FTH1 protects against osteoarthritis by MAPK pathway inhibition of extracellular matrix degradation.

OBJECTIVE: Ferritin heavy chain 1 (FTH1) is an important subunit of ferro-storing proteins and is indispensable for iron metabolism. Though it has been extensively studied in numerous organs and diseases, the relationship between FTH1 and osteoarthritis (OA) is unclear. DESIGN: Primary murine chondrocytes and cartilage explants were treated with FTH1 siRNA for 72 h. Mice were injected with adenovirus expressing FTH1 after destabilized medial meniscus (DMM) surgery. These approaches were used to determine the effect of FTH1 expression on the pathophysiology of OA. RESULTS: FTH1 expression was down regulated in OA patients and mice after DMM surgery. Knock down of FTH1 induced articular cartilage damage and extracellular matrix degradation in cartilage explants. Further, over expression of FTH1 reduced the susceptibility of chondrocytes to ferroptosis and reversed decrements in SOX9 and aggrecan after DMM surgery. Moreover, FTH1 relieved OA by inhibition of the chondrocyte MAPK pathway. CONCLUSION: This study found FTH1 to play an essential role in extracellular matrix degradation, ferroptosis, and chondrocytes senescence during OA progression. Further, injection of adenovirus expressing FTH1 may be a potential strategy for OA prevention and therapy.

A Comprehensive Strategy Based on High Clinical Translational Nanosystem for Programmable Immunotherapy of Triple Negative Breast Cancer.

Triple negative breast cancer (TNBCs), known as an immunologically cold tumor, is difficult to completely eliminate with existing monotherapies, let alone metastasis and recurrence. It is urgent to design a rational combination of multiple therapies to programmatically reconstitute tumor microenvironment (TME) and reverse the immune "cold" into "hot" inflammatory tumors to improve the therapeutic effect. Hence, in this work, a multifunctional nanosystem (FeSH NPs) that integrates metal-polyphenol coordination complex as a photothermal agent and polyphenol, salvianolic acid B (SAB) as immunomodulator is designed and fabricated for synergistic photothermal-immunotherapy of TNBCs combined with anti-PD-L1 antibody. Guided by photothermal/photoacoustic dual-mode imaging, photothermal therapy (PTT) caused by FeSH NPs induces immunogenic cell death (ICD) under 808 nm laser irradiation. Subsequently, the loaded SAB is released with the addition of deferoxamine mesylate (DFO) to remodel TME, specifically TGF-ß inhibition and PD-L1 upregulation, and eliminate the primary tumors. The combination of PTT and TME reprogramming by FeSH NPs further synergizes with anti-PD-L1 antibody to eradicate recurrence and inhibit metastasis of TNBCs concurrently. Given the biosafety of FeSH NPs throughout the lifecycle, this work provides a protocol with high clinical translational promise for comprehensive programmed therapeutics of immunologically cold tumors TNBCs.

Topical hemostatic agents in spinal surgery.

Spinal surgery can be associated with significant intraoperative blood loss which may lead to various complications. As the number of patients undergoing spinal surgery increases over time, accurate and effective hemostasis becomes critically important. Despite various surgical hemostatic techniques, conventional interventions such as compression, suture, ligation, and heat-generating cautery, are not suitable for osseous and epidural venous plexus bleeding during spinal procedures. Therefore, a variety of hemostatic agents have been developed to promote hemostasis. As they differ in terms of mechanism, form, application and potential adverse reactions, it is important to understand the natural features of existing agents. Here we comprehensively review currently available topical hemostatic agents from different sources and summarize their mechanisms of action, applications, and current or potential utilization in spinal surgery. We found hemostatic agents from different sources exert hemostatic actions through different mechanisms. In addition, topical hemostatic agents play various roles in spinal surgery including as hemostatic agent, dura mater repair, drug-carrier, skin closure, and fibrosis prevention. Compressive neurological complications are the most common complications of these hemostatic agents. Therefore, optimal use in spinal environments should match their features, indications, and efficacy with clinical conditions.

Facile Synthesis of High Molecular Weight Poly(ethylene glycol)-b-poly(amino acid)s by Relay Polymerization.

Poly(amino acid)s (PAAs) are one kind of favorable biopolymer that can be used as a drug or gene carrier. However, conventional ring-opening polymerization of PAAs is slow and needs a strict anhydrous environment with an anhydrous reagent as well as the product without enough high molecular weight (Mn), which limits the expanding of PAAs' application. Herein, we took BLG-NCA as the monomer to quickly synthesize one kind of high Mn amphiphilic copolymer, poly(ethylene glycol)-b-poly(γ-benzyl-l-glutamic acid) (PEG-PBLG), by relay polymerization with a simple one-pot method within 3 h in mild conditions (open air, moisture insensitive). In the polymerization process, ring-opening polymerization-induced self-assembly in sodium bicarbonate aqueous solution first occurred to obtain low Mn PEG-PBLG seeds without purification. Then γ-benzyl-l-glutamate N-carboxyanhydride (BLG-NCA) dichloromethane solution was added into PEG-PBLG seeds directly and stirred vigorously to form am emulsion; during this process, the amphiphilic PEG-PBLG seeds will anchor on the interface of DCM and water to ensure the concentration of α-helix rigid PBLG in DCM to maintain the following relay polymerization. Then, high Mn PEG-PBLG was obtained in mild conditions in one pot. We found that the α-helix rigid structure was essential for relay polymerization by studying the synthetic speed of amphiphilic copolymer with different secondary structures. MOE simulation results showed that PBLG and BLG-NCA tended to form a double hydrogen bond, which was beneficial to relay polymerization because of higher local concentrations that can produce more double hydrogen bonds. Our strategy can quickly obtain high Mn PEG-PBLG (224.9 KDa) within 3 h from PEG-NH2 and BLG-NCA in one pot and did not need an extra initiator. After deprotection, the poly(ethylene glycol)-b-poly(l-glutamate acid) (PEG-PGA) with high Mn as a second product can be used as an excellent antitumor drug carrier. The high Mn PEG-PGA can achieve an encapsulation rate of 86.7% and a drug loading rate of 47.3%, which is twice that of the low Mn PEG-PGA. As a result, the synthesis of PEG-PBLG by relay polymerization simplified the process of PEG-PAA polymerization and increased the Mn. In addition, this method opened a way to obtain other kinds of high Mn PEG-PBLG values in the future.

Innovative ultrasound-guided one-stop surgery for complex cardiovascular cases: a case report.

Elderly patients with multiple comorbidities often face complex cardiac challenges, including aortic valve issues and atrial septal defects. Traditional open-heart surgery may not be viable for this demographic. Transcatheter aortic valve implantation (TAVI) emerges as a preferred alternative. In this case, a frail patient with multiple comorbidities, atrial septal defect, and significant aortic stenosis and regurgitation underwent a one-stop procedure, combining TAVI and atrial septal defect closure, guided by advanced imaging, including three-dimensional ultrasound. Ultrasound played a pivotal role in the perioperative phase, offering precise screening and guidance. This innovative technique, minimizing surgical trauma and recovery time, significantly improved the patient's quality of life.

Efficient adsorption of radioactive iodine by covalent organic framework/chitosan aerogel.

Radioactive iodine is considered one of the most dangerous radioactive elements in nuclear waste. Therefore, effective capture of radioactive iodine is essential for developing and using nuclear energy to solve the energy crisis. Some materials that have been developed for removing radioactive iodine still suffer from complex synthesis, low removal capacity, and non-reusability. Herein, covalent organic framework (COF)/chitosan (CS) aerogels were prepared using vacuum freeze-drying, and the COF nanoparticles were tightly attached on the green biomass material CS networks. Due to the synergistic effect of both COF and CS, the composite aerogel shows a three-dimensional porous and stable structure in the recycle usage. The COF/CS aerogel exhibits excellent iodine adsorption capacity of 2211.58 mg g-1 and 5.62 g g-1 for static iodine solution and iodine vapor, respectively, better than some common adsorbents. Furthermore, COF/CS aerogel demonstrated good recyclability performance with 87 % of the initial adsorption capacity after 5 cycles. In addition, the interaction between iodine and imine groups, amino groups, and benzene rings of aerogel are the possible adsorption mechanisms. COF/CS aerogel has excellent adsorption properties, good chemical stability, and reusable performance, which is a potential and efficient adsorbent for industrial radioactive iodine adsorption from nuclear waste.

High-efficient removal of anionic dye from aqueous solution using metal-organic frameworks@chitosan aerogel rich in benzene structure.

With the exponentially increase of dye pollutants, the purification of dye wastewater has been an urgent ecological problem. As a novel type of porous adsorbent, metal-organic frameworks still face challenges in recyclability, agglomeration, and environmentally unfriendly synthesis. Herein, MOF-525 was in-situ growth onto the surface of the chitosan (CS) beads to fabricate MOF-525@CS aerogel. CS was utilized as substrate to uniformly disperse MOF-525, thereby significantly mitigating agglomeration and improving recyclability of MOF-525. The characterization results shown that MOF-525@CS aerogel had a high specific surface area of 103.0 m2·g-1, and MOF-525 was uniformly distributed in the 3D porous structure of CS, and the presence of benzoic acid was detected. The MOF-525@CS aerogel had a remarkable adsorption capacity of 1947 mg·g-1 for Congo red, which is greater than the sum of its parts. MOF-525@CS aerogel also inherited the rapid adsorption ability of MOF-525, removing 80 % of Congo red within 600 min. Such excellent adsorption performance can be attributed to the benzoic acid trapped by CS via CN band to enhance the π-π stacking interactions. Additionally, the utilization of benzoic acid makes the synthesis process of MOF-525@CS aerogel more environmentally friendly. The high-efficient MOF-525@CS aerogel is a competitive candidate for dye pollution adsorption.

Gut-derived ammonia contributes to alcohol-related fatty liver development via facilitating ethanol metabolism and provoking ATF4-dependent de novo lipogenesis activation.

BACKGROUND & AIMS: Dysbiosis contributes to alcohol-associated liver disease (ALD); however, the precise mechanisms remain elusive. Given the critical role of the gut microbiota in ammonia production, we herein aim to investigate whether and how gut-derived ammonia contributes to ALD. METHODS: Blood samples were collected from human subjects with/without alcohol drinking. Mice were exposed to the Lieber-DeCarli isocaloric control or ethanol-containing diets with and without rifaximin (a nonabsorbable antibiotic clinically used for lowering gut ammonia production) supplementation for five weeks. Both in vitro (NH4Cl exposure of AML12 hepatocytes) and in vivo (urease administration for 5 days in mice) hyperammonemia models were employed. RNA sequencing and fecal amplicon sequencing were performed. Ammonia and triglyceride concentrations were measured. The gene and protein expression of enzymes involved in multiple pathways were measured. RESULTS: Chronic alcohol consumption causes hyperammonemia in both mice and human subjects. In healthy livers and hepatocytes, ammonia exposure upregulates the expression of urea cycle genes, elevates hepatic de novo lipogenesis (DNL), and increases fat accumulation. Intriguingly, ammonia promotes ethanol catabolism and acetyl-CoA formation, which, together with ammonia, synergistically facilitates intracellular fat accumulation in hepatocytes. Mechanistic investigations uncovered that ATF4 activation, as a result of ER stress induction and general control nonderepressible 2 activation, plays a central role in ammonia-provoked DNL elevation. Rifaximin ameliorates ALD pathologies in mice, concomitant with blunted hepatic ER stress induction, ATF4 activation, and DNL activation. CONCLUSIONS: An overproduction of ammonia by gut microbiota, synergistically interacting with ethanol, is a significant contributor to ALD pathologies.

Validation of the Chinese version of the Sleep Regularity Questionnaire (SRQ) and analysis of influencing factors.

BACKGROUND: Currently, there is no instrument to measure sleep regularity in China. In this study, the Sleep Regularity Questionnaire（SRQ） was translated into Chinese, tested for reliability and validity, and analyzed for factors affecting sleep regularity. METHODS: The English version of the SRQ was translated into Chinese, and a total of 3642 individuals were included in this research. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were used to examine the underlying factor structure of the Chinese version of the SRQ and to measure its reliability and validity. In addition, the correlations between sleep regularity and general information, personal habits, self-control, stress, anxiety, and depression were explored. RESULTS: The Cronbach's α of the Chinese SRQ was 0.858, supporting the two-factor structure. Sleep regularity was statistically different between gender and ethnicity (p < 0.05), and personal habits (exercise, continued eating after dinner, smoking and drinking) had an effect on sleep regularity. Sleep regularity was positively associated with individual self-control and negatively associated with stress, anxiety, and depression. CONCLUSIONS: The Chinese version of the SRQ has excellent reliability and validity. There are two dimensions, namely circadian regularity and sleep continuity regularity, which can be used to assess the sleep regularity of Chinese adults. The results of this study showed that males and Han Chinese having better sleep regularity. And people with good lifestyle habits and greater self-control sleep more regularly, while stress, anxiety and depression can affect individuals' sleep regularity.

Enzymatic Acylation of Black Rice Anthocyanins and Evaluation of Antioxidant Capacity and Stability of Their Derivatives.

In this study, the structure of the anthocyanin fractions isolated from black rice (Oryza sativa L.) was modified by the enzyme catalysis method using caffeic acid as an acyl donor. At the same time, the effects of the acylation on the lipophilicity, antioxidant activity, and stability of black rice anthocyanins were comprehensively evaluated. The structural analyses of acylated derivatives based on ultraviolet-visible spectroscopy, Fourier-transform infrared spectroscopy, ultra-high-performance liquid chromatography-high-resolution mass spectrometry, and thermogravimetric analysis revealed that caffeic acid was efficiently grafted onto the anthocyanins of black rice through an acylated reaction, while the acylation binding site was on glucoside. When the mass ratios of anthocyanins to caffeic acid were 1:1, the A319/AVis-max value of acylated anthocyanins reached 6.37. Meanwhile, the lipophilicity of acylated derivatives was enhanced. The antioxidant capacity (DPPH and FRAP) and stability (thermal, pH, and light stability) were significantly increased. Overall, the study results provide deeper insights into controlling anthocyanin homeostasis in food processing, broadening the application of colored grain products.

Optimization of the Extraction Strategy for Polyphenols from Pieris Japonica and Evaluation of Its Antioxidant Activity.

Pieris Japonica, belonging to the Rhododendron family, is known for its anti-insect and analgesic properties. Despite previous research, the components and antioxidant activity of Pieris Japonica extract remain unclear. This study aims to identify the optimal extraction process for Pieris Japonica, determine its components, and evaluate its antioxidant capacity. An L9 (34) orthogonal method was employed to optimize the Pieris Japonica extraction process, with the polyphenol content serving as the extraction efficiency index. The extracted components were identified by high-performance liquid chromatography-mass spectrometry (HPLC/MS-MS). Antioxidant activity was assessed via the DPPH test, ABTS radical scavenging test, and FRAP reduction ability test. The optimal extraction process involved soaking Pieris Japonica powder in 60% ethanol with a weight-to-volume ratio of 1:20 (g/mL), followed by eight hours of reflux at 50°C. Under these conditions, the total polyphenol content was 11.2 ± 0.6 mg/g. HPLC/MS-MS revealed that flavonoids were the primary components in the Pieris Japonica extract. The FRAP method determined the total antioxidant capacity to be 1.00 ± 0.05 µmol/mL, while the DPPH method showed a radical scavenging rate of 42.21 ± 4.02%, and the ABTS method yielded a 85.74% scavenging rate, indicating a strong antioxidant activity. The primary components of Pieris Japonica extract were flavonoids, and the extracted plant material exhibited potent antioxidant activity.

[Platelet-rich Plasma Induces M2 Macrophage Polarization via Regulating AMPK Singling Pathway].

OBJECTIVE: To investigate the role of platelet-rich plasma (PRP) in inducing the M2 macrophage polarization via regulating AMPK singling pathway. METHODS: The expressions of M1 marker CD11c and M2 marker CD206 in macrophages of blank control group, LPS group, LPS+PRP group, and LPS+PRP+Compound C group were detected by flow cytometry. Western blot was used to observe the effects of PRP on the expression of AMPK-mTOR signaling pathway-related proteins at different times (12 h, 18 h and 24 h) after LPS treatment. RNA interference technology was used to silence the expression of AMPK in macrophages, and the expression of TGF-ß protein was subsequently examined by Western blot. RESULTS: LPS significantly reduced the expression of CD206 and increased the expression of CD11c (P <0.05). After the addition of PRP, the expression of CD206 was significantly increased (P <0.05), while the expression of CD11c was significantly decreased (P <0.05). Compared with LPS group, PRP treatment significantly increased the expressions of p-AMPK and p-ULK1 proteins at 12 h, 18 h and 24 h, while significantly decreased the expression of p-mTOR protein (P <0.05). After the addition of AMPK inhibitor Compound C, the expression of CD206 was significantly reduced (P <0.05) and the expression of CD11c was significantly increased compared with LPS+PRP group (P <0.05). After silencing the expression of AMPK in macrophages, the promotion effect of PRP on TGF-ß was significantly reduced (P <0.05). CONCLUSION: PRP can stimulate the transformation of macrophages to M2 type via AMPK signalling pathway.

HSP90B1-mediated plasma membrane localization of GLUT1 promotes radioresistance of glioblastomas.

Ionizing radiation is a popular and effective treatment option for glioblastoma (GBM). However, resistance to radiation therapy inevitably occurs during treatment. It is urgent to investigate the mechanisms of radioresistance in GBM and to find ways to improve radiosensitivity. Here, we found that heat shock protein 90 beta family member 1 (HSP90B1) was significantly upregulated in radioresistant GBM cell lines. More importantly, HSP90B1 promoted the localization of glucose transporter type 1, a key rate-limiting factor of glycolysis, on the plasma membrane, which in turn enhanced glycolytic activity and subsequently tumor growth and radioresistance of GBM cells. These findings imply that targeting HSP90B1 may effectively improve the efficacy of radiotherapy for GBM patients, a potential new approach to the treatment of glioblastoma.

Comparison of efficacy of single-port versus conventional laparoscopic treatment for uterine leiomyoma: a latest meta-analysis.

Objective: Single-port laparoscopy has been proposed as an ideal surgical method for the treatment of uterine leiomyoma. It can effectively remove the lesion, reduce the loss of hemoglobin, and has superior cosmetic effects. Therefore, we searched relevant studies and conducted a meta-analysis to evaluate the effect of single-port laparoscopy on myoma resection, hemoglobin loss, and scar beauty compared to conventional laparoscopy. Methods: We systematically searched PubMed, EMBASE, scope, Cochrane, CNKI, and other databases to find randomized controlled studies on the efficacy of single-port laparoscopy and traditional laparoscopy for meta-analysis. The main outcomes of our study were the duration of surgery, the reduction of hemoglobin, and the cosmetic effect of the postoperative scar. The effect model was selected according to heterogeneity (random effect model or fixed effect model), and the relevant sensitivity analysis and publication bias test were performed. Results: We searched a total of 501 related literature articles and finally included 19 studies involving 21 researchers. Comparison of single-port laparoscopic myomectomy with traditional surgery: Operation time had no significant difference (Standardized Mean Difference [SMD]: 0.13, 95% Confidence interval (CI), -0.04 to 0.30; I²=74%; P = 0.14); The reduction of hemoglobin is lower ([SMD]: -0.04; 95% CI, -0.23 to 0.14; I²=71%; P = 0.65), and the cosmetic effect of postoperative scar is more satisfactory ([SMD]: 0.42, 95% CI: 0.02 to 0.83; I²=72%, P= 0.04). There was no significant difference in conversion rate, postoperative pain, blood loss, postoperative gastrointestinal recovery time, or length of hospital stay. Conclusion: Compared with traditional laparoscopy, the operation time of the treatment of uterine leiomyoma by single-port laparoscopy is not extended, the reduction of hemoglobin is less, and the cosmetic effect of the scar is better. Therefore, single-port laparoscopy is superior to traditional surgery in the treatment of uterine leiomyoma. Systematic review registration: https://inplasy.com/inplasy-2023-3-0071/, identifier INPLASY202330071.

Electroacupuncture activates angiogenesis by regulating the PI3K/Pten/Thbs1 signaling pathway to promote the browning of adipose tissue in HFD-induced obese mice.

This study investigated the effect of electroacupuncture (EA) on the browning of white adipose tissue (WAT) via angiogenesis and its potential mechanism in obese mice. Four-week-old male C56BL/6 mice were randomly divided into a high-fat diet (HFD) and a normal chow diet (ND) group. After 12 weeks, HFD mice were randomly divided into two groups to receive or not receive EA for 3 weeks. After EA treatment, body weight, adipocyte size, serum glucose (GLU), triacylglycerol (TG), cholesterol (CHO), leptin (Lep), monocyte chemoattractant protein-1 (MCP-1), WAT browning-related genes, angiogenesis-related genes, and the PI3K/Pten/Thbs1 signaling pathway were evaluated. The results indicated that EA significantly reduced body weight, adipocyte size, and serum concentrations of GLU, TG, CHO, Lep and MCP-1 and promoted WAT browning. Angiogenesis and the PI3K/Pten/Thbs1 signaling pathway were all activated by EA intervention. The expression levels were consistent with the results of RNA-seq and confirmed via qRTPCR and WB. Our study showed that EA may activate angiogenesis via the PI3K/Pten/Thbs1 signaling pathway in WAT, thereby promoting the browning and thermogenesis of adipose tissue.

METTL3-mediated m6A modification of LINC00839 maintains glioma stem cells and radiation resistance by activating Wnt/ß-catenin signaling.

Long noncoding RNAs (lncRNAs) are involved in glioma initiation and progression. Glioma stem cells (GSCs) are essential for tumor initiation, maintenance, and therapeutic resistance. However, the biological functions and underlying mechanisms of lncRNAs in GSCs remain poorly understood. Here, we identified that LINC00839 was overexpressed in GSCs. A high level of LINC00839 was associated with GBM progression and radiation resistance. METTL3-mediated m6A modification on LINC00839 enhanced its expression in a YTHDF2-dependent manner. Mechanistically, LINC00839 functioned as a scaffold promoting c-Src-mediated phosphorylation of ß-catenin, thereby inducing Wnt/ß-catenin activation. Combinational use of celecoxib, an inhibitor of Wnt/ß-catenin signaling, greatly sensitized GSCs to radiation. Taken together, our results showed that LINC00839, modified by METTL3-mediated m6A, exerts tumor progression and radiation resistance by activating Wnt/ß-catenin signaling.

Alcoholic Setdb1 suppression promotes hepatosteatosis in mice by strengthening Plin2.

BACKGROUND AND AIMS: Hepatosteatosis is one of the early features of alcoholic liver disease (ALD) and pharmaceutical or genetic interfering of the development of hepatosteatosis will efficiently alleviate the progression of ALD. Currently, the role of histone methyltransferase Setdb1 in ALD is not yet well understood. METHOD: Lieber-De Carli diet mice model and NIAAA mice model were constructed to confirm the expression of Setdb1. The hepatocyte-specific Setdb1-knockout (Setdb1-HKO) mice was established to determine the effects of Setdb1 in vivo. Adenovirus-Setdb1 were produced to rescue the hepatic steatosis in both Setdb1-HKO and Lieber-De Carli mice. The enrichment of H3k9me3 in the upstream sequence of Plin2 and the chaperone-mediated autophagy (CMA) of Plin2 were identified by ChIP and co-IP. Dual-luciferase reporter assay was used to detect the interaction of Setdb1 3'UTR and miR216b-5p in AML12 or HEK 293 T cells. RESULTS: We found that Setdb1 was downregulated in the liver of alcohol-fed mice. Setdb1 knockdown promoted lipid accumulation in AML12 hepatocytes. Meanwhile, hepatocyte-specific Setdb1-knockout (Setdb1-HKO) mice exhibited significant lipid accumulation in the liver. Overexpression of Setdb1 was performed with an adenoviral vector through tail vein injection, which ameliorated hepatosteatosis in both Setdb1-HKO and alcoholic diet-fed mice. Mechanistically, downregulated Setdb1 promoted the mRNA expression of Plin2 by desuppressing H3K9me3-mediated chromatin silencing in its upstream sequence. Pin2 acts as a critical membrane surface-associated protein to maintain lipid droplet stability and inhibit lipase degradation. The downregulation of Setdb1 also maintained the stability of Plin2 protein through inhibiting Plin2-recruited chaperone-mediated autophagy (CMA). To explore the reasons for Setdb1 suppression in ALD, we found that upregulated miR-216b-5p bound to the 3'UTR of Setdb1 mRNA, disturbed its mRNA stability, and eventually aggravated hepatic steatosis. CONCLUSIONS: Setdb1 suppression plays an important role in the progression of alcoholic hepatosteatosis via elevating the expression of Plin2 mRNA and maintaining the stability of Plin2 protein. Targeting hepatic Setdb1 might be a promising diagnostic or therapeutic strategy for ALD.

Eukaryotic initiation factor 3b regulates the development and progression of breast cancer.

The tumorigenesis of breast cancer is a complex process involving multiple factors, among which abnormal gene expression is a key event. Nevertheless, studies on the regulation of gene expression have focused primarily on the transcriptional level, although the abnormal translation regulation is also closely related to tumorigenesis. Accumulating evidence has indicated the dysregulation of eukaryotic initiation factor (eIF) subunits in a variety of tumors, which contributes to the malignant transformation, tumor growth, metastasis, and the prognosis of patients. In this study, we examined the expression of eIF3b and found an upregulation of eIF3b in breast cancer cell lines as well as tumor tissues. In addition, the expression of eIF3b was related to the tumor stage with highest eIF3b expression in TNM stage III-IV and/or lymph node metastatic breast cancer. Furthermore, in vitro experiments demonstrated that eIF3b knockdown markedly inhibited tumor hyperplasia as well as the migration and invasion of breast cancer cells, while eIF3b overexpression showed the opposite effects. Importantly, eIF3b silencing inhibited the growth and pulmonary metastasis of xenograft tumor in breast cancer mouse model. Mechanistically, we found that eIF3b downregulation suppressed the malignant development of breast cancer by modulating Wnt/ß-catenin pathway. Collectively, our data suggested that eIF3b might not only participate in the tumorigenesis of breast cancer, but also promote the proliferation, invasion, and metastasis of tumor cells. Thus, eIF3b may service as a potential therapeutic target for the treatment of patients with breast cancer.

Brown adipose tissue-derived exosomes delay fertility decline in aging mice.

Introduction: Ovarian aging has steadily grown to be a significant health issue for women as a result of the increase in average life expectancy and the postponement of reproductive age. One of the important pathological foundations of ovarian aging is formed by mitochondrial dysfunction, which causes decreases in follicle quantity and oocyte quality. In recent years, brown adipose tissue (BAT) transplantation has been proven as an effective treatment for aging-related diseases, such as ovarian aging. However, BAT transplantation is an invasive operation with long-term risks. Therefore, we need to find an alternative strategy. Methods: We injected BAT-derived exosomes into eight-month-old C57BL/6 female mice. The fertility was detected by the estrous cycle and mating test. The changes of ovary and oocyte were measured by ovarian volume, organ coefficient, follicle counting, and oocyte maturation rate. ROS level, mitochondrial membrane potential and ATP level were measured to analyze the mitochondrial function of oocytes. The changes in metabolism were explored by cold stimulation test, body weight and blood sugar. The possible molecular mechanism was further investigated by RNA sequencing. Results: In terms of fertility, the estrous cycle of aging mice after BAT-derived exosome intervention was more regular, and the number of progenies and litters was increased. At the tissue level, the ovaries in the BAT-exosome group were larger, and the number of primordial follicles, secondary follicles, antral follicles and total follicles increased. At the cellular level, BAT-derived exosomes improved the maturation of oocytes in vivo and in vitro, increased the mitochondrial membrane potential and ATP levels of oocytes, and decreased ROS levels. Besides, BAT-derived exosomes ameliorated the metabolism and viability of aging mice. Furthermore, mRNA sequencing showed that BAT exosomes altered the expression levels of genes related to metabolism and the quality of oocytes. Conclusion: BAT-derived exosomes enhanced mitochondrial function, promoted follicle survival, improved fertility, and extended ovarian lifespan in aging mice.

Comparing the cost-effectiveness of sintilimab + pemetrexed plus platinum and pemetrexed plus platinum alone as a first-line therapy for Chinese patients with nonsquamous non-small cell lung cancer.

Background: Pemetrexed plus platinum alone is the conventional first-line therapy for locally advanced metastatic nonsquamous non-small cell lung cancer (NSCLC) without targetable genetic aberrations. The ORIENT-11 trial revealed that sintilimab + pemetrexed plus platinum could yield more survival benefits for patients with nonsquamous NSCLC. The present study aimed to assess the cost-effectiveness of sintilimab + pemetrexed plus platinum vs. that of pemetrexed plus platinum alone as the first-line therapy for patients with nonsquamous NSCLC to inform clinically rational drug use and provide a basis for medical decision-making. Methods: A partitioned survival model was created to evaluate the cost-effectiveness of two groups from the perspective of the healthcare system in China. The clinical data for adverse event probabilities and extrapolating long-term survival originally collected in a phase III clinical trial (ORIENT-11) were retrieved. Local public databases and literature were used to acquire data on utility and cost. The heemod package in R software was used to calculate the life years (LYs), quality-adjusted LYs (QALYs), and total costs in each group to generate the incremental cost-effectiveness ratio (ICER) in the base case and to conduct deterministic sensitivity analysis (DSA) and probabilistic sensitivity analysis (PSA). Results: Our base case analysis (BCA) revealed that sintilimab combined with pemetrexed plus platinum provided an increase of 0.86 in QALYs with an increasing cost of United State dollar (USD) $4,317.84 relative to pemetrexed plus platinum in Chinese patients with nonsquamous NSCLC who were negative for targetable genetic variations, which induced an ICER of USD $5,020.74/QALY. The ICER value was lower than the set threshold value. The results exhibited strong robustness in the sensitivity analysis. In DSA, the parameter for the overall survival (OS) curve in chemotherapy and the cost of best supportive care were the main factors that impacted the result of the ICER. The PSA indicated that sintilimab and chemotherapy combination therapy was cost-effective. Conclusions: This study suggests that the combination of sintilimab + pemetrexed plus platinum is cost-effective as a first-line therapy in Chinese patients with nonsquamous NSCLC who are negative for targetable genetic variations from the perspective of the healthcare system.