro and in vivo studies also suggested that GH01 is not only a non-toxic natural small molecule but also beneficial for restoration of liver injury in OVX mice. These results demonstrated that GH01 has great potential for osteoporosis treatment by simultaneous regulation of osteoblast and osteoclast differentiation.

Real-world experience with anti-programmed cell death protein 1 immunotherapy in patients with esophageal cancer: A retrospective single-center study.

The "real-world" data of programmed cell death protein 1 (PD-1) inhibitors in esophageal cancer (EPC) are still an unmet medical need, including the clinical efficacy and safety. Seventy-seven EPC data were studied retrospectively; the progression-free survival (PFS), risk factors (clinical stages larger than stage II, metastatic sites larger than 2, treatment lines larger than the first line, previous surgical treatment, combined positive score [CPS] expression, etc.), and the safety were analyzed. The median PFS for all patients was 7.2 months, clinical stage > stage II; the number of treatment lines > first line was significantly correlated with prognosis (all P < 0.05). Subgroup analysis showed that the median PFS of patients with clinical stage ≤ II was better; the results were the same for the patients with ≤2 metastatic sites, first-line PD-1 inhibitors, and not previously received radical surgery (all P < 0.05). Meanwhile, the incidence of adverse events (AEs) of varying degrees was 25.97% (20/77) in 20 patients and 6.49% (5/77) of grade 3/4 AEs. The highest AE was myelosuppression (15.58%), followed by liver function injury (7.79%). In addition, ≥2 lines of treatment and >2 metastatic sites predicted poor outcomes for patients with EPC who had failed first-line therapy or progressed with the combined immunotherapy and chemotherapy treatment strategy (all P < 0.05).

Characterization of triclosan-induced hepatotoxicity and triclocarban-triggered enterotoxicity in mice by multiple omics screening.

Triclosan (2,4,4'-trichloro-2'-hydroxydiphenyl ether, TCS) and triclocarban (3,4,4'-trichloro-carbanilide, TCC) are two antimicrobial agents commonly used for personal care products. Previous studies primarily focused on respective harmful effects of TCS and TCC. In terms of their structural similarities and differences, however, the structure-toxicity relationships on health effects of TCS and TCC exposure remain unclear. Herein, global 1H NMR-based metabolomics was employed to screen the changes of metabolic profiling in various biological matrices including liver, serum, urine, feces and intestine of mice exposed to TCS and TCC at chronic and acute dosages. Metagenomics was also applied to analyze the gut microbiota modulation by TCS and TCC exposure. Targeted MS-based metabolites quantification, histopathological examination and biological assays were subsequently conducted to supply confirmatory information on respective toxicity of TCS and TCC. We found that oral administration of TCS mainly induced significant liver injuries accompanied with inflammation and dysfunction, hepatic steatosis fatty acids and bile acids metabolism disorders; while TCC exposure caused marked intestine injuries leading to striking disruption of colonic morphology, inflammatory status and intestinal barrier integrity, intestinal bile acids metabolism and microbial community. These comparative results provide novel insights into structure-dependent mechanisms of TCS-induced hepatotoxicity and TCC-triggered enterotoxicity in mice.

Effect of e-cigarette refill liquid on follicular development and estrogen secretion in rats.

INTRODUCTION: Electronic cigarettes (e-cigarettes) have recently become popular as an alternative to conventional cigarettes. The aim of this study is to investigate the effects of e-cigarette refill liquid (e-liquid) on follicular development and estrogen secretion in rats and whether it is related to the Hippo signaling pathway, a pathway that can regulate follicle growth. METHODS: Ovaries from 21- and 35-day-old rats were divided into three groups: control (no intervention), 0.05 mg, and 0.5 mg (e-liquids containing 0.5 mg and 5 mg of nicotine/kg). The rates were cultured for three hours in vitro. At the end of culture, HE staining was performed to observe the follicle morphology and calculate the percentage of normal follicles, and the expression of Yes-associated protein (YAP, target factors of the Hippo signaling pathway) and CYP19 (aromatase, a key enzyme in estrogen synthesis) were observed by immunohistochemistry. Western blotting was performed to detect the expression levels of CYP19, YAP, phosphorylated YAP (PYAP), large tumor suppressor 2 (LATS2, factors upstream of YAP in the Hippo signaling pathway), and phosphorylated LATS2 (PLATS2). Estrogen concentrations were determined using ELISA. RESULTS: HE staining showed that the percentage of normal follicles decreased, and immunohistochemistry showed that the expression of CYP19 and YAP significantly decreased after e-liquid intervention. ELISA showed that the estrogen concentration in the ovaries decreased after e-liquid intervention. Western blot results indicated that CYP19, LATS2, and YAP expression, decreased after e-liquid intervention, but PLATS2 and PYAP expression increased. CONCLUSIONS: We found that the e-liquids may impair the development of rat ovarian follicles and reduce estrogen secretion through Hippo signaling pathway.

Inhibitional effects of metal Zn²âº on the reproduction of Aphis medicaginis and its predation by Harmonia axyridis.

BACKGROUND: Contamination, including metals, can disturb the reproductive processes of many organisms, including both prey and predatory insects. However, there is virtually no information on the effects of high level Zinc (Zn) pollution on aphids and ladybirds. The high concentrations of Zn²âº or Zn pollution inhibit reproduction in the phytophagous aphid, Aphis medicaginis, and the predatory ladybird Harmonia axyridis could provide important information. RESULTS: It was observed in this study that Zn concentrations in Vicia faba (broad bean) seeds and seedlings in all Zn²âº treatments were significantly higher than that in the control group, and increased with increasing Zn²âº concentrations in the solution. The rate of reproduction in A. medicaginis declined significantly (p<0.05) over time in the five groups fed on broad bean seedlings treated with different concentrations of Zn²âº solution compared with the control group. These results showed that higher concentrations of Zn²âº significantly inhibited the reproductive capacity of A. medicaginis. We also cloned and identified a gene encoding vitellogenin (Vg) from A. medicaginis, which has an important role in vitellogenesis, and therefore, reproduction was affected by exposure to Zn²âº. Expression of AmVg was reduced with increasing exposure to Zn²âº and also in the F1-F3 generations of aphids exposed to different Zn²âº concentrations. Predation by H. axyridis was also reduced in aphids exposed to high-levels of Zn²âº. Similarly, ovipositioning by H. axyridis was also reduced. CONCLUSIONS: Our results suggest that Zn²âº can significantly affect the reproductive capacity of both A. medicaginis and its predator H. axyridis, the former through effects on the expression of AmVg and the latter through avoidance of aphids containing high levels of Zn²âº.