Fusobacterium nucleatum-derived succinic acid induces tumor resistance to immunotherapy in colorectal cancer.

Immune checkpoint blockade therapy with anti-PD-1 monoclonal antibody (mAb) is a treatment for colorectal cancer (CRC). However, some patients remain unresponsive to PD-1 blockade. The gut microbiota has been linked to immunotherapy resistance through unclear mechanisms. We found that patients with metastatic CRC who fail to respond to immunotherapy had a greater abundance of Fusobacterium nucleatum and increased succinic acid. Fecal microbiota transfer from responders with low F. nucleatum, but not F. nucleatum-high non-responders, conferred sensitivity to anti-PD-1 mAb in mice. Mechanistically, F. nucleatum-derived succinic acid suppressed the cGAS-interferon-ß pathway, consequently dampening the antitumor response by limiting CD8+ T cell trafficking to the tumor microenvironment (TME) in vivo. Treatment with the antibiotic metronidazole reduced intestinal F. nucleatum abundance, thereby decreasing serum succinic acid levels and resensitizing tumors to immunotherapy in vivo. These findings indicate that F. nucleatum and succinic acid induce tumor resistance to immunotherapy, offering insights into microbiota-metabolite-immune crosstalk in CRC.

ZeXieYin Formula alleviates TMAO-induced cognitive impairment by restoring synaptic plasticity damage.

ETHNOPHARMACOLOGICAL RELEVANCE: Treating cognitive impairment is a challenging and necessary research topic. ZeXieYin Formula (ZXYF), is a traditional herbal formula documented in the book of HuangDiNeiJing. Our previous studies demonstrated the ameliorative effects of ZXYF on atherosclerosis by reducing the plasma trimethylamine oxide (TMAO) level. TMAO is a metabolite of gut microorganisms, our recent research found that the increasing level of TMAO may have adverse effects on cognitive functions. AIM OF THE STUDY: Our study mainly focused on the therapeutic effects of ZXYF on TMAO-induced cognitive impairment in mice and explored its underlying mechanism. MATERIALS AND METHODS: After the TMAO-induced cognitive impairment mice models were established, we applied behavioral tests to estimate the learning and memory ability of the ZXYF intervention mice. Liquid chromatography-mass spectrometry (LC-MS) was used to quantify the TMAO levels in plasma and the brain. The effects of ZXYF on the hippocampal synaptic structure and the neurons were observed by transmission electron microscopy (TEM) and Nissl staining. In addition, western-blotting (WB) and immunohistochemical (IHC) staining were used to detect the level of related proteins in the synaptic structure and further verify the changes in synaptic plasticity and the mTOR pathway after ZXYF administration. RESULTS: Behavioral tests showed that the learning and memory ability of mice impaired after a period of TMAO intervention and ZXYF could alleviate these changes. A series of results showed that ZXYF partly restored the damage of hippocampal synapse and neurons in TMAO-induced mice, at the same time, the expression of synapse-related proteins and mTOR pathway-related proteins were significantly regulated compared with the damage caused by TMAO. CONCLUSION: ZXYF could alleviate TMAO-induced cognitive impairment by improving synaptic function, reducing neuronal damage, regulating synapse-associated proteins, and regulating the mTOR signaling pathway.

Curcumin alleviated oxidation stress injury by mediating osteopontin in nephrolithiasis rats.

PURPOSE: To explore the role and mechanism of curcumin (Cur) in reducing oxidative stress damage in rats with nephrolithiasis induced by ethylene glycol (EG). METHODS: Thirty male rats were divided into normal control, model, positive (10% potassium citrate), Cur-10 (10 mg/kg curcumin) and Cur-20 (20 mg/kg curcumin) groups. RESULTS: The results of kidney tissue section stained by hematoxylin-eosin and von Kossa showed that curcumin treatment can inhibit the formation of kidney stones. The biochemical test results showed that the urea (Ur), creatinine (Cr), uric acid (UA), inorganic phosphorus and Ca2+ concentrations in urine decreased after being treated with curcumin. There were significant differences between different doses of curcumin (P < 0.05). Compared with the Cur-10 group, Cur-20 had a more significant inhibitory effect on malondialdehyde (MDA) (P < 0.05). In addition, reverse transcription polymerase chain reaction (PCR) detection and immunohistochemical results indicated that the osteopontin (OPN) in the kidney was significantly reduced after curcumin treatment. CONCLUSIONS: Curcumin could reduce the oxidative stress damage caused by EG-induced kidney stones.

Adjunctive efficacy of Lactis XLTG11 for Acute diarrhea in children: A randomized, blinded, placebo-controlled study.

OBJECTIVE: The aim of this study was to assess the efficacy and safety of Bifidobacterium animalis sp. Lactis XLTG11, as an adjunctive treatment for acute watery diarrhea in children, using a randomized, double-blinded, placebo-controlled study design. METHOD: Eligible children with diarrhea were randomly assigned into one of two groups: an intervention group (IG, n = 35), which received conventional treatment plus the probiotic, and a control group (CG, n = 35), which received only conventional treatment. Fecal samples were collected from all children before and after the intervention to measure biochemical indices and analyze gut microbiome (GM) composition. RESULT: The duration of diarrhea (121.3 ± 11.5 h) and hospital length of stay (3.4 ± 1.1 d) in the IG were significantly shorter than those in the CG (133.4 ± 14.1 h and 4 ± 1.3 d, respectively; P < 0.001 and P = 0.041, respectively). A higher percentage of children in the IG showed improvements compared with the CG (57.1% versus 25.7%, P < 0.001). The calprotectin level in the IG was significantly lower than that in the CG after the intervention (928.91 ± 158.90 ng/g versus 1029.86 ± 133.25 ng/g, P = 0.028). XLTG11 administration led to a higher abundance of species B. longum and < breve, increased α-diversity of the GM (P < 0.05), and upregulated the functional genes of the GM related to immunity and nutrient absorption. CONCLUSIONS: Administration of XLTG11 at a dose of 1 × 1010 CFU/d was effective in reducing the duration of diarrhea, inducing beneficial changes in GM composition and gene functions.

[Advances in molecular function of p62 protein and its role in diseases].

Sequestosome 1 (SQSTM1/p62) is a selective autophagy adaptor protein that plays an important role in the clearance of proteins to be degraded as well as in the maintenance of cellular proteostasis. p62 protein has multiple functional domains, which interact with several downstream proteins to precisely regulate multiple signaling pathways, thereby linking p62 to oxidative defense systems, inflammatory responses and nutrient sensing. Studies have shown that mutation or abnormal expression of p62 is closely related to the occurrence and development of various diseases, including neurodegenerative diseases, tumors, infectious diseases, genetic diseases and chronic diseases. This review summarizes the structural features and molecular functions of p62. Moreover, we systematically introduce its multiple functions in protein homeostasis and regulation of signaling pathways. Furthermore, the complexity and versatility of p62 in the occurrence and development of diseases are summarized, with the aim to provide a reference for understanding the function of p62 protein and facilitating related disease research.

Transperineal pelvic floor ultrasound in male.

INTRODUCTION: The pelvic floor (PF) is a highly complex structure which may be affected by various stimulating factors like decreased PF support. As ultrasound can dynamically observe the position and mobility of anatomical structures, However, there are very few studies on PF ultrasound in males. MATERIALS AND METHODS: Twenty-one male patients with normal conditions underwent transperineal pelvic floor ultrasound (TPFU) examination. Ultrasound was performed in a supine lithotomy position. The probe was pressed on the sagittal plane of the perineum and adjusted till the anorectal angle, as well as bladder, were located and the median prostate and pubic symphysis were visible on the sagittal plane. TPFU was carried out to observe the patterns of pelvic floor movement during different phases, measure ultrasound parameters of the PF in men, and assess the potential applications and prospects of the male PF. RESULTS: Two-dimensional male PF ultrasound can detect the bladder, prostate, male urethra, anus, rectum. Resting, Valsalva, and contraction phases of the PF are clearly shown, the pelvic organs in the Valsalva phase shift to the dorsal foot side, and shift to the cephalic ventral side when the levator ani muscle (LAM) contracts. Three-dimensional male PF ultrasound can visually show the shape and structure of the levator ani muscle hiatus. CONCLUSION: It is a feasible examination tool for detecting PF disorders. However, there are still many fields to explore in the future.

CerS5 deficiency promotes liver fibrosis development in non-alcoholic fatty liver disease.

BACKGROUND: Hepatocyte lipotoxicity mediated by sphingolipids was considered one of important factors in NAFLD development. Knocking out key enzymes for sphingolipids synthesis, such as DES-1, SPHK1 and CerS6, could reduce hepatocyte lipotoxicity and improve NAFLD progression. Previous studies showed that roles of CerS5 and CerS6 in sphingolipids metabolism were similar, but the role of CerS5 was controversial in NAFLD development. This study aimed to clarify the role and mechanism of CerS5 in NAFLD development. METHODS: Hepatocyte conditional CerS5 knockout (CerS5 CKO) and wild type (WT) mice were fed with standard control diet (SC) and choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) and then divided into four groups: CerS5 CKO-SC, CerS5 CKO-CDAHFD, WT-SC and WT-CDAHFD. RT-PCR, IHC and WB were used to analyze the expression of inflammatory, fibrosis and bile acids (BA) metabolism factors. RNA-seq was used to analyze differences of transcriptional levels of liver molecules among the four groups. Metabolomics was used to measured differences of hepatic BAs among the four groups. RESULTS: Hepatocyte specific knockout of CerS5 did not increase or reduce the severity of 8-weeks CDAHFD induced hepatic steatosis and inflammation, but significantly worsened the progression of liver fibrosis in these mice. At the molecular level, hepatocyte specific knockout of CerS5 did not increase or reduce expression of hepatic inflammatory factors: CD68, F4/80 and MCP-1, but increased expression of hepatic fibrosis factors: α-SMA, COL1α and TGF-ß in mice fed with CDAHFD. Transcriptome analysis showed that hepatocyte specific knockout of CerS5 significantly decreased the expression of hepatic cyp27a1, and decreased expression of cyp27a1 was further validated by RT-PCR and WB. Considering that cyp27a1 was a key enzyme in the alternative pathway of BA synthesis, we further found that hepatic BA pools in CerS5 CKO mice were more conducive to the progression of liver fibrosis, which were characterized by elevated hydrophobic 12α-OH BAs and decreased hydrophilic non-12α-OH BAs. CONCLUSION: CerS5 played an important role in the progression of NAFLD related fibrosis, and hepatocyte specific knockout of CerS5 accelerated the progression of NAFLD related fibrosis, which was possibly due to the inhibition of BA synthesis alternative pathway by knocking out hepatocyte CerS5.

Integrating Spatial Transcriptomics and Single-nucleus RNA Sequencing Reveals the Potential Therapeutic Strategies for Uterine Leiomyoma.

Uterine leiomyoma is the most common gynecological tumor in reproductive women. Tumor-host interface is a complex ecosystem with intimate cell-cell communications and a critical scenario for tumor pathogenesis and progression. The pseudocapsule is the main tumor-host interface of uterine leiomyoma, but its cellular spatial disposition and gene expression are poorly explored. This study mapped the cellular architecture and corresponding gene profiles of the leiomyoma and its surrounding pseudocapsule by integrating spatial transcriptomics and single-nucleus RNA-sequencing at the first time. Here, we reported that estrogen receptor alpha and progesterone receptor mediated the occurrence and development of uterine leiomyoma and that estrogen receptor beta involved in the angiogenesis, which explained the effectiveness of hormonotherapy. Therapeutic targets including ERK1/ERK2 pathway and IGF1-IGF1R were found and might be applied for non-hormonal therapy of uterine leiomyoma. Furthermore, the injection of prostaglandin E2 was initially presented for bleeding control during myomectomy, injection site should be located at the junction between pseudocapsule and leiomyoma, and surrounding pseudocapsule should not be eliminated. Collectively, a single-cell and spatially resolved atlas of human uterine leiomyoma and its surrounding pseudocapsule was established. The results revealed potentially feasible strategies for hormonotherapy, non-hormonal targeted therapy and bleeding control during myomectomy.

Pharmacokinetics of Nifedipine-Sustained Release Tablets in Healthy Subjects After a Single Oral Administration: Bioequivalence Analysis and Food Effects.

We compared newly developed delayed-release oral tablets (test) of 30-mg nifedipine (NFP) with its marketed counterpart (30 mg; reference) in healthy adult Chinese volunteers to assess the former's bioequivalence. This was a randomized, open-label, four-period, crossover trial study including fasting and fed trials. The participants were randomly administered test or reference formulations (1:1 ratio) throughout each period, with a 7-day washout period. In the next session, they were administered the alternate products. Liquid chromatography-tandem mass spectrometry and WinNonlin software were used to evaluate the bioequivalence of the maximum plasma concentration (Cmax ) of NFP and the area under the concentration-time curve (AUC). In total, 46 and 48 people participated in the fasting and postprandial trials. In both groups, the 90% confidence intervals of geometric mean ratios of Cmax , AUC from time zero to time t, and AUC from time zero to infinity were in the equivalence range (80%-125%). When NFP was administered concomitantly with a high-fat meal, time to maximum concentration was approximately twofold earlier, absorption was approximately 4.8% less, and Cmax exhibited a slight change relative to those under fasting conditions. Moreover, no serious adverse events were recorded in the participants. The present findings confirm the bioequivalence of test and reference formulations of NFP tablets under fasting and postprandial conditions.

Computational Study on Filament Growth Dynamics in Microstructure-Controlled Storage Media of Resistive Switching Memories.

The filament growth processes, crucial to the performance of nanodevices like resistive switching memories, have been widely investigated to realize the device optimization. With the combination of kinetic Monte Carlo (KMC) simulations and the restrictive percolation model, three different growth modes in electrochemical metallization (ECM) cells were dynamically reproduced, and an important parameter, the relative nucleation distance, was theoretically defined to measure different growth modes quantitatively; hence their transition can be well described. In our KMC simulations, the inhomogeneity of storage medium is realized through introducing evolutionary void versus non-void sites within it to mimic the real nucleation during filament growth. Finally, the renormalization group method was used in the percolation model to analytically illustrate void-concentration-dependent growth mode transition, fitting KMC simulation results quite well. Our study found that the nanostructure of the medium can dominate the filament growth dynamics, as the simulation images as well as the analytical results are consistent with experiments results. Our study spotlights a vital and intrinsic factor, void concentration (relative to defects, grains, or nanopores) of a storage medium, in inducing filament growth mode transition within ECM cells. This theoretically proves a mechanism to tune performance of ECM systems that controlling microstructures of the storage media can dominate the filament growth dynamics, indicating an accessible strategy, nanostructure processing, for device optimization of ECM memristors.

Stepwise changes in flavonoids in spores/pollen contributed to terrestrial adaptation of plants.

Protecting haploid pollen and spores against ultraviolet-B (UV-B) light and high temperature, two major stresses inherent to the terrestrial environment, is critical for plant reproduction and dispersal. Here, we show flavonoids play an indispensable role in this process. Firstly, we identified the flavanone naringenin, which serves to defend against UV-B damage, in the sporopollenin wall of all vascular plants tested. Secondly, we found that flavonols are present in the spore/pollen protoplasm of all euphyllophyte plants tested and that these flavonols scavenge ROS to protect against environmental stresses, particularly heat. Genetic and biochemical analyses showed that these flavonoids are sequentially synthesized in both the tapetum and microspores during pollen ontogeny in Arabidopsis (Arabidopsis thaliana). We show that stepwise increases in the complexity of flavonoids in spores/pollen during plant evolution mirrors their progressive adaptation to terrestrial environments. The close relationship between flavonoid complexity and phylogeny and its strong association with pollen survival phenotypes suggests that flavonoids played a central role in the progression of plants from aquatic environments into progressively dry land habitats.

Silicon-Based On-Chip Tunable High-Q-Factor and Low-Power Fano Resonators with Graphene Nanoheaters.

Tunable and low-power microcavities are essential for large-scale photonic integrated circuits. Thermal tuning, a convenient and stable tuning method, has been widely adopted in optical neural networks and quantum information processing. Recently, graphene thermal tuning has been demonstrated to be a power-efficient technique, as it does not require thick spacers to prevent light absorption. In this paper, a silicon-based on-chip Fano resonator with graphene nanoheaters is proposed and fabricated. This novel Fano structure is achieved by introducing a scattering block, and it can be easily fabricated in large quantities. Experimental results demonstrate that the resonator has the characteristics of a high quality factor (∼31,000) and low state-switching power (∼1 mW). The temporal responses of the microcavity exhibit qualified modulation speed with 9.8 µs rise time and 16.6 µs fall time. The thermal imaging and Raman spectroscopy of graphene at different biases were also measured to intuitively show that the tuning is derived from the joule heating effect of graphene. This work provides an alternative for future large-scale tunable and low-power-consumption optical networks, and has potential applications in optical filters and switches.

Early growth response factor 1 upregulates pro-fibrotic genes through activation of TGF-ß1/Smad pathway via transcriptional regulation of PAR1 in high-glucose treated HK-2 cells.

Tubulointerstitial fibrosis (TIF) makes a key role in diabetic kidney disease (DKD). In this study, we revealed that the expressions of Egr1 and protease-activated receptor 1 (PAR1) were increased in renal tissues of DKD rats. In vitro experiments demonstrated that both Egr1 overexpression and high glucose (HG) condition could promote the expressions of PAR1, fibronectin (FN) and collagen I (COL I). Furthermore, HG stimulation enhanced the binding capacity of Egr1 to PAR1 promoter. Both HG condition and Egr1 upregulation could increase, and thrombin inhibitor did not affect activity of TGF-ß1/Smad pathway via PAR1. Collectively, Egr1 is involved in TIF of DKD partly through activating TGF-ß1/Smad pathway via transcriptional regulation of PAR1 in HG treated HK-2 cells.

Regulatory network and targeted interventions for CCDC family in tumor pathogenesis.

CCDC (coiled-coil domain-containing) is a coiled helix domain that exists in natural proteins. There are about 180 CCDC family genes, encoding proteins that are involved in intercellular transmembrane signal transduction and genetic signal transcription, among other functions. Alterations in expression, mutation, and DNA promoter methylation of CCDC family genes have been shown to be associated with the pathogenesis of many diseases, including primary ciliary dyskinesia, infertility, and tumors. In recent studies, CCDC family genes have been found to be involved in regulation of growth, invasion, metastasis, chemosensitivity, and other biological behaviors of malignant tumor cells in various cancer types, including nasopharyngeal carcinoma, lung cancer, colorectal cancer, and thyroid cancer. In this review, we summarize the involvement of CCDC family genes in tumor pathogenesis and the relevant upstream and downstream molecular mechanisms. In addition, we summarize the potential of CCDC family genes as tumor therapy targets. The findings discussed here help us to further understand the role and the therapeutic applications of CCDC family genes in tumors.

Discovery of ML210-Based glutathione peroxidase 4 (GPX4) degrader inducing ferroptosis of human cancer cells.

Ferroptosis is an iron-dependent cell death caused by the accumulation of lipid peroxidation. The glutathione peroxidase 4 (GPX4) is an antioxidative enzyme and a major regulator of ferroptosis. Targeting GPX4 has become a promising strategy for cancer therapy. Here in this article, we designed and synthesized a series of GPX4 degraders using ML210 as a warhead. DC-2 among them has been found to have the best degradation activity with the DC50 value of 0.03 µM in HT1080 cells. It also showed an obvious cell growth inhibition effect with the IC50 value of 0.1 µM in HT1080 cells. Mechanism research showed that DC-2 induced GPX4 degradation via the ubiquitin-proteasome pathway and autophagy-lysosome pathway. GPX4 degradation induced by DC-2 could result in the accumulation of ROS and subsequent ferroptosis. The pharmacodynamics study showed that DC-2 could reduce the GPX4 level in HT1080 tumor tissue in mice and has a good safety profile. Above all, a potent and safe compound DC-2 has been found to induce GPX4 degradation and subsequent ferroptosis. This study may lay the foundation for a highly efficient and safe drug with a new mechanism for cancer therapy.

Rifabutin-containing Triple Therapy versus Bismuth Quadruple Therapy for Helicobacter pylori Rescue Treatment: A Multicenter, Randomized Controlled Trial.

BACKGROUND: To compare the efficacy and safety of rifabutin-containing triple therapy with bismuth quadruple therapy for rescue treatment of Helicobacter pylori (H. pylori). METHODS: This was a non-inferiority study trial of H. pylori treatment for subjects who had failed at least two prior treatments. Subjects were randomly assigned to receive rifabutin triple therapy with 14-day esomeprazole (20 mg bid), amoxicillin (1.0 g bid) and rifabutin (150 mg bid) or bismuth quadruple therapy with esomeprazole (20 mg bid), bismuth (220 mg bid), plus metronidazole (400 mg qid) and tetracycline (500 mg qid). Antimicrobial susceptibility was assessed by agar dilution and E-test methods. FINDINGS: From May 2021 to October 2022, a total of 364 subjects were randomized. The eradication rates by intention-to-treat, per-protocol, and modified intention-to-treat were 89.0% (162/182, 95% confidence interval (CI) 83.6%-92.8%), 94.0% (157/167, 95% CI 89.3%-96.7%) and 93.6% (162/173, 95% CI 89.0%-96.4%) for rifabutin triple group. For bismuth quadruple group, they were 89.6% (163/182, 95% CI 84.3%-93.2%), 95.3% (143/150, 95% CI 90.7%-97.7%) and 93.7% (163/174, 95% CI 89.0%-96.4%). INTERPRETATION: The rifabutin triple therapy is an alternative to classical bismuth quadruple therapy for the rescue treatment of H. pylori with lower side effects and higher compliance.

Structure-activity relationship study of RSL3-based GPX4 degraders and its potential noncovalent optimization.

Ferroptosis is an iron-dependent, non-apoptotic form of cell death involving in various disease processes. Mechanistically, glutathione peroxidase 4 (GPX4) which belongs to the redox enzyme can convert lipid hydroperoxides into innocuous lipid alcohol to protect cells from ferroptosis. Therefore, targeting manipulation of GPX4 may represent a promising strategy for regulating cell redox homeostasis and ferroptosis. In this work, we designed, synthesized and evaluated a series of RSL3-based GPX4 degraders using PROTAC strategy. The structure-activity relationship of these compounds with different E3 ligase ligands, linker lengths and chemical compositions was systematically studied. Compound R17 with carbon chain linker and lenalidomide E3 ligand was selected as the most potent GPX4 degrader for degrading GPX4 protein in nanomolar level either in wild tumor cells or in drug-resistant tumor cells. We also optimized the POI ligand of R17 with chloracetylamine replaced to propionamide to construct noncovalent GPX4 degrader NC-R17. Such noncovalent modification led to a moderate GPX4 degradation activity and represents a promising strategy for the development of noncovalent GPX4 PROTACs. In general, we screened a set of GPX4 degraders to give the compound R17 with excellent protein degradation activity, and further optimization gave the noncovalent degrader NC-R17 with moderate efficacy. These results lay a firm foundation for the discovery of novel anti-tumor drugs targeting GPX4 and offer the proof of concept for the design of noncovalent GPX4 PROTACs.

The elevated expression of LAG-3 on CD8+T cells correlates with disease severity of pulmonary TB.

OBJECTIVE: Lymphocyte-activation gene 3 (LAG-3) plays an important role in regulating T-cell responses and inducing peripheral tolerance. Our aim in this study was to investigate the relationship between LAG-3 and active tuberculosis (ATB) and the impact of LAG-3 blockade on CD8+T cells. METHODS: Flow cytometry was used to detect the expression of LAG-3 on CD4+T and CD8+T cells in the peripheral blood and bronchoalveolar lavage fluid from ATB patients and to explore the relationship between LAG-3 and ATB. RESULTS: The expression of LAG-3 on CD4+T and CD8+T cells in ATB patients was increased (P < 0.001), and CD8+T cells with high expression of LAG-3 were associated with sputum culture results (P < 0.05). We further analyzed the relationship between the expression of LAG-3 in CD8+T cells and the severity of tuberculosis and found that the expression of LAG-3 on CD8+T cells in smear-positive tuberculosis patients was significantly higher than that in sputum smear-negative tuberculosis patients (P < 0.05). LAG-3 expression on CD8+T cells was negatively correlated with the presence of lung lesions (P < 0.05). After stimulation with a tuberculosis-specific antigen, the expression of LAG-3 on tuberculosis-specific CD8+T cells was also upregulated, and LAG-3-expressing CD8+T cells showed reduced production of IFN-γ, decreased activation, and lower proliferation, while the function of CD8+T cells was restored when LAG-3 signaling was blocked. CONCLUSIONS: This study further explored the relationship between immune exhaustion caused by LAG-3 and immune escape of Mycobacterium tuberculosis and revealed that the elevated expression of LAG-3 on CD8+T cells correlates with functional defects of CD8+T cells and the severity of pulmonary TB.

Modeling Osteoarthritis: MiR-16-5p Attenuates IL-1ß Induced Chondrocyte Dysfunction by Targeting MAP2K1 through the MAPK Pathway.

OBJECTIVE: Osteoarthritis (OA) is a chronic joint disease characterized by cartilage degeneration, significantly reducing the quality of life. Previous report has confirmed that MAP2K1 acts as a potential therapeutic target in OA. Nevertheless, its specific function and related molecular mechanism in OA remain uncharacterized. Our report revealed the biological significance of MAP2K1 and elucidated its regulatory mechanism in OA. METHODS: Interleukin (IL)-1ß was utilized to stimulate human chondrocyte cell line CHON-001 for establishing the in vitro models of OA. Cell apoptosis and viability were determined by flow cytometry analysis and CCK-8 assay. Protein levels and gene expression were quantified by western blotting and RT-qPCR. Binding relation between miR-16-5p and MAP2K1 (mitogen-activated protein kinase kinase 1) was confirmed by luciferase reporter assay. RESULTS: IL-1ß treatment triggered CHON-001 cell injury by repressing cell viability and facilitating cell apoptosis. Moreover, IL-1ß stimulation upregulated MAP2K1 level in CHON-001 cells. MAP2K1 depletion attenuated IL-1ß-elicited CHON-001 cell injury. Mechanistically, miR-16-5p targeted MAP2K1 in CHON-001 cells. In rescue assays, MAP2K1 upregulation counteracted the suppressive impact of miR-16-5p enhancement on IL-1ß-triggered CHON-001 cell dysfunction. In addition, upregulated miR-16-5p suppressed IL-1ß-elicited activation of MAPK pathway in CHON-001 cells. CONCLUSIONS: MiR-16-5p mitigates IL-1ß-induced damage to chondrocyte CHON-001 by targeting MAP2K1 and inactivating the MAPK signaling.

Targeting lncRNA DDIT4-AS1 Sensitizes Triple Negative Breast Cancer to Chemotherapy via Suppressing of Autophagy.

In this study, it is found that the lncRNA, DNA damage inducible transcript 4 antisense RNA1 (DDIT4-AS1), is highly expressed in triple-negative breast cancer (TNBC) cell lines and tissues due to H3K27 acetylation in the promoter region, and promotes the proliferation, migration, and invasion of TNBC cells via activating autophagy. Mechanistically, it is shown that DDIT4-AS1 induces autophagy by stabilizing DDIT4 mRNA via recruiting the RNA binding protein AUF1 and promoting the interaction between DDIT4 mRNA and AUF1, thereby inhibiting mTOR signaling pathway. Furthermore, silencing of DDIT4-AS1 enhances the sensitivity of TNBC cells to chemotherapeutic agents such as paclitaxel both in vitro and in vivo. Using a self-activatable siRNA/drug core-shell nanoparticle system, which effectively deliver both DDIT4-AS1 siRNA and paclitaxel to the tumor-bearing mice, a significantly enhanced antitumor activity is achieved. Importantly, the codelivery nanoparticles exert a stronger antitumor effect on breast cancer patient-derived organoids. These findings indicate that lncRNA DDIT4-AS1-mediated activation of autophagy promotes progression and chemoresistance of TNBC, and targeting of DDIT4-AS1 may be exploited as a new therapeutic approach to enhancing the efficacy of chemotherapy against TNBC.