Aptamer-functionalized nanomaterials (AFNs) for therapeutic management of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) represents one of the deadliest cancers globally, making the search for more effective diagnostic and therapeutic approaches particularly crucial. Aptamer-functionalized nanomaterials (AFNs), an innovative nanotechnology, have paved new pathways for the targeted diagnosis and treatment of HCC. Initially, we outline the epidemiological background of HCC and the current therapeutic challenges. Subsequently, we explore in detail how AFNs enhance diagnostic and therapeutic efficiency and reduce side effects through the specific targeting of HCC cells and the optimization of drug delivery. Furthermore, we address the challenges faced by AFNs in clinical applications and future research directions, with a particular focus on enhancing their biocompatibility and assessing long-term effects. In summary, AFNs represent an avant-garde therapeutic approach, opening new avenues and possibilities for the diagnosis and treatment of HCC.

Abnormal mitochondrial iron metabolism damages alveolar type II epithelial cells involved in bleomycin-induced pulmonary fibrosis.

Rationale: Pulmonary fibrosis is a chronic progressive lung disease with limited therapeutic options. We previously revealed that there is iron deposition in alveolar epithelial type II cell (AECII) in pulmonary fibrosis, which can be prevented by the iron chelator deferoxamine. However, iron in the cytoplasm and the mitochondria has two relatively independent roles and regulatory systems. In this study, we aimed to investigate the role of mitochondrial iron deposition in AECII injury and pulmonary fibrosis, and to find potential therapeutic strategies. Methods: BLM-treated mice, MLE-12 cells, and primary AECII were employed to establish the mouse pulmonary fibrosis model and epithelial cells injury model, respectively. Mitochondrial transplantation, siRNA and plasmid transfection, western blotting (WB), quantitative real-time polymerase chain reaction (RT-qPCR), polymerase chain reaction (PCR), immunofluorescence, immunoprecipitation (IP), MitoSOX staining, JC-1 staining, oxygen consumption rate (OCR) measurement, and Cell Counting Kit-8 (CCK8) assay were utilized to elucidate the role of mitochondrial iron deposition in cell and lung fibrosis and determine its mechanism. Results: This study showed that prominent mitochondrial iron deposition occurs within AECII in bleomycin (BLM)-induced pulmonary fibrosis mouse model and in BLM-treated MLE-12 epithelial cells. Further, the study revealed that healthy mitochondria rescue BLM-damaged AECII mitochondrial iron deposition and cell damage loss. Mitoferrin-2 (MFRN2) is the main transporter that regulates mitochondrial iron metabolism by transferring cytosolic iron into mitochondria, which is upregulated in BLM-treated MLE-12 epithelial cells. Direct overexpression of MFRN2 causes mitochondrial iron deposition and cell damage. In this study, decreased ubiquitination of the ubiquitin ligase F-box/LRR-repeat protein 5 (FBXL5) degraded iron-reactive element-binding protein 2 (IREB2) and promoted MFRN2 expression as well as mitochondrial iron deposition in damaged AECII. Activation of the prostaglandin E2 receptor EP4 subtype (EP4) receptor signaling pathway counteracted mitochondrial iron deposition by downregulating IREB2-MFRN2 signaling through upregulation of FBXL5. This intervention not only reduced mitochondrial iron content but also preserved mitochondrial function and protected against AECII damage after BLM treatment. Conclusion: Our findings highlight the unexplored roles, mechanisms, and regulatory approaches of abnormal mitochondrial iron metabolism of AECII in pulmonary fibrosis. Therefore, this study deepens the understanding of the mechanisms underlying pulmonary fibrosis and offers a promising strategy for developing effective therapeutic interventions using the EP4 receptor activator.

Metabolic landscape and pathogenic insights: a comprehensive analysis of high ovarian response in infertile women undergoing in vitro fertilization.

BACKGROUND: In the realm of assisted reproduction, a subset of infertile patients demonstrates high ovarian response following controlled ovarian stimulation (COS), with approximately 29.7% facing the risk of Ovarian Hyperstimulation Syndrome (OHSS). Management of OHSS risk often necessitates embryo transfer cancellation, leading to delayed prospects of successful pregnancy and significant psychological distress. Regrettably, these patients have received limited research attention, particularly regarding their metabolic profile. In this study, we aim to utilize gas chromatography-mass spectrometry (GC-MS) to reveal these patients' unique serum metabolic profiles and provide insights into the disease's pathogenesis. METHODS: We categorized 145 infertile women into two main groups: the CON infertility group from tubal infertility patients and the Polycystic Ovary Syndrome (PCOS) infertility group. Within these groups, we further subdivided them into four categories: patients with normal ovarian response (CON-NOR group), patients with high ovarian response and at risk for OHSS (CON-HOR group) within the CON group, as well as patients with normal ovarian response (PCOS-NOR group) and patients with high ovarian response and at risk for OHSS (PCOS-HOR group) within the PCOS group. Serum metabolic profiles were analyzed using GC-MS. The risk criteria for OHSS were: the number of developing follicles > 20, peak Estradiol (E2) > 4000pg/mL, and Anti-Müllerian Hormone (AMH) levels > 4.5ng/mL. RESULTS: The serum metabolomics analysis revealed four different metabolites within the CON group and 14 within the PCOS group. Remarkably, 10-pentadecenoic acid emerged as a discernible risk metabolite for the CON-HOR, also found to be a differential metabolite between CON-NOR and PCOS groups. cysteine and 5-methoxytryptamine were also identified as risk metabolites for the PCOS-HOR. Furthermore, KEGG analysis unveiled significant enrichment of the aminoacyl-tRNA biosynthesis pathway among the metabolites differing between PCOS-NOR and PCOS-HOR. CONCLUSION: Our study highlights significant metabolite differences between patients with normal ovarian response and those with high ovarian response and at risk for OHSS within both the tubal infertility control group and PCOS infertility group. Importantly, we observe metabolic similarities between patients with PCOS and those with a high ovarian response but without PCOS, suggesting potential parallels in their underlying causes.

Differential mRNA profiles reveal the potential roles of genes involved in lactate stimulation in mouse macrophages.

Lactate is a glycolysis end product, and its levels are markedly associated with disease severity, morbidity, and mortality in sepsis. It modulates key functions of immune cells, including macrophages. In this investigation, transcriptomic analysis was performed using lactic acid, sodium lactate, and hydrochloric acid-stimulated mouse bone marrow-derived macrophages (iBMDM), respectively, to identify lactate-associated signaling pathways. After 24 h of stimulation, 896 differentially expressed genes (DEG) indicated were up-regulation, whereas 792 were down-regulated in the lactic acid group, in the sodium lactate group, 128 DEG were up-regulated, and 41 were down-regulated, and in the hydrochloric acid group, 499 DEG were up-regulated, and 285 were down-regulated. Subsequently, clinical samples were used to further verify the eight genes with significant differences, among which Tssk6, Ypel4, Elovl3, Trp53inp1, and Cfp were differentially expressed in patients with high lactic acid, indicating their possible involvement in lactic acid-induced inflammation and various physiological diseases caused by sepsis. However, elongation of very long chain fatty acids protein 3 (Elovl3) was negatively correlated with lactic acid content in patients. The results of this study provide a necessary reference for better understanding the transcriptomic changes caused by lactic acid and explain the potential role of high lactic acid in the regulation of macrophages in sepsis.

Insight into the Gas-Induced Phase Transformations in a 2D Switching Coordination Network via Coincident Gas Sorption and In Situ PXRD.

Switching coordination networks (CNs) that reversibly transform between narrow or closed pore (cp) and large pore (lp) phases, though fewer than their rigid counterparts, offer opportunities for sorption-related applications. However, their structural transformations and switching mechanisms remain underexplored at the molecular level. In this study, we conducted a systematic investigation into a 2D switching CN, [Ni(bpy)2(NCS)2]n, sql-1-Ni-NCS (1 = bpy = 4,4'-bipyridine), using coincident gas sorption and in situ powder X-ray diffraction (PXRD) under low-temperature conditions. Gas adsorption measurements revealed that C2H4 (169 K) and C2H6 (185 K) exhibited single-step type F-IVs sorption isotherms with sorption uptakes of around 180-185 cm3 g-1, equivalent to four sorbate molecules per formula unit. Furthermore, parallel in situ PXRD experiments provided insight into sorbate-dependent phase switching during the sorption process. Specifically, CO2 sorption induced single-step phase switching (path I) solely between cp and lp phases consistent with the observed single-step type F-IVs sorption isotherm. By contrast, intermediate pore (ip) phases emerged during C2H4 and C2H6 desorption as well as C3H6 adsorption, although they remained undetectable in the sorption isotherms. To our knowledge, such a cp-lp-ip-cp transformation (path II) induced by C2H4/6 and accompanied by single-step type F-IVs sorption isotherms represents a novel type of phase transition mechanism in switching CNs. By virtue of Rietveld refinements and molecular simulations, we elucidated that the phase transformations are governed by cooperative local and global structural changes involving NCS- ligand reorientation, bpy ligand twist and rotation, cavity edge (Ni-bpy-Ni) deformation, and interlayer expansion and sliding.

Ethane/Ethylene Separations in Flexible Diamondoid Coordination Networks via an Ethane-Induced Gate-Opening Mechanism.

Separating ethane (C2H6) from ethylene (C2H4) is an essential and energy-intensive process in the chemical industry. Here, we report two flexible diamondoid coordination networks, X-dia-1-Ni and X-dia-1-Ni0.89Co0.11, that exhibit gate-opening between narrow-pore (NP) and large-pore (LP) phases for C2H6, but not for C2H4. X-dia-1-Ni0.89Co0.11 thereby exhibited a type F-IV isotherm at 273 K with no C2H6 uptake and a high uptake (111 cm3 g-1, 1 atm) for the NP and LP phases, respectively. Conversely, the LP phase exhibited a low uptake of C2H4 (12.2 cm3 g-1). This C2H6/C2H4 uptake ratio of 9.1 for X-dia-1-Ni0.89Co0.11 far surpassed those of previously reported physisorbents, many of which are C2H4-selective. In situ variable-pressure X-ray diffraction and modeling studies provided insight into the abrupt C2H6-induced structural NP to LP transformation. The promise of pure gas isotherms and, more generally, flexible coordination networks for gas separations was validated by dynamic breakthrough studies, which afforded high-purity (99.9%) C2H4 in one step.

Semisupervised 3D segmentation of pancreatic tumors in positron emission tomography/computed tomography images using a mutual information minimization and cross-fusion strategy.

Background: Accurate segmentation of pancreatic cancer tumors using positron emission tomography/computed tomography (PET/CT) multimodal images is crucial for clinical diagnosis and prognosis evaluation. However, deep learning methods for automated medical image segmentation require a substantial amount of manually labeled data, making it time-consuming and labor-intensive. Moreover, addition or simple stitching of multimodal images leads to redundant information, failing to fully exploit the complementary information of multimodal images. Therefore, we developed a semisupervised multimodal network that leverages limited labeled samples and introduces a cross-fusion and mutual information minimization (MIM) strategy for PET/CT 3D segmentation of pancreatic tumors. Methods: Our approach combined a cross multimodal fusion (CMF) module with a cross-attention mechanism. The complementary multimodal features were fused to form a multifeature set to enhance the effectiveness of feature extraction while preserving specific features of each modal image. In addition, we designed an MIM module to mitigate redundant high-level modal information and compute the latent loss of PET and CT. Finally, our method employed the uncertainty-aware mean teacher semi-supervised framework to segment regions of interest from PET/CT images using a small amount of labeled data and a large amount of unlabeled data. Results: We evaluated our combined MIM and CMF semisupervised segmentation network (MIM-CMFNet) on a private dataset of pancreatic cancer, yielding an average Dice coefficient of 73.14%, an average Jaccard index score of 60.56%, and an average 95% Hausdorff distance (95HD) of 6.30 mm. In addition, to verify the broad applicability of our method, we used a public dataset of head and neck cancer, yielding an average Dice coefficient of 68.71%, an average Jaccard index score of 57.72%, and an average 95HD of 7.88 mm. Conclusions: The experimental results demonstrate the superiority of our MIM-CMFNet over existing semisupervised techniques. Our approach can achieve a performance similar to that of fully supervised segmentation methods while significantly reducing the data annotation cost by 80%, suggesting it is highly practicable for clinical application.

Tumor mutational burden as a predictive biomarker for non-small cell lung cancer treated with immune checkpoint inhibitors of PD-1/PD-L1.

BACKGROUND: The significant clinical benefits of PD-1/PD-L1 immune checkpoint inhibitors (ICIP) in non-small cell lung cancer (NSCLC) have been widely recognized, emphasizing the urgent need for a reliable biomarker. In this study, we find the remarkable capacity of tumor mutational burden (TMB) to serve as an accessible and streamlined indicator. PATIENTS AND METHODS: We designed a retrospective cohort study, consisting of 600 NSCLC patients treated with ICIP. Association between TMB and overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) has been explored. RESULTS: A strong positive correlation between TMB levels and OS, PFS rates, clinical benefit has been found when TMB > = 16(TMB > = 16 mutations/megabase (mut/Mb)). However, when TMB < 16, increasing TMB values did not exhibit a gradual stepwise increase in OS and PFS rates. The median months of OS in the TMB > = 16 and < 16 are 35.58, and 10.71 months respectively with average 12.39 months (p < 0.0001). The median months of PFS in the TMB > = 16 and < 16 are not-obtained, and 2.79 months respectively with an average of 3.32 months (p < 0.0001). The DCR in the TMB > = 16 and < 16 are 71.4% and 44.2% respectively with an average of 47.7% (p < 0.0001). The ORR in the TMB > = 16 and < 16 are 49.4% and 20.8% respectively with an average of 24.5% (p < 0.0001). CONCLUSION: The TMB > = 16 shows significantly associated with optimal ICIP treatment outcomes, including higher patient survival rates, delayed disease progression, and significant clinical benefits. These results present the potential of TMB as a promising biomarker candidate for NSCLC patients undergoing ICIP treatment.

Regulatory effects of natural products on N6-methyladenosine modification: A novel therapeutic strategy for cancer.

N6-methyladenosine (m6A) is considered to be the most common and abundant epigenetics modification in messenger RNA (mRNA) and noncoding RNA. Abnormal modification of m6A is closely related to the occurrence, development, progression, and prognosis of cancer. m6A regulators have been identified as novel targets for anticancer drugs. Natural products, a rich source of traditional anticancer drugs, have been utilized for the development of m6A-targeting drugs. Here, we review the key role of m6A modification in cancer progression and explore the prospects and structural modification mechanisms of natural products as potential drugs targeting m6A modification for cancer treatment.

J24335 exerts neuroprotective effects against 6-hydroxydopamine-induced lesions in PC12 cells and mice.

Parkinson's disease is the second most prevalent age-related neurodegenerative disease and disrupts the lives of people aged >60 years. Meanwhile, single-target drugs becoming inapplicable as PD pathogenesis diversifies. Mitochondrial dysfunction and neurotoxicity have been shown to be relevant to the pathogenesis of PD. The novel synthetic compound J24335 (11-Hydroxy-1-(8-methoxy-5-(trifluoromethyl)quinolin-2-yl)undecan-1-one oxime), which has been researched similarly to J2326, has the potential to be a multi-targeted drug and alleviate these lesions. Therefore, we investigated the mechanism of action and potential neuroprotective function of J24335 against 6-OHDA-induced neurotoxicity in mice, and in PC12 cell models. The key target of action of J24335 was also screened. MTT assay, LDH assay, flow cytometry, RT-PCR, LC-MS, OCR and ECAR detection, and Western Blot analysis were performed to characterize the neuroprotective effects of J24335 on PC12 cells and its potential mechanism. Behavioral tests and immunohistochemistry were used to evaluate behavioral changes and brain lesions in mice. Moreover, bioinformatics was employed to assess the drug-likeness of J24335 and screen its potential targets. J24335 attenuated the degradation of mitochondrial membrane potential and enhanced glucose metabolism and mitochondrial biosynthesis to ameliorate 6-OHDA-induced mitochondrial dysfunction. Animal behavioral tests demonstrated that J24335 markedly improved motor function and loss of TH-positive neurons and dopaminergic nerve fibers, and contributed to an increase in the levels of dopamine and its metabolites in brain tissue. The activation of both the CREB/PGC-1α/NRF-1/TFAM and PKA/Akt/GSK-3ß pathways was a major contributor to the neuroprotective effects of J24335. Furthermore, bioinformatics predictions revealed that J24335 is a low toxicity and highly BBB permeable compound targeting 8 key genes (SRC, EGFR, ERBB2, SYK, MAPK14, LYN, NTRK1 and PTPN1). Molecular docking suggested a strong and stable binding between J24335 and the 8 core targets. Taken together, our results indicated that J24335, as a multi-targeted neuroprotective agent with promising therapeutic potential for PD, could protect against 6-OHDA-induced neurotoxicity via two potential pathways in mice and PC12 cells.

[Effect of 4 kinds of prosthodontic materials on masticatory and gingival function].

PURPOSE: To investigate the effect of 4 kinds of prosthodontic materials on masticatory and gingival function. METHODS: A total of 167 patients with dental defects who underwent prosthodontic treatment from October 2019 to January 2022 were collected. They were randomly divided into 4 groups with 41 cases in the pure titanium group, 40 cases in the cobalt-chromium alloy group, 43 cases in the nickel-chromium alloy group and 43 cases in the zirconium dioxide group. The curative effect and satisfaction degree after 6 months of treatment in 4 groups were recorded and compared. The masticatory function (chewing efficiency, bite force), gingival function[plaque index(PLI), gingival index(GI) and sulcus bleeding index(SBI)], gingival crevicular fluid inflammation-related indicators[tumor necrosis factor alpha(TNF-α), interleukin-6(IL-6), aspartate aminotransferase(AST) and alkaline phosphatase (alkaline phosphatase, ALP)] before and after treatment were measured and compared in 4 groups. Statistical analysis was performed with SPSS 20.0 software package. RESULTS: There was no significant difference in curative effect in 4 groups(P＞0.05). Before and after treatment, there was no significant difference in mastication efficiency and bite force in 4 groups(P＞0.05). Before treatment, there was no significant difference in PLI, GI, SBI, gingival crevicular fluid weight, TNF-α, IL-6, AST and ALP in gingival crevicular fluid in 4 groups(P＞0.05). Compared with before treatment, PLI, GI and SBI in 4 groups were decreased after treatment (P＜0.05), and the decrease was in the order of cobalt-chromium alloy group≈nickel-chromium alloy group＜pure titanium group＜zirconia dioxide group. Before treatment, there was no significant difference in the weight of gingival crevicular fluid, TNF-α, IL-6, AST and ALP in gingival crevicular fluid in 4 groups(P＞0.05). The crevicular fluid weight, TNF-α, IL-6, AST and ALP in gingival crevicular fluid were significantly increased(P＜0.05), and the increase was in the order of zirconia group＜pure titanium group＜cobalt-chromium alloy group≈nickel-chromium alloy group. There was no significant difference in restoration integrity and color satisfaction in 4 groups(P＞0.05), but there was significant difference in marginal fitness and sensitivity satisfaction in 4 groups(P＜0.05). CONCLUSIONS: Pure titanium, cobalt-chromium alloy, nickel-chromium alloy and zirconium dioxide can be used for the treatment of dentition defects, and they all can obtain satisfactory chewing function. In addition, zirconium dioxide restoration has the effect of improving gingival function and inflammation-related indicators of gingival crevicular fluid with a broader application prospect.

Herbivory by Striped Stem Borer Triggers Polyamine Accumulation in Host Rice Plants to Promote Its Larval Growth.

Polyamines (PAs) are ubiquitous low-molecular-weight aliphatic polycations in all living organisms, which are crucial for plant response to abiotic and biotic stresses. The role of PAs in plant disease resistance has been well documented. However, their involvement in plant-pest interactions remains unclear. Here, the role of PAs in rice against striped stem borer (SSB, Chilo suppressalis Walker), a destructive pest in rice production worldwide, was investigated. SSB larval infestation led to a substantial accumulation of free putrescine (Put) in rice seedlings, which was in parallel with an elevated expression of host PA biosynthesis genes Arginine Decarboxylase1 (ADC1) and ADC2. Moreover, SSB larval oral secretion application with wounding further raised the transcripts of ADC1 and ADC2 in rice compared with wounding treatment alone. The larval growth on both rice plants and artificial diet was promoted by the exogenous application of PA and inhibited by a PA biosynthesis inhibitor. On the other hand, the rice defense responses, including polyphenol oxidase (PPO) and peroxidase (POD) activities, as well as protease inhibitor level, were enhanced by a Put supplement and reduced by an ADC inhibitor. Our results indicate that SSB herbivory triggers polyamine accumulation in host rice plants, which is beneficial to SSB in rice-SSB interaction.

Omentin-1 induces mechanically activated fibroblasts lipogenic differentiation through pkm2/yap/pparγ pathway to promote lung fibrosis resolution.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by extensive extracellular matrix (ECM) deposition by activated myofibroblasts, which are specialized hyper-contractile cells that promote ECM remodeling and matrix stiffening. New insights on therapeutic strategies aimed at reversing fibrosis by targeting myofibroblast fate are showing promise in promoting fibrosis resolution. Previously, we showed that a novel adipocytokine, omentin-1, attenuated bleomycin (BLM)-induced lung fibrosis by reducing the number of myofibroblasts. Apoptosis, deactivation, and reprogramming of myofibroblasts are important processes in the resolution of fibrosis. Here we report that omentin-1 reverses established lung fibrosis by promoting mechanically activated myofibroblasts dedifferentiation into lipofibroblasts. Omentin-1 promotes myofibroblasts lipogenic differentiation by inhibiting dimerization and nuclear translocation of glycolytic enzymes pyruvate kinase isoform M2 (PKM2) and activation of the downstream Yes-associated protein (YAP) by increasing the cofactor fructose-1,6-bisphosphate (F1, 6BP, FBP). Moreover, omentin-1 activates proliferator-activated receptor gamma (PPARγ) signaling, the master regulator of lipogenesis, and promotes the upregulation of the lipogenic differentiation-related protein perilipin 2 (PLIN2) by suppressing the PKM2-YAP pathway. Ultimately, omentin-1 facilitates myofibroblasts transformation into the lipofibroblast phenotype, with reduced collagen synthesis and enhanced degradation properties, which are crucial mechanisms to clear the ECM deposition in fibrotic tissue, leading to fibrosis resolution. Our results indicate that omentin-1 targets mechanical signal accelerates fibrosis resolution and reverses established lung fibrosis by promoting myofibroblasts lipogenic differentiation, which is closely associated with ECM clearance in fibrotic tissue. These findings suggest that targeting mechanical force to promote myofibroblast lipogenic differentiation is a promising therapeutic strategy against persistent lung fibrosis.

Sp1 mediated the inhibitory effect of glutamate on pulmonary surfactant synthesis.

BACKGROUND: Studies have shown that the release of endogenous glutamate (Glu) participates in lung injury by activating N-methyl-D-aspartate receptor (NMDAR), but the mechanism is still unclear. This study was to investigate the effects and related mechanisms of Glu on the lipid synthesis of pulmonary surfactant (PS) in isolated rat lung tissues. METHODS: The cultured lung tissues of adult SD rats were treated with Glu. The amount of [3H]-choline incorporation into phosphatidylcholine (PC) was detected. RT-PCR and Western blot were used to detect the changes of mRNA and protein expression of cytidine triphosphate: phosphocholine cytidylyltransferase alpha (CCTα), a key regulatory enzyme in PC biosynthesis. Western blot was used to detect the expression of NMDAR1, which is a functional subunit of NMDAR. Specific protein 1 (Sp1) expression plasmids were used. After transfected with Sp1 expression plasmids, the mRNA and protein levels of CCTα were detected by RT-PCR and Western blot in A549 cells. After treated with NMDA and MK-801, the mRNA and protein levels of Sp1 were detected by RT-PCR and Western blot in A549 cells. RESULTS: Glu decreased the incorporation of [3H]-choline into PC in a concentration- and time- dependent manner. Glu treatment significantly reduced the mRNA and protein levels of CCTα in lungs. Glu treatment up-regulated NMDAR1 protein expression, and the NMDAR blocker MK-801 could partially reverse the reduction of [3H]-choline incorporation induced by Glu (10-4 mol/L) in lungs. After transfected with Sp1 plasmid for 30 h, the mRNA and protein expression levels of CCTα were increased and the protein expression of Sp1 was also up-regulated. After A549 cells were treated with NMDA, the level of Sp1 mRNA did not change significantly, but the expression of nucleus protein in Sp1 was significantly decreased, while the expression of cytoplasmic protein was significantly increased. However, MK-801could reverse these changes. CONCLUSIONS: Glu reduced the biosynthesis of the main lipid PC in PS and inhibited CCTα expression by activating NMDAR, which were mediated by the inhibition of the nuclear translocation of Sp1 and the promoter activity of CCTα. In conclusion, NMDAR-mediated Glu toxicity leading to impaired PS synthesis may be a potential pathogenesis of lung injury.

Antiosteoporosis effect and possible mechanisms of the ingredients of Radix Achyranthis Bidentatae in animal models of osteoporosis: systematic review and meta-analysis of in vivo studies.

BACKGROUND: The effect and mechanisms of the ingredients (IRAB) of Radix Achyranthis Bidentatae (RAB) on treating osteoporosis (OP) remains debated. We aimed to summary the evidence to evaluate the efficacy of IRAB for animal model OP and elucidate the potential mechanism of IRAB in the treatment of OP. METHODS: In this review and meta-analysis, we searched PubMed, EMBASE, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang, Chinese Biomedical Literature Database, as well as Chinese VIP databases for targeting articles published from inception to March 2023 in English or Chinese. All randomized controlled animal trials that assessed the efficacy and safety of IRAB for OP were included. We excluded trials according to exclusion criteria. The CAMARADES 10-item quality checklist was utilized to test the risk of potential bias for each including study and modifications were performed accordingly. The primary outcome measures were bone mineral density of the femoral neck (F-BMD), serum calcium (Ca), serum phosphorus (P), serum alkaline phosphatase (ALP), bone gla protein (BGP), bone maximum stress (M-STRESS). The secondary outcome measure was the antiosteoporosis mechanisms of IRAB. RESULTS: Data from nine articles were included in the systematic review and meta-analysis, which focused on 196 animals. Egger's test revealed the presence of publication bias in various studies regarding the primary outcome. Administration of IRAB or RAB could significantly increases the F-BMD (SMD = 2.09; 95% CI = 1.29 to 2.89; P < 0.001, I2 = 76%), Ca (SMD = 0.86; 95% CI = 0.39to1.34; P = 0.07, I2 = 49%); P (SMD = 1.01; 95% CI = 0.45-4.57; P = 0.08, I2 = 50%), BGP (SMD = 2.13; 95% CI = 1.48 to 2.78; I2 = 46%, P = 0.10), while the ALP (SMD = - 0.85; 95% CI = - 1.38 to - 0.31; I2 = 46%, P = 0.10) was remarkably decreased in OP model animals. Moreover, the bone biomechanical indicator M-STRESS (SMD = 2.39; 95% CI = 1.74-3.04; I2 = 32%, P = 0.21) was significantly improved. CONCLUSION: Collectively, the findings suggest that the RAB or IRAB could be an effective drug or an ingredient in diet for the clinical treatment of OP in future.

PRPF8 controls alternative splicing of PIRH2 to modulate the p53 pathway and survival of human ESCs.

Human embryonic stem cells (hESCs) have great potential for developmental biology and regenerative medicine. However, extensive apoptosis often occurs when hESCs respond to various stresses or injuries. Understanding the molecular control and identifying new factors associated with hESC survival are fundamental to ensure the high quality of hESCs. In this study, we report that PRPF8, an RNA spliceosome component, is essential for hESC survival. PRPF8 knockdown (KD) induces p53 protein accumulation and activates the p53 pathway, leading to apoptosis in hESCs. Strikingly, silencing of p53 rescues PRPF8 KD-induced apoptosis, indicating that PRPF8 KD triggers hESC apoptosis through activating the p53 pathway. In search for the mechanism by which p53 pathway is activated by PRPF8 KD, we find that PRPF8 KD alters alternative splicing of many genes, including PIRH2 which encodes an E3 ubiquitin ligase of p53. PIRH2 has several isoforms such as PIRH2A, PIRH2B, and PIRH2C. Intriguingly, PRPF8 KD specifically increases the transcript level of the PIRH2B isoform, which lacks a RING domain and E3 ligase activity. Functionally, PIRH2B KD partially rescues the reduction in cell numbers and upregulation of P21 caused by PRPF8 KD in hESCs. The finding suggests that PRPF8 controls alternative splicing of PIRH2 to maintain the balance of p53 pathway activity and survival of hESCs. The PRPF8/PIRH2/p53 axis identified here provides new insights into how p53 pathway and hESC survival are precisely regulated at multiple layers, highlighting an important role of posttranscriptional machinery in supporting hESC survival.

Sources, size-resolved deposition in the human respiratory tract and health risks of submicron black carbon in urban atmosphere in Pearl River Delta, China.

Black carbon (BC) has a significantly negative impact on air quality, climate and human health. Here we investigated the sources and health effects of BC in urban area of the Pearl River Delta (PRD) based on online data measured by Aerodyne soot particle high-resolution time of flight aerosol mass spectrometer (SP-AMS). In urban PRD, BC particles mainly came from vehicle emissions especially heavy-duty vehicle exhausts (contributing 42.9 % of total BC mass concentration), long-range transport (27.6 %), and aged biomass combustion emissions (22.3 %). Indicated by source analysis using simultaneous aethalometer data, BC associated with local secondary oxidation and transport may also be originated from fossil fuel combustion, especially traffic sources in urban and surrounding areas. Size-resolved BC mass concentrations provided by SP-AMS, for the first time to our best knowledge, were used to calculate BC deposition in the human respiratory tract (HRT) of different populations (children, adults, and the elderly) by the Multiple-Path Particle Dosimetry (MPPD) model. We found that submicron BC was deposited more in the pulmonary (P) region (49.0-53.2 % of the total BC deposition dose), while less in the tracheobronchial (TB, 35.6-37.2 %) and head (HA, 11.2-13.8 %) regions. Adults suffered the highest BC deposition (1.19 µg day-1) than the elderly (1.09 µg day-1) and children (0.25 µg day-1). BC deposition rate was greater at night (especially 18:00-24:00) than during the daytime. The maximum deposition in the HRT was found for BC particles around 100 nm, mainly in deeper respiratory regions (TB and P), which may cause more serious health effects. Adults and the elderly group are confronted with the notable carcinogenic risk of BC in the urban PRD, up to 29 times higher than the threshold. Our study emphasizes the need to control BC pollution in the urban area, especially nighttime vehicle emissions.

[Effect of Scutellarin on Proliferation of Acute Myeloid Leukemia Cells and Its Related Mechanism].

OBJECTIVE: To investigate the effect of scutellarin (SCU) on proliferation, cell cycle and apoptosis of acute myeloid leukemia (AML) cells and its related molecular mechanism. METHODS: Human AML HL-60 cells were cultured in vitro. The cells were treated with SCU at the concentration of 0, 2, 4, 8, 16, 32, 64 µmol/L, and the inhibition rate of cell proliferation was detected by CCK-8 method. Then HL-60 cells were treated with SCU at the concentration of 4, 8, 16 µmol/L, and the negative control group (NC group) was set. The cell cycle distribution and apoptosis were detected by flow cytometry, and the expression of cell cycle, apoptosis and JAK2/STAT3 pathway related proteins were detected by Western blot. RESULTS: SCU significantly inhibited the proliferation of HL-60 cells in a concentration- and time-dependent manner(r =0.958,r =0.971). Compared with NC group, the proportion of cells in G0/G1 phase and apoptosis rate of HL-60 cells in 4, 8, 16 µmol/L SCU group were significantly increased, and the proportion of cells in S phase was significantly decreased (P <0.05). The relative protein expression levels of p21, p53, caspase-3 and Bax were significantly increased, while the relative protein expression levels of CDK2, cyclin E and Bcl-2 were significantly decreased (P <0.05). The ratio of p-JAK2/JAK2 and p-STAT3/STAT3 were significantly decreased (P <0.05). The changes of above-mentioned indexes were concentration dependent. CONCLUSION: SCU can inhibit the proliferation of AML cells, induce cell cycle arrest and apoptosis, and its mechanism may be related to the regulation of JAK2/STAT3 signaling pathway.

Clinical application of enhanced recovery after surgery concept in laparoscopic treatment of pediatric acute appendicitis.

BACKGROUND: This study assesses whether enhanced recovery after surgery (ERAS) is beneficial in treating acute appendicitis in pediatrics by laparoscopic techniques. METHOD: The children with acute appendicitis (n = 116) were divided into the ERAS group (n = 54) and the control group (n = 62). Then the preoperative data, intraoperative observation indexes, and postoperative data were analyzed. RESULTS: There was no significant difference in preoperative data and intraoperative observation indexes between the two groups. C-reactive protein (CRP) and white blood cell (WBC) in the ERAS group were significantly lower than those in the control group 3 days after the operation. Moreover, no significant difference in the visual analog score (VAS) between the two groups 3 days after the operation, but the other postoperative observation indexes in the ERAS group were significantly better than those in the control group. Nausea and vomiting in the ERAS group were significantly lower than those in the control group, with no significant difference in other complications between the two groups. CONCLUSION: ERAS could improve children's comfort, reduce some postoperative complications, reduce hospitalization expenses, and speed up recovery from acute appendicitis treated by laparoscopy. Therefore, it has clinical application value.

Efficacy of concurrent chemoradiotherapy alone for loco-regionally advanced nasopharyngeal carcinoma: long-term follow-up analysis.

BACKGROUND: To analysis the clinical outcomes of concurrent chemoradiotherapy (CCRT) alone based on 10-year results for loco-regionally advanced nasopharyngeal carcinoma (LANPC), so as to provide evidence for individualized treatment strategy and designing appropriate clinical trial for different risk LANPC patients. METHODS: Consecutive patients with stage III-IVa (AJCC/UICC 8th) were enrolled in this study. All patients received radical intensity-modulated radiotherapy (IMRT) and concurrent cisplatin chemotherapy (CDDP). The hazard ratios (HRs) of death risk in patients with T3N0 was used as baseline, relative HRs were calculated by a Cox proportional hazard model to classify different death risk patients. Survival curves for the time-to-event endpoints were analyzed by the Kaplan-Meier method and compared using the log-rank test. All statistical tests were conducted at a two-sided level of significance of 0.05. RESULTS: A total of 456 eligible patients were included. With 12-year median follow-up, 10-year overall survival (OS) was 76%. 10-year loco-regionally failure-free survival (LR-FFS), distant failure-free survival (D-FFS) and failure-free survival (FFS) were 72%, 73% and 70%, respectively. Based on the relative hazard ratios (HRs) of death risk, LANPC patients were classified into 3 subgroups, low-risk group (T1-2N2 and T3N0-1) contained 244 patients with HR < 2; medium-risk group (T3N2 and T4N0-1) contained 140 patients with HR of 2 - 5; high-risk group (T4N2 and T1-4N3) contained 72 patients with HR > 5. The 10-year OS for patients in low-, medium-, and high-risk group were 86%, 71% and 52%, respectively. Significantly differences of OS rates were found between each of the two groups (low-risk group vs. medium-risk group, P < 0.001; low-risk group vs. high-risk group, P < 0.001; and medium-risk group vs. high-risk group, P = 0.002, respectively). Grade 3-4 late toxicities included deafness/otitis (9%), xerostomia (4%), temporal lobe injury (5%), cranial neuropathy (4%), peripheral neuropathy (2%), soft tissue damage (2%) and trismus (1%). CONCLUSIONS: Our classification criteria demonstrated that significant heterogeneity in death risk among TN substages for LANPC patients. IMRT plus CDDP alone maybe suitable for low-risk LANPC (T1-2N2 or T3N0-1), but not for medium- and high-risk patients. These prognostic groupings provide a practicable anatomic foundation to guide individualized treatment and select optimal targeting in the future clinical trials.