Abelmoschi Corolla polysaccharides and related metabolite ameliorates colitis via modulating gut microbiota and regulating the FXR/STAT3 signaling pathway.

Ulcerative Colitis (UC) is a chronic inflammatory disease of the intestinal tract with unknown definitive etiology. Polysaccharides are among the most important active components of Abelmoschi Corolla, exhibitings various pharmacological activities such as antioxidation and immunomodulation. However, no studies have yet reported the application of Abelmoschi Corolla Polysaccharides (ACP) in treating UC. This study aims to highlight the therapeutic efficacy of ACP in UC and reveal the underlying mechanism. The potential therapeutic effect is initially verified using a dextran sodium sulfate (DSS)-induced colitis model. 16S rRNA sequencing is performed using feces samples and untargeted metabolomics using serum samples to further reveal that ACP reprograms the dysbiosis triggered by UC progression, increases the abundance of Bacteroides spp., Blautia spp., and Parabacteroides spp. at the genus level and enriches the serum concentration of 7-ketodeoxycholic acid (7-KDA). Furthermore, using the FXR-/- mouse model, it is revealed that Farnesoid X Receptor (FXR) is a key target for ACP and the metabolite 7-KDA to block STAT3 phosphorylation by repairing the intestinal barrier to attenuate UC. Taken together, this work highlights the therapeutic potential of ACP against UC, mainly exerting its effects via modulating gut microbiota and regulating the FXR/STAT3 signaling pathway.

Primary breast angiosarcoma: A case report.

RATIONALE: Primary breast angiosarcoma is a rare tumor, accounting for only 0.05% of all malignant breast tumors. The primary breast angiosarcoma typically presents with nonspecific clinical manifestations, which can easily lead to misdiagnosis. Potential factors contributing to misdiagnosis include skin changes that may be erroneously attributed to breast trauma-induced bruising and breast swelling that may be mistaken for inflammatory diseases or other benign tumors. PATIENT CONCERNS: A 19-year-old female was admitted to the hospital due to repeated lump formation in the left breast for 9 months after left breast trauma. DIAGNOSES: The diagnosis of primary breast angiosarcoma was confirmed on hematoma biopsy. INTERVENTIONS: Due to the patient's condition, no special treatment was given postoperatively. After then, there was a recurrence in the chest wall, and the patient received 2 cycles of chemotherapy, resulting in a reduction in the size and lightening of the recurrent chest wall mass. When chemotherapy intolerance happened, the patient chose to discontinue treatment. OUTCOMES: After an 18-month follow-up, the recurrent chest wall mass increased and the patient died from bleeding. LESSONS: Primary breast angiosarcoma has a low incidence but high malignancy, with a high recurrence and metastasis rate, leading to a poor prognosis. The adjuvant chemotherapy, radiotherapy, targeted therapy, and other treatments should be considered to reduce the local recurrence rate and prolong patient survival.

Age-related changes in the bacterial composition of healthy female facial skin in Beijing area.

OBJECTIVE: Exploring the effects of age on microbial community structure and understanding the effects of chronological ageing as well as sun exposure on microbial community diversity. METHOD: The microbial characteristics of the facial skin of 98 adult women aged 18-70 years were studied using 16S rRNA gene sequencing, and differences based on age and reported sun exposure were assessed. RESULTS: The cheek skin's bacterial diversity and richness increased with age. The relative abundance of Cutibacterium decreased with age, while the relative abundance of Corynebacterium, Anaerococcus, Paracoccus, Micrococcus, Kocuria, Kytococcus, and Chryseobacterium increased. In addition, an increase in Micrococcus and a decrease in Cutibacterium were observed in volunteers with more than 2 h of daily sun exposure compared to volunteers with <2 h of daily sun exposure. Under low-sunlight conditions, Cutibacterium was more prevalent in the youth group, and Corynebacterium, Anaerococcus, and Kytococcus were more prevalent in the older group. CONCLUSION: The diversity and composition of the bacterial community on the cheeks are affected by age and extrinsic factors (sun exposure) may also play a role in this.

OBJECTIF: Étudier les effets de l'âge sur la structure de la communauté microbienne et comprendre les effets du vieillissement chronologique ainsi que de l'exposition au soleil sur la diversité de la communauté microbienne. MÉTHODE: Les caractéristiques microbiennes de la peau du visage de 98 femmes adultes âgées de 18 à 70 ans ont été étudiées à l'aide du séquençage génétique de l'ARNr 16S, et les différences basées sur l'âge et l'exposition au soleil rapportée ont été évaluées. RÉSULTAT: La diversité et la richesse bactériennes de la peau des joues ont augmenté avec l'âge. L'abondance relative de Cutibacterium a diminué avec l'âge, tandis que l'abondance relative de Corynebacterium, Anaerococcus, Paracoccus, Micrococcus, Kocuria, Kytococcus et Chryseobacterium a augmenté. De plus, une augmentation de Micrococcus et une diminution de Cutibacterium ont été observées chez des volontaires ayant été exposés au soleil pendant plus de 2 heures par jour par rapport à des volontaires ayant été exposés au soleil pendant moins de 2 heures par jour. Dans des conditions de faible luminosité, Cutibacterium était plus prévalent dans le bras des personnes jeunes, et Corynebacterium, Anaerococcus et Kytococcus étaient plus prévalents dans le bras des personnes plus âgées. CONCLUSION: La diversité et la composition de la communauté bactérienne sur les joues sont affectées par l'âge et des facteurs extrinsèques (exposition au soleil) peuvent également y jouer un rôle.

Biotic interactions and environmental modifications determine symbiotic microbial diversity and stability.

Taking amphibians as island models, we examined the effects of interspecific interaction on the diversity and stability of microbial ecological. As skin area increased, the diversity and stability of skin microbes decreased, but the strength of negative interactions increased significantly. In contrast, as gut area increased, the diversity and stability of gut microbes increased, but the strength of interactions remained constant. These results indicate that microbial interactions are affected by habitat properties. When living in fluctuating environments without strong filtering, microorganisms can enhance their negative interactions with other taxa by changing the pH of their surroundings. In contrast, the pH of the gut is relatively stable, and colonized microorganisms cannot alter the gut pH and inhibit other colonizers. This study demonstrates that in the field of microbiology, diversity and stability are predominantly influenced by the intensity of interspecies interactions. The findings in this study deepen our understanding of microbial diversity and stability and provide a mechanistic link between species interactions, biodiversity, and stability in microbial ecosystems.

Esrra regulates Rplp1-mediated translation of lysosome proteins suppressed in metabolic dysfunction-associated steatohepatitis and reversed by alternate day fasting.

OBJECTIVE: Currently, little is known about the mechanism(s) regulating global and specific protein translation during metabolic dysfunction-associated steatohepatitis (MASH; previously known as non-alcoholic steatohepatitis, NASH). METHODS: Unbiased label-free quantitative proteome, puromycin-labelling and polysome profiling were used to understand protein translation activity in vitro and in vivo. RESULTS: We observed a global decrease in protein translation during lipotoxicity in human primary hepatocytes, mouse hepatic AML12 cells, and livers from a dietary mouse model of MASH. Interestingly, proteomic analysis showed that Rplp1, which regulates ribosome and translation pathways, was one of the most downregulated proteins. Moreover, decreased Esrra expression and binding to the Rplp1 promoter, diminished Rplp1 gene expression during lipotoxicity. This, in turn, reduced global protein translation and Esrra/Rplp1-dependent translation of lysosome (Lamp2, Ctsd) and autophagy (sqstm1, Map1lc3b) proteins. Of note, Esrra did not increase its binding to these gene promoters or their gene transcription, confirming its regulation of their translation during lipotoxicity. Notably, hepatic Esrra-Rplp1-dependent translation of lysosomal and autophagy proteins also was impaired in MASH patients and liver-specific Esrra knockout mice. Remarkably, alternate day fasting induced Esrra-Rplp1-dependent expression of lysosomal proteins, restored autophagy, and reduced lipotoxicity, inflammation, and fibrosis in hepatic cell culture and in vivo models of MASH. CONCLUSIONS: Esrra regulation of Rplp1-mediated translation of lysosome/autolysosome proteins was downregulated during MASH. Alternate day fasting activated this novel pathway and improved MASH, suggesting that Esrra and Rplp1 may serve as therapeutic targets for MASH. Our findings also provided the first example of a nuclear hormone receptor, Esrra, to not only regulate transcription but also protein translation, via induction of Rplp1.

Value of multiparametric magnetic resonance imaging in distinguishing sinonasal lymphoma from sinonasal carcinoma: a case control study.

BACKGROUND: The study aimed to evaluate the diagnostic efficacy of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) parameters in distinguishing sinonasal lymphoma from sinonasal carcinoma. METHODS: Forty-two participants with histologically confirmed sinonasal lymphomas and fifty-two cases of sinonasal carcinoma underwent imaging with a 3.0T MRI scanner. DCE-MRI and DWI were conducted, and various parameters including type of time-intensity curve(TIC), time to peak, peak enhancement, peak contrast enhancement, washout rate, apparent diffusion coefficient (ADC), and relative ADC were measured. Binary logistic regression and receiver operating characteristic (ROC) curve analysis were employed to assess the diagnostic capability of individual and combined indices for differentiating nasal sinus lymphoma from nasal sinus carcinoma. RESULTS: Sinonasal lymphoma predominantly exhibited type II TIC(n = 20), whereas sinonasal carcinoma predominantly exhibited type III TIC(n = 23). Significant differences were observed in all parameters except washout ratio (p < 0.05), and ADC value emerged as the most reliable diagnostic tool in single parameter. Combined DCE-MRI parameters demonstrated superior diagnostic efficacy compared to individual parameters, with the highest efficiency (area under curve = 0.945) achieved when combining all parameters of DCE-MRI and DWI. CONCLUSIONS: Multiparametric evaluation involving contrast-enhanced dynamic MRI and DWI holds considerable diagnostic value in distinguishing sinonasal lymphoma from sinonasal carcinoma.

A multifunctional nanoplatform for precision-guided therapeutic intervention in bacterial infection.

Skin wound infection has become a global clinical problem in recent years. Curcumin (Cur) and polylysine (PLL) are natural products with strong antibacterial properties. However, the poor water solubility and low stability of Cur and the cationic toxicity of PLL limit their application. In this study, we synthesized a macromolecular hyaluronic acid (HA)-curcumin drug (HC) via esterification. HC was attracted by electrostatic interactions with positively charged PLL to form a spherical nanocomplex (HCP) with hyaluronidase (HAase) and pH dual response under ultrasonication. HCP was found to target the bacterial infection microenvironment and release Cur and PLL for synergistic antibacterial action. In addition, HCP was proven to exhibit good biocompatibility and broad spectrum antibacterial activity to bacterial strains S. aureus and E. coli and antibacterial biofilm activities in vitro. In vivo experiments showed that HCP could inhibit pathogens and promote wound healing. These results prove that HCP can be used as a new strategy for the treatment and management of infected wounds.

[Early Warning of Regional Groundwater Pollution： A Case Study for Plain Area of Barkol-Yiwu Basin].

Groundwater pollution early warning is an effective means for regional groundwater pollution prevention. The groundwater pollution early warning model coupled with the current situation of groundwater quality, groundwater quality variation trend, and groundwater pollution risk were applied to the plain area of Barkol-Yiwu Basin, and the regional scale groundwater pollution early warning was realized by combining the early warning of groundwater quality status and trend. The TOPSIS method based on comprehensive weight was used to evaluate the current situation of groundwater quality. The variation trend of groundwater quality was analyzed by calculating the trend interpolation results of 18 in-situ groundwater quality monitoring wells. The groundwater vulnerability map, groundwater pollution load map, and groundwater function value map were superimposed using the superposition index method to evaluate groundwater pollution risk. The results showed that the groundwater quality was good and relatively good, and the poor groundwater quality in some areas was mainly affected by the shallow groundwater depth and the large porosity of the vadose zone. Groundwater quality was stable from 2011 to 2022, mainly due to the leakage of wastewater generated by industries and agriculture into groundwater, resulting in the deterioration of groundwater quality in some areas. Groundwater pollution risk was generally low, and the dual effects of high vulnerability and high pollution load of groundwater led to local areas with high pollution risk. The early warning level of groundwater pollution was generally low, and the heavy and highly heavy warning areas accounted for 16.4% and 17.5% of the study area, respectively, mainly distributed in Xiamaya Township of Yiwu County and northern Santanghu Town, Dahongliuxia Township, and Dahe Town of Barkol County. The quaternary sediments exposed were mainly sandy pebbles, with developed pores and strong water permeability. The interception and adsorption capacity of pollutants were weak. Pollutants produced by industries, agriculture, and life easily leaked into groundwater aquifers, resulting in poor groundwater quality and high risk of groundwater pollution, which ultimately led to a high early warning level of groundwater pollution in some areas. The research on early warning of groundwater pollution provided an important theoretical basis for the development of groundwater pollution remediation.

iPSC-Derived Astrocytes and Neurons Replicate Brain Gene Expression, Epigenetic, Cell Morphology and Connectivity Alterations Found in Autism.

Excessive inflammatory reactions and oxidative stress are well-recognized molecular findings in autism and these processes can affect or be affected by the epigenetic landscape. Nonetheless, adequate therapeutics are unavailable, as patient-specific brain molecular markers for individualized therapies remain challenging. METHODS: We used iPSC-derived neurons and astrocytes of patients with autism vs. controls (5/group) to examine whether they replicate the postmortem brain expression/epigenetic alterations of autism. Additionally, DNA methylation of 10 postmortem brain samples (5/group) was analyzed for genes affected in PSC-derived cells. RESULTS: We found hyperexpression of TGFB1, TGFB2, IL6 and IFI16 and decreased expression of HAP1, SIRT1, NURR1, RELN, GPX1, EN2, SLC1A2 and SLC1A3 in the astrocytes of patients with autism, along with DNA hypomethylation of TGFB2, IL6, TNFA and EN2 gene promoters and a decrease in HAP1 promoter 5-hydroxymethylation in the astrocytes of patients with autism. In neurons, HAP1 and IL6 expression trended alike. While HAP1 promoter was hypermethylated in neurons, IFI16 and SLC1A3 promoters were hypomethylated and TGFB2 exhibited increased promoter 5-hydroxymethlation. We also found a reduction in neuronal arborization, spine size, growth rate, and migration, but increased astrocyte size and a reduced growth rate in autism. In postmortem brain samples, we found DNA hypomethylation of TGFB2 and IFI16 promoter regions, but DNA hypermethylation of HAP1 and SLC1A2 promoters in autism. CONCLUSION: Autism-associated expression/epigenetic alterations in iPSC-derived cells replicated those reported in the literature, making them appropriate surrogates to study disease pathogenesis or patient-specific therapeutics.

[Two new pinophol derivatives from endophytic fungus Penicillium herquei JX4 hosted in Ceriops tagal].

An OSMAC strategy was used to study secondary metabolites and anti-inflammatory activities of the endophytic fungus Penicillium herquei JX4 hosted in Ceriops tagal. The PDB ferment of fungus P. herquei JX4 was isolated, purified, and identified by using silica gel column chromatography, gel column chromatography, octadecylsilyl(ODS) column chromatography, and semi-preparative high-performance liquid chromatography. Two new pinophol derivatives, pinophol H(1) and pinophol I(2) were isolated and identified, and they were evaluated in terms of the inhibitory activities against the nitric oxide(NO) production induced by lipopolysaccharide(LPS) in mouse macrophage RAW264.7 cells. The results showed that compound 1 had significant inhibitory activity on NO production, with an IC_(50) value of 8.12 µmol·L~(-1).

Deep Eutectic Solvent-Assisted Corrosion Boosting Bulk FeCoNiCrMo High-Entropy Alloys as Highly Efficient Oxygen Evolution Reaction Catalyst.

The key to enhancing water electrolysis efficiency lies in selecting highly efficient catalysts. Currently, high-entropy alloys (HEAs) are utilized in electrocatalysis applications owing to their diverse elemental composition, disordered elemental distribution, and the high solubility of each element, endowing them with excellent catalytic performance. The experiments were conducted using isoatomic FeNiCrMo HEA as a precursor, with a high-activity three-dimensional nanoporous structure rapidly synthesized via electrochemical one-step dealloying in a choline chloride-thiourea (ChCl-TU) deep eutectic solvent (DES). The results indicate that the dealloyed Fe20Co20Ni20Cr20Mo20 HEA mainly consists of two phases: face-centered cubic and σ phases. The imbalance in the distribution of elements in these two phases leads to quite different corrosion speeds with the FCC phase being preferentially corroded. Furthermore, synergistic electron coupling between surface atoms in the three-dimensional nanoporous structure strengthens the behavior of the oxygen evolution reaction (OER). At a current density of 40 mA cm-2, the overpotential after dealloying decreased to 370 mV, demonstrating excellent stability. The technique demonstrated in this work provides a novel approach to improve the catalytic activity of OER.

Neoadjuvant therapy of sequential TACE, camrelizumab, and apatinib for single huge hepatocellular carcinoma (NEO-START): study protocol for a randomized controlled trial.

BACKGROUND: The high recurrence rate after liver resection emphasizes the urgent need for neoadjuvant therapy in hepatocellular carcinoma (HCC) to enhance the overall prognosis for patients. Immune checkpoint inhibitors, camrelizumab combined with an anti-angiogenic tyrosine kinase inhibitor (TKI) apatinib, have emerged as a first-line treatment option for patients with unresectable HCC, yet its neoadjuvant application in combination with transarterial chemoembolization (TACE) in HCC remains unexplored. Therefore, this study aims to investigate the efficacy and safety of sequential TACE, camrelizumab, and apatinib as a neoadjuvant therapy for single, huge HCC. METHODS: This multi-center, open-label randomized phase 3 trial will be conducted at 7 tertiary hospitals. Patients with single huge (≥ 10 cm in diameter), resectable HCC will be randomly assigned in a 1:1 ratio to arm of surgery alone or arm of neoadjuvant therapy followed by surgery. In the neoadjuvant therapy group, patients will receive TACE within 1 week after randomization, followed by camrelizumab (200 mg q2w, 4 cycles), along with apatinib (250 mg qd, 2 months). Patients will receive liver resection after neoadjuvant therapy unless the disease is assessed as progressive. The primary outcome is recurrence-free survival (RFS) at 1 year. The planned sample size of 60 patients will be calculated to permit the accumulation of sufficient RFS events in 1 year to achieve 80% power for the RFS primary endpoint. DISCUSSION: Synergistic effects provided by multimodality therapy of locoregional treatment, TKI, and anti-programmed cell death 1 inhibitor significantly improved overall survival for patients with unresectable HCC. Our trial will investigate the efficacy and safety of the triple combination of TACE, camrelizumab, and apatinib as a neoadjuvant strategy for huge, resectable HCC. TRIAL REGISTRATION: www.chitr.org.cn ChiCTR2300078086. Registered on November 28, 2023. Start recruitment: 1st January 2024. Expected completion of recruitment: 15th June 2025.

Unraveling the signaling network between dysregulated microRNA and mRNA expression in sevoflurane-induced developmental neurotoxicity in rat.

Research has indicated that general anesthesia may cause neuroapoptosis and long-term cognitive dysfunction in developing animals, however, the precise mechanisms orchestrating these outcomes remain inadequately elucidated within scholarly discourse. The purpose of this study was to investigate the impact of sevoflurane on the hippocampus of developing rats by analyzing the changes in microRNA and mRNA and their interactions. Rats were exposed to sevoflurane for 4 h on their seventh day after birth, and the hippocampus was collected for analysis of neuroapoptosis by Western blot and immunohistochemistry. High-throughput sequencing was conducted to analyze the variances in miRNA and mRNA expression levels, and the Morris water maze was employed to assess long-term memory in rats exposed to sevoflurane after 8 weeks. The results showed that sevoflurane exposure led to dysregulation of 5 miRNAs and 306 mRNAs in the hippocampus. Bioinformatic analysis revealed that these dysregulated miRNA-mRNA target pairs were associated with pathological neurodevelopment and developmental disorders, such as regulation of axonogenesis, regulation of neuron projection development, regulation of neuron differentiation, transmission of nerve impulse, and neuronal cell body. Further analysis showed that these miRNAs formed potential network interactions with 44 mRNAs, and two important nodes were identified, miR-130b-5p and miR-449c-5p. Overall, this study suggests that the dysregulation of the miRNA-mRNA signaling network induced by sevoflurane may contribute to neurodevelopmental toxicity in the hippocampus of rats and be associated with long-term cognitive dysfunction.

RSVP-based BCI for inconspicuous targets: detection, localization, and modulation of attention.

OBJECTIVE: While Brain-Computer Interface (BCI) based on Rapid Serial Visual Presentation (RSVP) is widely used in target detection, patterns of Event-Related Potential (ERP), as well as the performance on detecting inconspicuous targets remain unknown. Moreover, participant-screening methods to excluded 'BCI-blind' users are still lacking. APPROACH: A RSVP paradigm was designed with targets of varied concealment, size, and location. ERPs (e.g. P300 and N2pc) and target detection accuracy were compared among these conditions. The relationship between participants' attention scores and target detection accuracy was also analyzed to test attention level as a criterion for participant screening. MAIN RESULTS: Statistical analysis showed conditions of target concealment and size had significant influences on ERP. In particular, ERP for inconspicuous targets, such as concealed and small targets, had lower amplitude and longer latency. In consistent, the accuracy of detection in inconspicuous condition was significantly lower than that of conspicuous condition. In addition, a significant association was found between attention scores and target detection accuracy for camouflaged targets. SIGNIFICANCE: The study was the first to address ERP features among multiple dimensions of concealment, size, and location. The conclusion provided insights into the relationship between ERP decoding and properties of targets. In addition, the association between attention scores and detection accuracy implied a promising method in screening well-behaved participants for camouflaged target detection.

One-step synthesized multisize AuAg alloy nanoparticles with high SERS sensitivity in directly detecting SARS-CoV-2 spike protein.

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in widespread disease transmission, challenging the stability of global healthcare systems. Surface-enhanced Raman scattering (SERS) as an easy operation, fast, and low-cost technology illustrates a good potential in detecting SARS-CoV-2. In the study, one-step fabrication of gold-silver alloy nanoparticles (AuAgNPs) with adjustable metal proportions and diameters is employed as SERS substrates. The angiotensin-converting enzyme 2 (ACE2) functionalized AuAgNPs are applied as sensor surfaces to detect SARS-CoV-2 S protein. By optimizing the SERS substrates, ACE2/Au35Ag65NPs illustrate higher performance in detecting the SARS-CoV-2 S protein with a limit of detection (LOD) of 10 fg/mL in both phosphate-buffered saline (PBS) and pharyngeal swabs solution (PSS). It also provides excellent reproducibility with a relative standard deviation (RSD) of 7.7 % and 7.9 %, respectively. This easily preparable and highly reproducible SERS substrate has good potential in the practical application of detecting SARS-CoV-2.

Association between short-term ozone exposure and allergic conjunctivitis in China: A multi-city case-crossover study.

Short-term exposure to ozone has been linked to multiple allergic diseases, but the relationship between ozone exposure and allergic conjunctivitis (AC) remains unclear. This study aimed to investigate the association between short-term exposure to ozone and the risk of AC. We conducted a time-stratified case-crossover study across five Chinese cities from 2014 to 2022. Daily outpatient visit records for AC were identified in five hospitals using either the diagnosis name or ICD-10 code H10.1. Data on air pollution and meteorological conditions were also collected. We first examined the city-specific association between short-term ozone exposure and AC using conditional logistic regression. A random-effects meta-analysis was then conducted to obtain overall estimates. During the study period, 130,093 outpatient visits for AC occurred, with 58.8% (76,482) being male and 41.2% (53,611) female. A one-standard-deviation (SD) increase in ozone was associated with an 8.3% increase (95% CI: 3.8%, 13.0%) in AC outpatient visits. Similar positive associations were observed when adjusting for other pollutants (PM2.5, CO, SO2 and NO2) in two-pollutant and multi-pollutant models. Furthermore, the positive association remained consistent when using mixed-effects regression models or further adjusting for meteorological conditions. In addition, no effect modification of the AC-ozone association by sex, age and season was apparent. This study provides evidence supporting a positive association between short-term ozone exposure and AC risk in China. This highlights the potential value of mitigating ozone pollution to reduce the risk of ocular surface disorders.

Mitochondrial­associated endoplasmic reticulum membrane interference in ovarian cancer (Review).

The mitochondria­associated endoplasmic reticulum (ER) membrane (MAM), serving as a vital link between the mitochondria and ER, holds a pivotal role in maintaining the physiological function of these two organelles. Its specific functions encompass the participation in the biosynthesis and functional regulation of the mitochondria, calcium ion transport, lipid metabolism, oxidative stress and autophagy among numerous other facets. Scientific exploration has revealed that MAMs hold potential as effective therapeutic targets influencing the mitochondria and ER within the context of cancer therapy. The present review focused on elucidating the related pathways of mitochondrial autophagy and ER stress and their practical application in ovarian cancer, aiming to identify commonalities existing between MAMs and these pathways, thereby extending to related applications of MAMs in ovarian cancer treatment. This endeavor aimed at exploring new potential for MAMs in clinically managing ovarian cancer.

Ubiquitin-induced RNF168 condensation promotes DNA double-strand break repair.

Rapid accumulation of repair factors at DNA double-strand breaks (DSBs) is essential for DSB repair. Several factors involved in DSB repair have been found undergoing liquid-liquid phase separation (LLPS) at DSB sites to facilitate DNA repair. RNF168, a RING-type E3 ubiquitin ligase, catalyzes H2A.X ubiquitination for recruiting DNA repair factors. Yet, whether RNF168 undergoes LLPS at DSB sites remains unclear. Here, we identified K63-linked polyubiquitin-triggered RNF168 condensation which further promoted RNF168-mediated DSB repair. RNF168 formed liquid-like condensates upon irradiation in the nucleus while purified RNF168 protein also condensed in vitro. An intrinsically disordered region containing amino acids 460-550 was identified as the essential domain for RNF168 condensation. Interestingly, LLPS of RNF168 was significantly enhanced by K63-linked polyubiquitin chains, and LLPS largely enhanced the RNF168-mediated H2A.X ubiquitination, suggesting a positive feedback loop to facilitate RNF168 rapid accumulation and its catalytic activity. Functionally, LLPS deficiency of RNF168 resulted in delayed recruitment of 53BP1 and BRCA1 and subsequent impairment in DSB repair. Taken together, our finding demonstrates the pivotal effect of LLPS in RNF168-mediated DSB repair.

Dihydroartemisinin remodels tumor micro-environment and improves cancer immunotherapy through inhibiting cyclin-dependent kinases.

Cancer immunotherapies are ineffective in nonresponding patients due to absence of immune responses. Here, we identified that dihydroartemisinin (DHA) induced immunogenic cell death (ICD) in hepatocellular carcinoma (HCC), proved by release or surface expose of damage-associated molecular patterns and in vivo protective vaccine activity. Mechanistically, DHA can inhibit cyclin-dependent kinases (CDKs), leading to a buildup of intracellular reactive oxygen species (ROS), which induces immunogenic cell death. In both Hepa1-6 and H22 tumor bearing mice, DHA exerted anti-tumor activity through increasing tumor-infiltrating CD8+ T cells with expression of activation makers (CD25 and CD69), secretion of intracellular cytokines (IFN-γ and TNF-α) and activated dendritic cells expressing MHCⅡ, CD80 and CD86. In hepa1-6 tumor bearing mice, DHA decreased immunosuppressive myeloid-derived suppressor cells. Furthermore, DHA enhanced the anti-PD-1 antibody and chimeric antigen receptor (CAR) T cell-mediated tumor suppression through recruitment and activation of endogenous CD8+ T cells. Overall, we demonstrated that by inhibiting CDKs, DHA can remodel tumor micro-environment to amplify anti-tumor immune responses in HCC. These findings provide a promising therapy option for HCC patients.