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Haoyue Hu,1,* Yanyang Liu,1,* Songtao Tan,1,* Xiao Xiao Xie,1 Jun He,1,2 Feng Luo,1 Li Wang1 1Lung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Oncology, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Feng Luo; Li WangLung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaEmail hxyyluofeng@sina.com; wangli37029192@sina.comBackground: With a high frequency of 30%, KRAS mutations in patients with non-small cell lung cancer (NSCLC) often lead to their poor response to most anti-cancer therapies. As a multi-target tyrosine kinase inhibitor, Anlotinib shows clinical efficacy against several types of cancer. However, its effects on KRAS mutant NSCLC and the underlying molecular mechanisms remain unclear.Materials and Methods: Cell counting Kit-8 assay, colony formation assay, flow cytometry analysis, wound healing scratch assay, Transwell assay and xenograft mouse model were used to evaluate the anti-cancer effects of Anlotinib. The potential molecular mechanisms were determined by immunohistochemistry (IHC) and Western blotting.Results: Anlotinib inhibited proliferation of KRAS mutant lung cancer cells and induced apoptosis in vitro. In addition, the migration and invasion abilities of these cells were also decreased after treatment with Anlotinib. It significantly suppressed tumor growth in vivo and prolonged the survival of the xenograft-bearing mice, which correlated to lower expression levels of Ki67 in the tumor tissues. Mechanistically, Anlotinib downregulated MEK and ERK as well as their phosphorylated forms in the KRAS mutant lung cancer cells.Conclusion: Anlotinib inhibits the growth of KRAS mutant lung cancer cells partly via the suppression of the MEK/ERK pathway. Our findings provide novel insights into treating recalcitrant KRAS mutated NSCLC.Keywords: Anlotinib, KRAS-mutated, lung cancer, signal pathways

Xue Shen,1 Tingting Li,1 Zhongyuan Chen,1 Yue Geng,1 Xiaoxue Xie,1 Shun Li,1,2 Hong Yang,1,2 Chunhui Wu,1,2 Yiyao Liu1,2 1Department of Biophysics, School of Life Science and Technology, 2Center for Information in Biology, University of Electronic Science and Technology of China, Chengdu, Sichuan, People’s Republic of China Abstract: Cancer diagnosis and treatment represent an urgent medical need given the rising cancer incidence over the past few decades. Cancer theranostics, namely, the combination of diagnostics and therapeutics within a single agent, are being developed using various anticancer drug-, siRNA-, or inorganic materials-loaded nanocarriers. Herein, we demonstrate a strategy of encapsulating quantum dots, superparamagnetic Fe3O4 nanocrystals, and doxorubicin (DOX) into biodegradable poly(D,L-lactic-co-glycolic acid) (PLGA) polymeric nanocomposites using the double emulsion solvent evaporation method, followed by coupling to the amine group of polyethyleneimine premodified with polyethylene glycol-folic acid (PEI-PEG-FA [PPF]) segments and adsorption of vascular endothelial growth factor (VEGF)-targeted small hairpin RNA (shRNA). VEGF is important for tumor growth, progression, and metastasis. These drug-loaded luminescent/magnetic PLGA-based hybrid nanocomposites (LDM-PLGA/PPF/VEGF shRNA) were fabricated for tumor-specific targeting, drug/gene delivery, and cancer imaging. The data showed that LDM-PLGA/PPF/VEGF shRNA nanocomposites can codeliver DOX and VEGF shRNA into tumor cells and effectively suppress VEGF expression, exhibiting remarkable synergistic antitumor effects both in vitro and in vivo. The cell viability was ~14% when treated with LDM-PLGA/PPF/VEGF shRNA nanocomposites ([DOX] =25 µg/mL), and in vivo tumor growth data showed that the tumor volume decreased by 81% compared with the saline group at 21 days postinjection. Magnetic resonance and fluorescence imaging data revealed that the luminescent/magnetic hybrid nanocomposites may also be used as an efficient nanoprobe for enhanced T2-weighted magnetic resonance and fluorescence imaging in vitro and in vivo. The present work validates the great potential of the developed multifunctional LDM-PLGA/PPF/VEGF shRNA nanocomposites as effective theranostic agents through the codelivery of drugs/genes and dual-modality imaging in cancer treatment. Keywords: doxorubicin, codelivery, dual-modality imaging, synergistic antitumor effects, VEGF shRNA

Objectives: Periampullary diverticulum (PAD) is usually incidentally discovered during abdominal imaging, gastrointestinal endoscopy, and endoscopic retrograde cholangiopancreatography (ERCP). The influence of PAD on ERCP outcomes is unclear. The aim of this systematic review and meta-analysis was to provide an up-to-date evaluation of the impact of PAD on cannulation and ERCP-related complications., Methods: PubMed, Web of Science, Cochrane Library and EMBASE databases were searched for relevant articles published up to October 31, 2023. The rates of successful cannulation and post-ERCP complications were compared between the PAD and non-PAD groups. The quality of the studies was evaluated with the Newcastle-Ottawa Scale (NOS). The meta-analysis was conducted using Review Manager 5.3., Results: Twenty-eight articles were included. Non-PAD was associated with a relatively high cannulation success rate (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.54-0.97, p = 0.03). However, after 2015, PAD was not correlated with cannulation failure (OR 0.81, 95% CI 0.59-1.11, p = 0.20). Compared with intradiverticular papilla (IDP), non-IDP had a higher successful cannulation rate (OR 0.42, 95% CI 0.25-0.72, p = 0.002), while IDP increased the difficult cannulation rate (OR 1.60, 95% CI 1.05-2.44, p = 0.03). Additionally, PAD increased the incidence of ERCP-related pancreatitis (OR 1.24, 95% CI 1.10-1.40, p = 0.0006) and bleeding (OR 1.34, 95% CI 1.03-1.73, p = 0.03)., Conclusions: Although PAD, especially IDP, decreased the cannulation success rate, PAD was no longer considered a significant obstacle to cannulation after 2015. PAD increased the incidence of post-ERCP pancreatitis and bleeding., (© 2024 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Our previous study has identified that glutamate in the red nucleus (RN) facilitates the development of neuropathic pain through metabotropic glutamate receptors (mGluR). Here, we further explored the actions and possible molecular mechanisms of red nucleus mGluR Ⅰ (mGluR1 and mGluR5) in the development of neuropathic pain induced by spared nerve injury (SNI). Our data indicated that both mGluR1 and mGluR5 were constitutively expressed in the RN of normal rats. Two weeks after SNI, the expressions of mGluR1 and mGluR5 were significantly boosted in the RN contralateral to the nerve injury. Administration of mGluR1 antagonist LY367385 or mGluR5 antagonist MTEP to the RN contralateral to the nerve injury at 2 weeks post-SNI significantly ameliorated SNI-induced neuropathic pain. However, unilateral administration of mGluRⅠ agonist DHPG to the RN of normal rats provoked a significant mechanical allodynia, this effect could be blocked by LY367385 or MTEP. Further studies indicated that the expressions of TNF-α and IL-1β in the RN were also elevated at 2 weeks post-SNI. Administration of mGluR1 antagonist LY367385 or mGluR5 antagonist MTEP to the RN at 2 weeks post-SNI significantly inhibited the elevations of TNF-α and IL-1β. However, administration of mGluR Ⅰ agonist DHPG to the RN of normal rats significantly enhanced the expressions of TNF-α and IL-1β, these effects were blocked by LY367385 or MTEP. These results suggest that activation of red nucleus mGluR1 and mGluR5 facilitate the development of neuropathic pain by stimulating the expressions of TNF-α and IL-1β. mGluR Ⅰ maybe potential targets for drug development and clinical treatment of neuropathic pain., Competing Interests: Declaration of competing interest The authors have approved the manuscript entitled “Red nucleus mGluR1 and mGluR5 facilitate the development of neuropathic pain through stimulating the expressions of TNF-α and IL-1β” and agreed with the submission to Neurochemistry International. All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Deoxyribonuclease 2 (DNase II) plays a key role in clearing cytoplasmic double-stranded DNA (dsDNA). Deficiency of DNase II leads to DNA accumulation in the cytoplasm. Persistent dsDNA in neurons is an early pathological hallmark of senescence and neurodegenerative diseases including Alzheimer's disease (AD). However, it is not clear how DNase II and neuronal cytoplasmic dsDNA influence neuropathogenesis. Tau hyperphosphorylation is a key factor for the pathogenesis of AD. The effect of DNase II and neuronal cytoplasmic dsDNA on neuronal tau hyperphosphorylation remains unclarified., Methods: The levels of neuronal DNase II and dsDNA in WT and Tau-P301S mice of different ages were measured by immunohistochemistry and immunolabeling, and the levels of DNase II in the plasma of AD patients were measured by ELISA. To investigate the impact of DNase II on tauopathy, the levels of phosphorylated tau, phosphokinase, phosphatase, synaptic proteins, gliosis and proinflammatory cytokines in the brains of neuronal DNase II-deficient WT mice, neuronal DNase II-deficient Tau-P301S mice and neuronal DNase II-overexpressing Tau-P301S mice were evaluated by immunolabeling, immunoblotting or ELISA. Cognitive performance was determined using the Morris water maze test, Y-maze test, novel object recognition test and open field test., Results: The levels of DNase II were significantly decreased in the brains and the plasma of AD patients. DNase II also decreased age-dependently in the neurons of WT and Tau-P301S mice, along with increased dsDNA accumulation in the cytoplasm. The DNA accumulation induced by neuronal DNase II deficiency drove tau phosphorylation by upregulating cyclin-dependent-like kinase-5 (CDK5) and calcium/calmodulin activated protein kinase II (CaMKII) and downregulating phosphatase protein phosphatase 2A (PP2A). Moreover, DNase II knockdown induced and significantly exacerbated neuron loss, neuroinflammation and cognitive deficits in WT and Tau-P301S mice, respectively, while overexpression of neuronal DNase II exhibited therapeutic benefits., Conclusions: DNase II deficiency and cytoplasmic dsDNA accumulation can initiate tau phosphorylation, suggesting DNase II as a potential therapeutic target for tau-associated disorders., (© 2024. The Author(s).)

Background: Escalating cases of multidrug-resistant tuberculosis (MDR-TB) pose a major challenge to global TB control efforts, necessitating innovative diagnostics to empower decentralized detection of gene mutations associated with resistance to rifampicin (RIF) and isoniazid (INH) in Mycobacterium tuberculosis (M. tuberculosis) in resource-constrained settings., Methods: Combining multiplex fluorescent PCR and Multiple Probes Melting Analysis, we identified mutations in the rpoB, katG, ahpC and inhA genes from sputum specimens. We first constructed a reference plasmid library comprising 40 prevalent mutations in the target genes' resistance determining regions and promoters, serving as positive controls. Our assay utilizes a four-tube asymmetric PCR method with specifically designed molecular beacon probes, enabling simultaneous detection of all 40 mutations. We evaluated the assay's effectiveness using DNA isolated from 50 clinically confirmed M. tuberculosis sputum specimens, comparing our results with those obtained from Sanger sequencing and retrospective validation involving bacteriological culture and phenotypic drug susceptibility testing (pDST). We also included the commercial Xpert MTB/RIF assay for accuracy comparison., Results: Our data demonstrated remarkable sensitivity in detecting resistance to RIF and INH, achieving values of 93.33% and 95.24%, respectively, with a specificity of 100%. The concordance between our assay and pDST was 98.00%. Furthermore, the accuracy of our assay was comparable to both Sanger sequencing and the Xpert assay. Importantly, our assay boasts a 4.2-h turnaround time and costs only $10 per test, making it an optimal choice for peripheral healthcare settings., Conclusion: These findings highlight our assay's potential as a promising tool for rapidly, accurately, and affordably detecting MDR-TB., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

The neurotoxic α-synuclein (α-syn) oligomers play an important role in the occurrence and development of Parkinson's disease (PD), but the factors affecting α-syn generation and neurotoxicity remain unclear. We here first found that thrombomodulin (TM) significantly decreased in the plasma of PD patients and brains of A53T α-syn mice, and the increased TM in primary neurons reduced α-syn generation by inhibiting transcription factor p-c-jun production through Erk1/2 signaling pathway. Moreover, TM decreased α-syn neurotoxicity by reducing the levels of oxidative stress and inhibiting PAR1-p53-Bax signaling pathway. In contrast, TM downregulation increased the expression and neurotoxicity of α-syn in primary neurons. When TM plasmids were specifically delivered to neurons in the brains of A53T α-syn mice by adeno-associated virus (AAV), TM significantly reduced α-syn expression and deposition, and ameliorated the neuronal apoptosis, oxidative stress, gliosis and motor deficits in the mouse models, whereas TM knockdown exacerbated these neuropathology and motor dysfunction. Our present findings demonstrate that TM plays a neuroprotective role in PD pathology and symptoms, and it could be a novel therapeutic target in efforts to combat PD. Schematic representation of signaling pathways of TM involved in the expression and neurotoxicity of α-syn. A TM decreased RAGE, and resulting in the lowered production of p-Erk1/2 and p-c-Jun, and finally reduce α-syn generation. α-syn oligomers which formed from monomers increase the expression of p-p38, p53, C-caspase9, C-caspase3 and Bax, decrease the level of Bcl-2, cause mitochondrial damage and lead to oxidative stress, thus inducing neuronal apoptosis. TM can reduce intracellular oxidative stress and inhibit p53-Bax signaling by activating APC and PAR-1. B The binding of α-syn oligomers to TLR4 may induce the expression of IL-1β, which is subsequently secreted into the extracellular space. This secreted IL-1β then binds to its receptor, prompting p65 to translocate from the cytoplasm into the nucleus. This translocation downregulates the expression of KLF2, ultimately leading to the suppression of TM expression. By Figdraw., (© 2024. The Author(s).)

This study employed microcirculation visualization and metabolomics methods to explore the effect and possible mechanism of Dalbergia cochinchinensis in ameliorating coronary microvascular dysfunction(CMD) induced by microsphere embolization in rats. Sixty SPF-grade male SD rats were randomized into sham, model, and low-, medium-, and high-dose [1.5, 3.0, and 6.0 g·kg~(-1)·d~(-1), respectively] D. cochinchinensis water extract groups. The rats in sham and model groups were administrated with equal volume of normal saline by gavage once a day for 7 consecutive days. The rat model of CMD was prepared by injecting polyethylene microspheres into the left ventricle, while the sham group was injected with an equal amount of normal saline. A blood flow meter was used to measure blood flow, and a blood rheometer to measure blood viscosity and fibrinogen content. An automatic biochemical analyzer and reagent kits were used to measure the serum levels of myocardial enzymes, glucose, and nitric oxide(NO). Hematoxylin-eosin(HE) staining was used to observe the pathological changes of myocardial tissue. DiI C12/C18 perfusion was used to infuse coronary microvessels, and the structural and morphological changes were observed using a confocal laser scanning microscope. AngioTool was used to analyze the vascular area, density, radius, and mean E lacunarity in the microsphere embolization area, and vascular blood flow resistance was calculated based on Poiseuille's law. Non-targeted metabolomics based on high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry(UPLC-Q-TOF-MS) was employed screen potential biomarkers and differential metabolites regulated by D. cochinchinensis and the involved metabolic pathways were enriched. The pharmacodynamic results showed that compared with the model group, D. cochinchinensis significantly increased mean blood flow, reduced plasma fibrinogen content, lowered the levels of myocardial enzymes such as creatine kinase(CK), creatine kinase-MB(CK-MB), and lactate dehydrogenase(LDH), alleviate myocardial injury, and protect damaged myocardium. In addition, D. cochinchinensis significantly increased serum NO content, promoted vascular smooth muscle relaxation, dilated blood vessels, lowered serum glucose(GLU) level, improved myocardial energy metabolism, and alleviated pathological changes in myocardial fibrosis and inflammatory cell infiltration. The results of coronary microcirculation perfusion showed that D. cochinchinensis improved the vascular morphology, increased the vascular area, density, and radius, reduced vascular mean E lacunarity and blood flow resistance, and alleviated vascular endothelial damage in CMD rats. The results of metabolomics identified 45 differential metabolites between sham and model groups, and D. cochinchinensis recovered the levels 25 differential metabolites, which were involved in 8 pathways including arachidonic acid metabolism, arginine biosynthesis, and sphingolipids metabolism. D. cochinchinensis can ameliorate coronary microcirculation dysfunction caused by microsphere embolization in rats, and it may alleviate the pathological changes of CMD rats by regulating inflammatory reaction, endothelial damage, and phospholipid metabolism.

Centrifugal partition chromatography in the pH-zone-refining mode was successfully applied to the separation of alkaloids from the crude extract of Corydalis decumbens. The experiment was performed with a two-phase solvent system composed of petroleum ether-ethyl acetate-ethanol-water (5:5:3:7, v/v/v/v) where triethylamine (10 mM) was added to the stationary phase and hydrochloric acid (10 mM) to the mobile phase. From 1.6 g of the crude extract, 43 mg protopine, 189 mg (+)-egenine, and 158 mg tetrahydropalmatine were obtained with a purity of 98.2%, 94.6%, and 96.7%, respectively. Tetrahydropalmatine showed an interesting anticomplement effect with CH 50 0.11 and AP 50 0.25 mg/mL, respectively. In a mechanistic study, tetrahydropalmatine interacted with C1, C3, C4, and C5 components in the complement activation cascade., (© 2023 Wiley-VCH GmbH.)

Cancer-testis antigen CT23 is a class of tumor-associated antigens (TAA) characterized by restricted expression in male germ cells and a variety of tumor tissues. Numerous studies have shown that CT23 is closely related to tumor cell viability, proliferation, metastasis and invasion. CT23 is immunogenic and can cause specific immune response in tumor patients. Therefore, it is considered to be one of the best target antigens for designing therapeutic tumor vaccines and T-cell-mediated tumor immunotherapy. In this study, we initially obtained seven HLA-A*0201-restricted CT23 epitope candidate peptides through the T cell epitope prediction program. Subsequently, a T2 cell binding assay revealed the potential binding of all candidate peptides with HLA-A2 molecules. Notably, peptide P7 (ALLVLCYSI) exhibited the highest affinity, as evidenced by a fluorescence index (FI) of 2.19. Dendritic cells (DCs) loaded with CT23 candidate peptide can stimulate CD8 + T cell activation and proliferation, and compared with other candidate peptides, candidate peptide P7 is superior. The cytotoxic T lymphocytes (CTLs) stimulated by the peptide P7 had killing effect on tumor cells (HLA-A*0201 + , CT23 + ), but no killing effect on tumor cells (HLA-A*0201 - , CT23 + ). The CTLs induced by the peptide P7 also had a specific killing effect on T2 cells bearing the peptide P7. In summary, our findings suggest that the CT23 peptide P7 (ALLVLCYSI) can induce immune responses and holds potential for tumor-specific CTL therapy.

Understanding the mechanisms behind porcine primordial germ cell like cells (pPGCLCs) development, differentiation, and gametogenesis is crucial in the treatment of infertility. In this study, SOX9 + skin derived stem cells (SOX9 + SDSCs) were isolated from fetal porcine skin and a high-purity SOX9 + SDSCs population was obtained. The SOX9 + SDSCs were induced to transdifferentiate into PGCLCs during 8 days of cultured. The results of RNA-seq, western blot and immunofluorescence staining verified SDSCs have the potential to transdifferentiate into PGCLCs from aspects of transcription factor activation, germ layer differentiation, energy metabolism, and epigenetic changes. Both adherent and suspended cells were collected. The adherent cells were found to be very similar to early porcine primordial germ cells (pPGCs). The suspended cells resembled late stage pPGCs and had a potential to enter meiotic process. This SDSCs culture-induced in vitro model is expected to provide suitable donor cells for stem cell transplantation in the future., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To evaluate adolescent pelvic coronal inclination angle change after flatfoot treated with arthroereisis. Method: A case-series study. From June 2018 to September 2020, 25 children with flexible flat foot and pelvic obliquity were included in this retrospective study in Peking University Shenzhen Hospital. There were 17 males and 8 females with a mean age of (11.2±2.2) years (9-15 years). There were 5 cases of unilateral flatfoot and 20 cases of bilateral flatfoot. All of the patients were surgically treated with arthroereisis. Regular follow-up was done in 3 months, 1 and 2 years postoperatively. Weightbearing fluoroscopy of entire lower limb and foot were investigated to measure Meary's angle, calcaneal pitch angle, height difference at ankle and pelvic plane, pelvic inclination and sacrum-iliac distance (F value) on coronal plane. Results: The mean Mearys' angle at 3 month postoperatively was improved when compared with that before the operation (3.1°±1.5° vs 25.9°±4.3°, P <0.001), and it remained at the same level 2 years after the operation (compared with that at 1 year after the operation, P =0.748). The calcaneal pitch angle improved significantly at 3-month follow-up when compared with that before the operation (16.6°±2.4° vs 9.9°±1.5°, P <0.001), and there was no significant change between 1 year and 2 years after operation ( P =0.542). The height difference at mortise plane were also reduced at the 3-month follow-up( P <0.001), and it remained at the same level at 1 year and 2 years after the operation ( P =0.159). Pelvic height difference decreased dramatically from (12.4±1.7) mm (before operation) to (7.1±1.2) mm(3 month after the operation) ( P <0.001), it decreased to (3.6±1.8) mm 1 year after the operation (compared with that at 3 months after the operation, P <0.001), and no further reduction was observed 2 years after the surgery ( P =0.483). The pelvic inclination angle and sacrum-iliac distance were also improved at 3-month follow-up when compared with those before the operation (both P <0.001), and they declined further 1 year after the operation(both P <0.05), but the decreasing trend disappeared at the 2-year follow-up (both P >0.05). Conclusion: For adolescent flexible flat foot patients with pelvic obliquity, the coronal inclination and pelvic height discrepancy would partially recovered with correction of flatfoot deformity, but it could not be completely corrected in the mean follow-up period of 2 years after the operation.

Background: The catenin beta 1 gene (CTNNB1) plays a crucial role in the malignant progression of various cancers. Recent studies have suggested that CTNNB1 hyperactivation is closely related to the occurrence and development of bladder cancer (BCa). As a member of the deubiquitinating enzyme (DUB) family, ubiquitin C-terminal hydrolase L3 (UCHL3) is abnormally expressed in various cancers. In this study, we discovered that UCHL3 is a novel oncogene in bladder cancer, suggesting it is a promising target against bladder cancer., Methods: We utilized CRISPR‒Cas9 technology to construct cell lines with UCHL3 stably overexpressed or knocked out. The successful overexpression or knockout of UCHL3 was determined using Western blotting. Then, we performed CCK-8, colony formation, soft agar and Transwell migration assays to determine the impact of the UCHL3 gene on cell phenotype. RNA-seq was performed with UCHL3-depleted T24 cells (established via CRISPR-Cas9-mediated genomic editing). We analyzed differences in WNT pathway gene expression in wild-type and UCHL3-deficient T24 cell lines using a heatmap and by gene set enrichment analysis (GSEA). Then, we validated the effect of UCHL3 on the Wnt pathway using a dual fluorescence reporter. We then analyzed the underlying mechanisms involved using Western blots, co-IP, and immunofluorescence results. We also conducted nude mouse tumor formation experiments. Moreover, conditional UCHL3-knockout mice and bladder cancer model mice were established for research., Results: We found that the overexpression of UCHL3 boosted bladder cancer cell proliferation, invasion and migration, while the depletion of UCHL3 in bladder cancer cells delayed tumor tumorigenesis in vitro and in vivo. UCHL3 was highly associated with the Wnt signaling pathway and triggered the activation of the Wnt signaling pathway, which showed that its functions depend on its deubiquitination activity. Notably, Uchl3-deficient mice were less susceptible to bladder tumorigenesis. Additionally, UCHL3 was highly expressed in bladder cancer cells and associated with indicators of advanced clinicopathology., Conclusion: In summary, we found that UCHL3 is amplified in bladder cancer and functions as a tumor promoter that enhances proliferation and migration of tumor cells in vitro and bladder tumorigenesis and progression in vivo. Furthermore, we revealed that UCHL3 stabilizes CTNNB1 expression, resulting in the activation of the oncogenic Wnt signaling pathway. Therefore, our findings strongly suggest that UCHL3 is a promising therapeutic target for bladder cancer., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Shark variable domain of new antigen receptors (VNARs) are the smallest naturally occurring binding domains with properties of low complexity, small size, cytoplasmic expression, and ease of engineering. Green fluorescent protein (GFP) molecules have been analyzed in conventional microscopy, but their spectral characteristics preclude their use in techniques offering substantially higher resolution. Besides, the GFP molecules can be quenched in acidic environment, which makes it necessary to develop anti-GFP antibody to solve these problems. In view of the diverse applications of GFP and unique physicochemical features of VNAR, the present study aims to generate VNARs against GFP. Here, we identified 36 VNARs targeting eCGP123, an extremely stable GFP, by phage display from three immunized sharks. These VNARs bound to eCGP123 with affinity constant K D values ranging from 6.76 to 605 nM. Among them, two lead VNARs named aGFP-14 and aGFP-15 with nanomolar eCGP123-binding affinity were selected for in-depth characterization. aGFP-14 and aGFP-15 recognized similar epitopes on eCGP123. X-ray crystallography studies clarified the mechanism by which aGFP14 interacts with eCGP123. aGFP-14 also showed cross-reaction with EGFP, with K D values of 47.2 nM. Finally, immunostaining analyses demonstrated that aGFP-14 was able to bind effectively to the EGFP expressed in both cultured cells and mouse brain tissues, and can be used as a fluorescence amplifier for EGFP. Our research demonstrates a feasible idea for the screening and production of shark-derived VNARs. The two high-affinity VNARs developed in the study contribute to the diversity of GFP sdAbs and may enhance the applications of GFP., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

According to estimations, approximately about 15% of couples worldwide suffer from infertility, in which individuals with azoospermia or oocyte abnormalities cannot be treated with assisted reproductive technology. The skin-derived stem cells (SDSCs) differentiation into primordial germ cell-like cells (PGCLCs) is one of the major breakthroughs in the field of stem cells intervention for infertility treatment in recent years. However, the cellular origin of SDSCs and their dynamic changes in transcription profile during differentiation into PGCLCs in vitro remain largely undissected. Here, the results of single-cell RNA sequencing indicated that porcine SDSCs are mainly derived from multipotent dermal fibroblast progenitors (MDFPs), which are regulated by growth factors (EGF/bFGF). Importantly, porcine SDSCs exhibit pluripotency for differentiating into three germ layers and can effectively differentiate into PGCLCs through complex transcriptional regulation involving histone modification. Moreover, this study also highlights that porcine SDSC-derived PGCLCs specification exhibit conservation with the human primordial germ cells lineage and that its proliferation is mediated by the MAPK signaling pathway. Our findings provide substantial novel insights into the field of regenerative medicine in which stem cells differentiate into germ cells in vitro, as well as potential therapeutic effects in individuals with azoospermia and/or defective oocytes., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

In order to understand the occurrence of PAHs in soil and crops, the enrichment capacity of different crops for PAHs, and the distribution characteristics of PAHs in different parts of crops, the crops and soil planted in the farmland around Urumqi were studied as examples. Samples were collected in the farmland gathering area in the suburb of Urumqi in July 2021. A total of 100 crop samples were collected, including 21 crop species and 45 surface soil samples. The results showed that 16 types of PAHs were detected in the soil and crops. The total concentration of PAHs in farmland soil ranged from 19.06 to 1870.86 μg·kg -1 , and the average concentration was 127.40 μg·kg -1 . Seven carcinogenic PAHs accounted for 42.85%-79.20% of the 16 types of PAHs, among which BaP was the main pollutant in the soil. Through the characteristic ratio method, it was found that the main sources of PAHs in the soil were biomass and coal combustion. Total PAHs in crops ranged from 1.86 μg·kg -1 to 974.05 μg·kg -1 , with an average of 303.30 μg·kg -1 . Different crops had different enrichment capacities for PAHs. Among the 21 crops sampled, the accumulative content of PAHs in pumpkin was the highest (431.75 μg·kg -1 ). In leaf vegetable crops, the content of PAHs in leaves was higher than that in roots and fruits. In fruit and vegetable crops, the PAH content in fruit was higher than that in the root or leaf. There was a significant correlation between high cyclic PAHs in soil and PAHs in plant leaves. The health risk assessment of PAHs in crops showed that dietary intake had potential carcinogenic risk and even had high carcinogenic risk in adult male and female groups, which requires further attention.

This study aimed to analyze the effect of Bletilla striata polysaccharide(BSP) on endogenous metabolites in serum of tumor-bearing mice treated with 5-fluorouracil(5-FU) by untargeted metabolomics techniques and explore the mechanism of BSP in alleviating the toxic and side effects induced by 5-FU. Male BALB/C mice were randomly divided into a normal group, a model group, a 5-FU group, and a 5-FU + BSP group, with eight mice in each group. Mouse colon cancer cells(CT26) were transplanted into the mice except for those in the normal group to construct the tumor-bearing mouse model by subcutaneous injection, and 5-FU chemotherapy and BSP treatment were carried out from the second day of modeling. The changes in body weight, diarrhea, and white blood cell count in the peripheral blood were recorded. The mice were sacrificed and sampled when the tumor weight of mice in the model group reached approximately 1 g. TUNEL staining was used to detect the cell apoptosis in the small intestine of each group. The proportions of hematopoietic stem cells and myeloid progenitor cells in bone marrow were measured by flow cytometry. Five serum samples were selected randomly from each group for untargeted metabolomics analysis. The results showed that BSP was not effective in inhibiting colon cancer in mice, but diarrhea, leukopenia, and weight loss caused by 5-FU chemotherapy were significantly improved after BSP intervention. In addition, apoptotic cells decreased in the small intestinal tissues and the percentages of hematopoietic stem cells and myeloid progenitor cells in bone marrow were significantly higher after BSP treatment. Metabolomics results showed that the toxic and side effects of 5-FU resulted in significant decrease in 29 metabolites and significant increase in 22 metabolites in mouse serum. Among them, 19 disordered metabolites showed a return to normal levels in the 5-FU+BSP group. The results of pathway enrichment indicated that metabolic pathways mainly involved pyrimidine metabolism, arachidonic acid metabolism, and steroid hormone biosynthesis. Therefore, BSP may ameliorate the toxic and side effects of 5-FU in the intestinal tract and bone marrow presumably by regulating nucleotide synthesis, inflammatory damage, and hormone production.

Amyloid-β (Aβ) plays an important role in the neuropathology of Alzheimer's disease (AD), but some factors promoting Aβ generation and Aβ oligomer (Aβo) neurotoxicity remain unclear. We here find that the levels of ArhGAP11A, a Ras homology GTPase-activating protein, significantly increase in patients with AD and amyloid precursor protein (APP)/presenilin-1 (PS1) mice. Reducing the ArhGAP11A level in neurons not only inhibits Aβ generation by decreasing the expression of APP, PS1, and β-secretase (BACE1) through the RhoA/ROCK/Erk signaling pathway but also reduces Aβo neurotoxicity by decreasing the expressions of apoptosis-related p53 target genes. In APP/PS1 mice, specific reduction of the ArhGAP11A level in neurons significantly reduces Aβ production and plaque deposition and ameliorates neuronal damage, neuroinflammation, and cognitive deficits. Moreover, Aβos enhance ArhGAP11A expression in neurons by activating E2F1, which thus forms a deleterious cycle. Our results demonstrate that ArhGAP11A may be involved in AD pathogenesis and that decreasing ArhGAP11A expression may be a promising therapeutic strategy for AD treatment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The study aimed to investigate the effect of anemoside B4(B4) on fatty acid metabolism in mice with colitis-associated cancer(CAC). The CAC model was established by azoxymethane(AOM)/dextran sodium sulfate(DSS) in mice. Mice were randomly divided into a normal group, a model group, and low-, medium-, and high-dose anemoside B4 groups. After the experiment, the length of the mouse colon and the size of the tumor were measured, and the pathological alterations in the mouse colon were observed using hematoxylin-eosin(HE) staining. The slices of the colon tumor were obtained for spatial metabolome analysis to analyze the distribution of fatty acid metabolism-related substances in the tumor. The mRNA levels of SREBP-1, FAS, ACCα, SCD-1, PPARα, ACOX, UCP-2, and CPT-1 were determined by real-time quantitative PCR(RT-qPCR). The results revealed that the model group showed decreased body weight(P&lt;0.05) and colon length(P&lt;0.001), increased number of tumors, and increased pathological score(P&lt;0.01). Spatial metabolome analysis revealed that the content of fatty acids and their derivatives, carnitine, and phospholipid in the colon tumor was increased. RT-qPCR results indicated that fatty acid de novo synthesis and β-oxidation-related genes, such as SREBP-1, FASN, ACCα, SCD-1, ACOX, UCP-2, and CPT-1 mRNA expression levels increased considerably(P&lt;0.05, P&lt;0.001). After anemoside B4 administration, the colon length increased(P&lt;0.01), and the number of tumors decreased in the high-dose anemoside B4 group(P&lt;0.05). Additionally, spatial metabolome analysis showed that anemoside B4 could decrease the content of fatty acids and their derivatives, carnitine, and phospholipids in colon tumors. Meanwhile, anemoside B4 could also down-regulate the expression of FASN, ACCα, SCD-1, PPARα, ACOX, UCP-2, and CPT-1 in the colon(P&lt;0.05, P&lt;0.01, P&lt;0.001). The findings of this study show that anemoside B4 may inhibit CAC via regulating fatty acid metabolism reprogramming.

Since the discovery of fluorescent proteins (FPs), their rich fluorescence spectra and photochemical properties have promoted widespread biological research applications. FPs can be classified into green fluorescent protein (GFP) and its derivates, red fluorescent protein (RFP) and its derivates, and near-infrared FPs. With the continuous development of FPs, antibodies targeting FPs have emerged. The antibody, a class of immunoglobulin, is the main component of humoral immunity that explicitly recognizes and binds antigens. Monoclonal antibody, originating from a single B cell, has been widely applied in immunoassay, in vitro diagnostics, and drug development. The nanobody is a new type of antibody entirely composed of the variable domain of a heavy-chain antibody. Compared with conventional antibodies, these small and stable nanobodies can be expressed and functional in living cells. In addition, they can easily access grooves, seams, or hidden antigenic epitopes on the surface of the target. This review provides an overview of various FPs, the research progress of their antibodies, particularly nanobodies, and advanced applications of nanobodies targeting FPs. This review will be helpful for further research on nanobodies targeting FPs, making FPs more valuable in biological research.

MAPK/JNK signaling is pivotal in carcinogenesis. However, ubiquitin-mediated homeostasis of JNK remains to be verified. Here, with results from RNA sequencing (RNA-seq) and luciferase reporter pathway identification, we show that USP14 orchestrates MAPK/JNK signaling and identify USP14 as a deubiquitinase that interacts and stabilizes JNK. USP14 is elevated in colorectal cancer patients and is positively associated with JNK protein and downstream gene expression. USP14 ablation reduces cancer cell proliferation in vitro and colorectal tumorigenesis in vivo by downregulating MAPK/JNK pathway activation. Moreover, USP14 expression is induced by TNF-α, forming a feedback loop with JNK and leading to tumor amplification. Our study suggests that elevated expression of USP14 promotes MAPK/JNK signaling by stabilizing JNK, which in turn augments colorectal carcinogenesis, indicating a potential therapeutic target for colorectal cancer patients with increased USP14 expression., (© 2023. The Author(s).)

Background: Radiotherapy (RT) is the standard treatment for nasopharyngeal carcinoma (NPC). However, due to individual differences in radiosensitivity, biomarkers are needed to tailored radiotherapy to cancer patients. However, comprehensive genome-wide radiogenomic studies on them are still lacking. The aim of this study was to identify genetic variants associated with radiotherapy response in patients with NPC., Methods: This was a large‑scale genome-wide association analysis (GWAS) including a total of 981 patients. 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant loci were further genotyped using MassARRAY system and TaqMan SNP assays in the validation stages of 847 patients. This study used logistic regression analysis and multiple bioinformatics tools such as PLINK, LocusZoom, LDBlockShow, GTEx, Pancan-meQTL and FUMA to examine genetic variants associated with radiotherapy efficacy in NPC., Results: After genome-wide level analysis, 19 SNPs entered the validation stage (P < 1 × 10 - 6 ), and rs11130424 ultimately showed statistical significance among these SNPs. The efficacy was better in minor allele carriers of rs11130424 than in major allele carriers. Further stratified analysis showed that the association existed in patients in the EBV-positive, smoking, and late-stage (III and IV) subgroups and in patients who underwent both concurrent chemoradiotherapy and induction/adjuvant chemotherapy., Conclusion: Our study showed that rs11130424 in the CACNA2D3 gene was associated with sensitivity to radiotherapy in NPC patients., Trial Registration Number: Effect of genetic polymorphism on nasopharyngeal carcinoma chemoradiotherapy reaction, ChiCTR-OPC-14005257, Registered 18 September 2014, http://www.chictr.org.cn/showproj.aspx?proj=9546 ., (© 2023. The Author(s).)

Metal-organic framework (MOF) glass is a new type of glass material, but it usually lacks sufficient porosity. Thus, regulating the pore structure of MOF glass to improve its adsorption performance is very important. Herein, we found that the porosity of MOF glasses agZIF-62 and agZIF-76 can be regulated via an ammonia-immersion approach. After ammonia immersion, the resulting agZIF-62-NH 3 and agZIF-76-NH 3 could be maintained in their glass states or converted to their amorphous states, respectively. Their porosity changed according to the gas adsorption experiments. Notably, compared with agZIF-62 and agZIF-76, the iodine uptake capacities for agZIF-62-NH 3 and agZIF-76NH 3 increased by 12 and 21 times, respectively. This work shows that the subsequent treatment of MOF glass can regulate their adsorption performance.

Objective: Glioblastoma multiforme (GBM), the most malignant intracranial neoplasm, is associated with a high mortality and recurrence rate due to the aggressive nature and heterogeneity of the tumor. Some of the molecular markers involved in the tumorigenesis of GBM are essential in prognosis, diagnosis, and treatment. Due to the limitations of therapeutic effects, this study aims to explore novel biomarkers with prognostic value and to provide new insights into therapeutic targets., Methods: The expression profile of mRNAs in GBM was detected by RNA-sequencing, and differentially expressed genes were identified by integrating the data from RNA-seq results and the GEPIA2 database. Of the total 40 hub genes, FN1, P4HB, and PPIB showed prognostic significance based on both GEPIA2 and CGGA databases. The validation of FN1, P4HB, and PPIB expression by qPCR and correlation analysis with clinicopathological features were performed in 41 GBM tissues from our institution., Results: Kaplan-Meier analysis revealed that FN1 and P4HB expressions levels were related to the overall survival (OS) of GBM patients (P<0.05). Multivariate analysis showed that FN1 overexpression (HR=9.199, P=0.002) was an independent and unfavorable prognostic factor for GBM patients. The median survival time was 8.5 months and 21 months for high and low expressions of FN1, respectively., Conclusion: It was suggested that FN1 could be an ideal target for prognosis and a potential therapeutic target in GBM., (© 2022. Huazhong University of Science and Technology.)

The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein is the major target for antibody therapeutics. Shark-derived variable domains of new antigen receptors (VNARs) are the smallest antibody fragments with flexible paratopes that can recognize protein motifs inaccessible to classical antibodies. This study reported four VNARs binders (JM-2, JM-5, JM-17, and JM-18) isolated from Chiloscyllium plagiosum immunized with SARS-CoV-2 RBD. Biolayer interferometry showed that the VNARs bound to the RBD with an affinity K D ranging from 38.5 to 2720 nM, and their Fc fusions had over ten times improved affinity. Gel filtration chromatography revealed that JM-2-Fc, JM-5-Fc, and JM-18-Fc could form stable complexes with RBD in solution. In addition, five bi-paratopic VNARs, named JM-2-5, JM-2-17, JM-2-18, JM-5-18, and JM-17-18, were constructed by fusing two VNARs targeting distinct RBD epitopes based on epitope grouping results. All these bi-paratopic VNARs except for JM-5-18 showed higher RBD binding affinities than its component VNARs, and their Fc fusions exhibited further enhanced binding affinities, with JM-2-5-Fc, JM-2-17-Fc, JM-2-18-Fc, and JM-5-18-Fc having K D values lower than 1 pM. Among these Fc fusions of bi-paratopic VNARs, JM-2-5-Fc, JM-2-17-Fc, and JM-2-18-Fc could block the angiotensin-converting enzyme 2 (ACE2) binding to the RBD of SARS-CoV-2 wildtype, Delta, Omicron, and SARS-CoV, with inhibition rates of 48.9~84.3%. Therefore, these high-affinity VNAR binders showed promise as detectors and therapeutics of COVID-19.

Background: Genetic variants associated with acute side effects of radiotherapy in nasopharyngeal carcinoma (NPC) remain largely unknown., Methods: We performed a two-stage genome-wide association analysis including a total of 1084 patients, where 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant variants were then validated in an independent cohort of 765 patients using the MassARRAY system. Gene mapping, linkage disequilibrium, genome-wide association analysis, and polygenic risk score were conducted or calculated using FUMA, LDBlockShow, PLINK, and PRSice software programs, respectively., Results: Five SNPs (rs6711678, rs4848597, rs4848598, rs2091255, and rs584547) showed statistical significance after validation. Radiotherapy toxicity was more serious in mutant minor allele carriers of all five SNPs. Stratified analysis further indicated that rs6711678, rs4848597, rs4848598, and rs2091255 correlated with skin toxicity in patients of EBV positive, late stage (III and IV), receiving both concurrent chemoradiotherapy and induction/adjuvant chemotherapy, and with OR values ranging from 1.92 to 2.66. For rs584547, high occurrence of dysphagia was found in A allele carriers in both the discovery (P = 1.27 × 10 - 6 , OR = 1.55) and validation (P = 0.002, OR = 4.20) cohorts. Furthermore, prediction models integrating both genetic and clinical factors for skin reaction and dysphagia were established. The area under curve (AUC) value of receiver operating characteristic (ROC) curves were 0.657 (skin reaction) and 0.788 (dysphagia)., Conclusions: Rs6711678, rs4848597, rs4848598, and rs2091255 on chromosome 2q14.2 and rs584547 were found to be novel risk loci for skin toxicity and dysphagia in NPC patients receiving radiotherapy., Trial Registration: Chinese Clinical Trial Register (registration number: ChiCTR-OPC-14005257 and CTXY-140007-2)., (© 2022. The Author(s).)

Pinelliae rhizoma (PR), one kind of commonly-used Chinese herbs, is generally prescribed to treat various respiratory diseases, including acute lung injury (ALI). However, the accurate bioactive ingredients of PR and the underlying pharmacological mechanism have both not been fully elucidated. Therefore, this study aimed to identify the bioactive ingredients that could alleviate lipopolysaccharide (LPS)-induced ALI and explore the possible mechanism involved. Our results confirmed that LPS infection indeed caused acute inflammatory damage in mice lung, accompanying with the enhancement of IL-1β contents and the activation of the NLRP3 inflammasome in lung tissue and macrophagocyte, all of which were remarkably ameliorated by PR treatment. Next, mechanistically, LPS was found to trigger endoplasmic reticulum (ER) stress and downstream cellular calcium ions (Ca 2+ ) release via activating Bip/ATF4/CHOP signaling pathway. Like PR, 4-PBA (a specific inhibitor of ER stress) not only obviously reversed Bip/ATF4/CHOP-mediated ER stress, but also significantly attenuated LPS-induced activation of the NLRP3 inflammasome. Furthermore, the bioactive ingredients of PR, which generated the anti-inflammatory effects, were screened by metabolomics and network pharmacology. In vitro experiments showed that chrysin, dihydrocapsaicin, and 7,8-dihydroxyflavone (7,8-DHF) notably suppressed LPS-induced ER stress and following NLRP3 inflammasome activation. In conclusion, our findings suggested that PR alleviated LPS-induced ALI by inhibiting ER stress-mediated NLRP3 inflammasome activation, which is mainly relevant with these three bioactive ingredients. This study provided a theoretical basis for the clinical application of PR to treat ALI, and these bioactive ingredients of PR would be promising therapeutic drugs for the treatment of ALI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Zhang, Shen, Huang, Deng, Zhou, Yue, Shen, Zhou and Gao.)

In order to investigate the characteristics of typical pesticide residues in farmland soil of different plant types in Shaya County and to evaluate the level of human health risk and ecological risk caused by pesticide residues, a total of 55 samples of plants, soil, and water from nine areas of Shaya county were collected on September 29, 2020. The occurrence levels of 47 typical pesticides in the samples were analyzed using gas chromatography-mass spectrometry (GC-MS). The results showed that a total of 23 pesticides were detected in three environmental media, and the maximum concentrations of pesticides in soil, plants, and water were 70.58 μg·kg -1 , 1832.18 μg·kg -1 , and 188.53 μg·L -1 , respectively. The levels of pesticide residues in the three environmental media in Shaya county were characterized as plants>water>soil. From the detection of pesticides in different plant types, P1, P2, P6, and P8 in the center of the county were the most seriously polluted. The plants with a high pesticide load level in the corresponding areas were cotton, walnut, red jujube, and poplar, and the pesticides with a high concentration contribution were hexachlorocyclohexanes, chlorpyrifos, cyhalothrin, fluvalinate, metalaxyl, difenoconazole, and procymidone. The human health risks of adults and children caused by oral intake, skin contact, and respiratory inhalation were evaluated. The results showed that oral intake was the main exposure route, and the risk level of children was significantly higher than that of adults but was within the acceptable range. The ecological risk level of earthworms in soil was subsequently evaluated. The results showed that the potential ecological risk level of a single pesticide was low, and the potential ecological risk level of bifenthrin was the largest. The calculation of the total ecological risk of mixed pesticides showed that areas P1, P4, P7, and P9 were at moderate risk, whereas other areas were at low risk. Therefore, the use of some pesticides in Shaya County should be restricted.

Objective: The study evaluated the efficacy of combined epigenetic drugs of decitabine (DAC), valproic acid (VPA), and trichostatin A (TSA) on immunotherapy against glioma., Methods: The expression and prognosis of MAGE-D4 in glioma were analyzed online, and the expression of MAGE-D4 and HLA-A2 in glioma induced by epigenetic drugs was detected by qRT-PCR, Western blot, and flow cytometry. The methylation status of the MAGE-D4 promoter was determined by pyrosequencing. An HLA-A2 restricted MAGE-D4 peptide was predicted and synthesized. An affinity assay and a peptide/HLA complex stability assay were performed to determine the affinity between peptide and HLA. CCK8 assay, CFSE assay, ELISA and ELISPOT were performed to detect the function of MAGE-D4 peptide-specific T cells. Flow cytometry, ELISA, and cytotoxicity assays were used to detect the cytotoxicity effect of MAGE-D4 peptide-specific T cells combined with epigenetic drugs against glioma in vitro . Finally, the glioma-loaded mouse model was applied to test the inhibitory effect of specific T cells on gliomas in vivo ., Results: MAGE-D4 was highly expressed in glioma and correlated with poor prognosis. Glioma cells could be induced to express MAGE-D4 and HLA-A2 by epigenetic drugs. MAGE-D4-associated peptides were found that induce DCs to stimulate the highest T-cell activities of proliferation, IL-2 excretion, and IFN-γ secretion. MAGE-D4 peptide-specific T cells treated with TSA only or combining TSA and DAC had the most cytotoxicity effect, and its cytotoxicity effect on glioma cells decreased significantly after HLA blocking. In vivo experiments also confirmed that MAGE-D4-specific T cells inhibit TSA-treated glioma., Conclusion: MAGE-D4 is highly expressed in glioma and correlated with the prognosis of glioma. The novel MAGE-D4 peptide identified was capable of inducing MAGE-D4-specific T cells that can effectively inhibit glioma growth, and the epigenetic drug application can enhance this inhibition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bi, Zhang, Zeng, Liu, Nong, Xie, Li, Lin, Luo, Ge and Xie.)

Objective: Cancer/testis antigen FMR1NB is aberrantly expressed in various types of cancer, but not in normal tissues except for testis. This study aimed to investigate the expression and functional role of FMR1NB in glioma., Methods: The expression of FMR1NB mRNA and protein was determined using RT-PCR and immunohistochemistry, respectively, in glioma specimens from 83 patients at follow-up. The effects of siRNA-mediated FMR1NB silencing on malignant biological behaviors were evaluated in glioma cell lines A172 and U251., Results: FMR1NB mRNA and protein expression was detected in 58.8% (77/131) and 46.34% (57/123) of glioma tissues, respectively. FMR1NB protein was positively correlated with World Health Organization grade and found to be an independent prognostic marker for poor outcome. Knockdown of FMR1NB induced apoptosis and suppressed proliferation, adhesion, migration, and invasion by modulating the expression of cyclin A, CDK2, caspase-3, E-cadherin, and N-cadherin in A172 and U251 cells., Conclusion: Our findings suggest that FMR1NB contributes to the tumorigenesis of glioma cells and may represent a potential prognostic biomarker and an attractive therapeutic target in glioma., (© 2022. Huazhong University of Science and Technology.)

Background: Noninvasive prenatal diagnosis (NIPD) based on cell-free DNA (cfDNA) has been introduced into the clinical application for some monogenic disorders but not for tuberous sclerosis (TSC) yet, which is an autosomal dominant disease caused by various variations in TSC1 or TSC2 gene. We aimed to explore the feasibility of NIPD on TSC., Methods: We recruited singleton pregnancies at risk of TSC from 14 families with a proband child. Definitive NIPD for TSC was performed using targeted next-generation sequencing of cfDNA in parallel with maternal white blood cell DNA (wbcDNA). The NIPD results were validated by amniocentesis or postnatal gene testing and follow-up of the born children., Results: Missense mutations, nonsense mutations, frameshift mutations, and splice-site variants which were obtained through de-novo, maternal, or paternal inheritance were included. The mean and minimum gestational weeks of NIPD were 17.18 ± 5.83 and 8 weeks, respectively. The NIPD results were 100% consistent with the amniocentesis or postnatal gene testing and follow-up of the born children., Conclusion: This study demonstrates that NIPD based on cfDNA is feasible for TSC, but required to be confirmed with more samples. Studies on TSC can contribute to the application and promotion of NIPD for monogenic disorders., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Cardiovascular disease (CVD) is a leading threat to global public health. Although associations between temperature and CVD hospitalization have been suggested for developed countries, limited evidence is available for developing countries or rural residents. Moreover, the effect of apparent temperature (AT) on the spectrum of cause-specific CVDs remains unknown. Based on 2,024,147 CVD hospitalizations for rural residents from eight regions in Fujian Province, China, during 2010-2016, a quasi-Poisson regression with distributed lag non-linear model was fitted to estimate the AT effect on daily CVD hospitalization for each region, and then pooled in a meta-regression that included regional indicators related to rural residents. Stratified analyses were performed according to the cause of hospitalization, sex and age groups. Finally, we calculated the fraction of CVD hospitalizations attributable to AT, as a reflection of the burden associated with AT. The heat effect appeared at lag 0-1 days, with 19% (95% CI, 11-26%) increased risk of CVD hospitalization, which was worse for ischemic heart disease, heart failure, arrhythmias and ischemic stroke. The decreased AT was associated with increase of hemorrhagic stroke at lag 0-28 days. People aged 65 and above suffered more from the heat effect on cardiovascular and cerebrovascular diseases. Regions with a lower gross value of agricultural production, rural residents' per capita net income, number of air conditioners and water heaters were more susceptible. A large number of hospitalizations were attributable to heat for most subcategories. High AT level increased CVD hospitalization, and the subcategories had different susceptibilities. The effects were modified by individual and regional characteristics. These findings have important implications for the development of targeted interventions and for hospital service planning., (Copyright © 2022. Published by Elsevier Ltd.)

Objective: Glioblastoma (GBM) is the most common, invasive, and malignant primary brain tumor with a poor prognosis and high recurrence rate. It's known that some microRNAs (miRNAs) which are associated with tumorigenesis and progression can be considered as prognostic and therapeutic targets in tumors including GBM. This study aims to highlight the potential role of the core miRNAs in GBM and their potential use as a prognostic and therapeutic biomarker., Methods: Differentially expressed miRNAs (DEmiRNAs) were identified in GBM by integrating miRNA-sequencing results and a GBM microarray dataset from the Gene Expression Omnibus (GEO) database through bioinformatics tools. The dysregulated miRNAs were identified by survival analysis through Chinese Glioma Genome Atlas (CGGA). Target genes of the dysregulated miRNAs were predicted on MiRWalk and miRTarBase database. TAM2.0 database, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis were used to analyze the function of the dysregulated miRNAs. Subsequently, protein-protein interaction (PPI) network analysis was used to identify the top 20 hub targets of the up-regulated and down-regulated miRNAs, respectively. Then, core miRNAs in GBM were identified by constructing dysregulated miRNA-differentially expressed hub gene networks. Validation of the core miRNAs expression was detected in 41 GBM tissues compared to 8 normal brain tissues. Furthermore, the potential biomarkers were identified by clinical correlation analysis and survival analysis., Results: Totally, 68 intersecting DEmiRNAs were identified, 40 of which were upregulated and the other 28 miRNAs were downregulated. Two upregulated and 4 downregulated miRNAs showed prognostic significance. Most differentially expressed hub genes were regulated by the miR-28-5p and miR-1224-5p, which were respectively upregulated and downregulated in GBM. The correlation between miR-1224-5p level and recurrence was statistically significant (P=0.011). Survival analysis showed that high miR-28-5p level and high miR-1224-5p level were both associated with better prognosis. Moreover, high miR-1224-5p level was an independent prognosis factor for GBM patients according to the cox regression analysis., Conclusion: MiRNA-1224-5p could be a potential target for the prognosis and treatment in GBM., (© 2022. Huazhong University of Science and Technology.)

Background: Extranodal NK/T-cell lymphoma (ENKTL) is a subtype of non-Hodgkin's lymphoma that accounts for approximately 3-8% of all malignant lymphomas. So far, ENKTL has no standard treatment guidelines, and the current treatment methods pose adverse effects. The combination of programmed death receptors (PD-1) and programmed death receptors' ligands (PD-L1) downregulates effector T cells; hence, it may be an effective treatment for NK/T-cell lymphoma. Here, we report a patient diagnosed with ENKTL whose health was significantly improved after PD-1 immunotherapy. At the same time, the patient suffered from related renal toxic side effects. Immunotherapy is an emerging treatment method for tumors, and the early diagnosis and identification of its side effects are vital for the diagnosis and treatment of tumors., Case Report: Laboratory tests, pathological examinations, and the patient's history were performed to estimate the severity and the cause of renal insufficiency. The patient with ENKTL developed transient renal damage during immunotherapy. During the next treatment and examination, renal insufficiency was irrelevant to PD-1 inhibitors and avoided unnecessary drug withdrawal., Conclusions: In the present case report, we discuss a patient who developed a severe transient renal impairment during immunotherapy and review published studies regarding immunotherapy and its renal-related side effects. We also outline how to critically distinguish whether a patient's kidney injury is anti-PD-1 treatment. We also provide insights to oncologists to develop an effective follow-up treatment plan for early detection and management of any anti-PD-1 treatment side effects.

This study aims to establish a rapid and sensitive UPLC-MS/MS method for simultaneously determining the content of strychnine and paeoniflorin in plasma and brain tissue of rats, and compare the pharmacokinetic behavior and brain tissue distribution of paeoniflorin combined with normal and toxic doses of strychnine in rats after percutaneous administration. Compared with those in the toxic-dose strychnine group, the AUC&#95;(0-t), AUC&#95;(0-∞), and C&#95;(max) of strychnine decreased by 51.51%, 45.68%, and 46.03%, respectively(P&lt;0.01), and the corresponding values of paeoniflorin increased by 91.41%, 102.31%, and 169.32%, respectively(P&lt;0.01), in the compatibility group. Compared with the normal-dose strychnine group, the compatibility group showed insignificantly decreased C&#95;(max), AUC&#95;(0-t), and AUC&#95;(0-∞) of strychnine, increased C&#95;(max) and T&#95;(max) of paeoniflorin(P&lt;0.01), 66.88% increase in AUC&#95;(0-t), and 70.55% increase in AUC&#95;(0-∞) of paeoniflorin. In addition, the brain tissue concentration of strychnine decreased and that of paeoniflorin increased after compatibility. The combination of paeoniflorin with normal dose and toxic dose of strychnine can inhibit the percutaneous absorption of strychnine, and greatly promote the percutaneous penetration of paeoniflorin, whereas the interaction mechanism remains to be explored. The UPLC-MS/MS method established in this study is easy to operate and has good precision. It is suitable for in vivo study of pharmacokinetic behavior and brain tissue distribution of paeoniflorin and strychnine after percutaneous administration in rats, which provides reference for the safe and rational clinical use of strychnine and the combined use of drugs, and lays a solid foundation for the development of external preparations containing Strychni Semen.

Purpose: Vascularized pedicled bone-grafting from the cuboid to the talus provides low donor site morbidity and satisfactory outcomes in patients with early-stage talar avascular necrosis. We investigated the anatomy of the rotational vascularized pedicled bone graft from the cuboid., Methods: 15 embalmed cadaver specimens were perfused with red latex via the popliteal artery. The lateral malleolus was dissected. The course of the lateral tarsal artery and the vascular territory in the cuboid supplied by the lateral tarsal artery were observed. Vessel diameters were measured., Results: The course of the lateral tarsal artery to the cuboid was consistent, and a vascularized pedicle of the lateral tarsal artery was present in all specimens. Mean diameter of the lateral tarsal artery was 1.40 ± 0.12 mm (range 1.67-1.25). Mean length of the vascularized pedicle was 67.15 ± 3.18 mm (range 62.43-74.36). The pedicle bone graft was long enough to reach the bony border of both the lateral and medial malleolus., Conclusion: A vascularized pedicled cuboid bone graft based on the lateral tarsal artery has clinical utility for early-stage talar avascular necrosis., (© 2021. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Objective: To evaluate the efficacy of combined epigenetic drugs of decitabine (DAC), valproic acid (VPA) and trichostatin A (TSA) on immunotherapy with a murine model of hepatocellular carcinoma (HCC)., Methods: Dendritic cells (DCs) transduced with recombinant lentivirus expressing a cancer-testis antigen, acrosin binding protein (ACRBP), are referred to as DC/ACRBP. CD8 + T cells were harvested from spleens of C57BL/6 mice and activated by DC/ACRBP. Cytotoxicity of DC/ACRBP-activated T cells was analyzed by cytotoxicity and murine xenograft assays., Results: Cytotoxicity assay results revealed that DC/ACRBP-activated T cells exhibited the highest cytotoxicity against HCC cells pre-treated with triple drugs (DAC+VPA+TSA) compared with dual drugs (DAC+VPA and DAC+TSA) and single drug (DAC, VPA and TSA) respectively. Analyses of RT-PCR and immunoblotting demonstrated that the highest ACRBP expression of HCC cells was induced by the triple drugs compared with the single and dual drugs. These results indicated that DC/ACRBP-activated T cells might be ACRBP-specific lymphocytes, and the augmented cytotoxicity may be dependent on the upregulation of ACRBP expression. These assumptions were further confirmed by xenograft tumor assay. Tumor cells of mice administrated with the triple drugs exhibited increased ACRBP expression compared with those of mice without administration. As expected, DC/ACRBP-activated T cells adopted by mice injected with the triple drugs, compared with those adopted by mice without injection, remarkably impeded growth and facilitated apoptosis of tumor cells., Conclusion: These data suggested that combined treatment with DAC, VPA and TSA may enhance the anti-tumor efficacy of ACRBP-specific T cells by upregulating ACRBP expression in HCC., Competing Interests: None., (AJTR Copyright © 2021.)

Traditional optical switches relying on the weak, volatile thermo-optic or electro-optic effects of Si or SiN waveguides show a high consumption and large footprint. In this paper, we reported an electric-driven phase change optical switch consisting of a Si waveguide, Ge 2 Sb 2 Te 5 (GST) thin film and graphene heater suitable for large-scale integration and high-speed switching. The reversible transition between the amorphous and crystalline states was achieved by applying two different voltage pulses of 1.4 V (SET) and 4 V (RESET). The optical performance of the proposed switch showed a high extinction ration of 44-46 dB in a wide spectral range (1525-1575 nm), an effective index variation of Δ n eff  = 0.49 and a mode loss variation of Δ α  = 15 dB μ m -1 at the wavelength of 1550 nm. In thermal simulations, thanks to the ultra-high thermal conductivity of graphene, the proposed switch showed that the consumption for the SET process was only 3.528 pJ with a 1.4 V pulse of 5 ns, while a 4 V pulse of 1.5 ns was needed for RESET process with a consumption of 1.05 nJ. Our work is helpful to analyze the thermal-conduction phase transition process of on-chip phase change optical switches, and the design of the low-energy-consumption switch is conducive to the integrated application of photonic chips., (© 2021 IOP Publishing Ltd.)

To study the effect of anemoside B4 on rats with chronic obstructive pulmonary disease (COPD).Seventy-two SD male rats were randomly divided into blank group and model group.The method of exposure to cigarette smoke and combined with lipopolysaccharide (LPS) was used to replicate the rat model of COPD.After the model was maintained for 5 weeks,the rats were randomly divided into model group,dexamethasone group (0.81 mg·kg~(-1)) and anemoside B4 low,medium and high (2,4,8 mg·kg~(-1)) dose groups,a group of 12 animals were administered,and then the administration was started.The administration was maintained until the28th day,and the pulmonary function parameters of rats were measured by an animal pulmonary function instrument.After testing the rat lung function parameters,immediately draw rat alveolar lavage fluid (BALF),and use high-throughput protein chip technology to determined the expression levels of inflammatory cytokines in rat BALF.HE staining was used to observe the general pathological changes of rat lung and tracheal tissue.Masson staining was used to observe the collagen deposition in rat lung tissue.Real-time q PCR method was used to determine the mRNA expression level of related genes in rat lung tissue.Western blot method was used to determine the expression levels of related proteins in rat lung tissues.According to the findings,compared with the model group,the dexamethasone group and the anemoside B4 drug groups had different degrees of increase in the lung function parameters of rats (P&lt;0.01,P&lt;0.05),improved the expression level of inflammatory cytokines in the BALF of rats to varying degrees (P&lt;0.01,P&lt;0.05),and improved the pathological structure of rat lung tissue to varying degrees.Relative mRNA expressions of matrix metalloproteinase 2 (MMP-2),matrix metalloproteinase 12 (MMP-12),matrix metalloproteinase inhibitor 1 (TIMP-1),interleukin-6 (IL-6),and transforming growth factor-β1 (TGF-β1) were significantly reduced (P&lt;0.01);whereas relative mRNA expressions of matrix metalloproteinase 9(MMP-9) and matrix metalloproteinase inhibitor 2 (TIMP-2) were increased significantly (P&lt;0.01).The mRNA and protein expression levels of T-box transcription factor (T-bet),interleukin-12 (IL-12) and signal transducer and activator of transcription 4(STAT4) reduced to varying degrees (P&lt;0.01,P&lt;0.05).The mRNA of transcription factor GATA3 (binding protein-3),interleukin-4 (IL-4) and signal transducer and activator of transcription 6 (STAT6) in rat lung tissues and the protein expression levels of IL-4 and STAT6 were increased to varying degrees (P&lt;0.01,P&lt;0.05).In conclusion,anemoside B4 has a certain protective effect on COPD rats caused by cigarette smoke exposure and combined with LPS.The mechanism of action may be related to the regulation of IL-12/STAT4 and IL-4/STAT6 signaling pathways.

MicroRNA (miRNA), a non-coding single-stranded RNA molecule with 20-23 nucleotides encoded by endogenous genes, plays an essential role in maintaining normal cell function and regulating cell proliferation, differentiation, apoptosis, autophagy, and cell metabolism. The imbalance between miRNA and genes can cause a series of diseases, including malignancies. miRNA-326 (miR-326) is extensively known for its core regulation of various biological processes. This review presents an overview of the highlights of miR-326 in female-related diseases. To understand the impact of miR-326 on female disorders, we search all published studies about miR-326 having a high incidence in female conditions, including cervical cancer, endometrial cancer, breast cancer, intrauterine adhesion, and multiple autoimmune diseases. We aim to learn about the mutual regulation mechanism between miR-326 and related genes and signaling pathways, as well as to elaborate on the value of miR-326 as a potential biomarker and therapeutic target of female diseases. Our results provide reliable evidence and new strategies for treating female tumors and autoimmune diseases., Competing Interests: VIIIThe authors declare that there are no conflicts of interest., (2021 The Japan Society of Histochemistry and Cytochemistry.)

Radiation-induced hair cell injury is detrimental for human health but the underlying mechanism is not clear. MicroRNAs (miRNAs) have critical roles in various types of cellular biological processes. The present study investigated the role of miR-222 in the regulation of ionizing radiation (IR)-induced cell injury in auditory cells and its underlying mechanism. Real-time PCR was performed to identify the expression profile of miR-222 in the cochlea hair cell line HEI-OC1 after IR exposure. miRNA mimics or inhibitor-mediated up- or down-regulation of indicated miRNA was applied to characterize the biological effects of miR-222 using MTT, apoptosis and DNA damage assay. Bioinformatics analyses and luciferase reporter assays were applied to identify an miRNA target gene. Our study confirmed that IR treatment significantly suppressed miR-222 levels in a dose-dependent manner. Up-regulation of miR-222 enhances cell viability and alleviated IR-induced apoptosis and DNA damage in HEI-OC1 cells. In addition, BCL-2-like protein 11 (BCL2L11) was validated as a direct target of miR-222. Overexpression of BCL2L11 abolished the protective effects of miR-222 in IR-treated HEI-OC1 cells. Moreover, miR-222 alleviated IR-induced apoptosis and DNA damage by directly targeting BCL2L11. The present study demonstrates that miR-222 exhibits protective effects against irradiation-induced cell injury by directly targeting BCL2L11 in cochlear cells., (© 2021 The Author(s).)

Background: The combination of preoperative progressive pneumoperitoneum (PPP) and botulinum toxin type A (BTA) in adjuvant treatment of large parastomal hernia (LPH) has not been reported in the previous literature. Methods: From February 2018 to June 2019, 16 patients were diagnosed with LPH in our hospital were included in this study. All patients received PPP and BTA treatment to expand abdominal volume and extend abdominal muscle before surgery. The laparoscopic Sugarbaker method was preferred for defect close. Results: Before and after PPP and BTA, the mean volume of the parastomal hernia (VPH) was 1,522 and 1,644 cc, respectively ( P < 0.01), and the mean volume of the abdominal cavity (VAC) was 5,847 and 9,408 cc, respectively ( P < 0.01). The VPH/VAC ratio was decreased by an average of 8.4% after the combination management. And the lateral abdominal muscle length was increased by an average of 4.8 cm/side ( P < 0.01). These patients underwent surgery successfully, and no hernia recurrence after (17.6 ± 2.4) months of follow-up. Conclusions: The combination of PPP and BTA effectively expand the abdominal volume, decrease the risk of abdominal compartment syndrome (ACS) postoperatively, and beneficial to laparoscopic repair of LPH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tang, Ma, Xie, Chen, Zong and Zhou.)

The ketogenic diet has been widely used in the treatment of various nervous system and metabolic-related diseases. Our previous research found that a ketogenic diet exerts a protective effect and promotes functional recovery after spinal cord injury. However, the mechanism of action is still unclear. In this study, different dietary feeding methods were used, and myelin expression and gene level changes were detected among different groups. We established 15 RNA-seq cDNA libraries from among 4 different groups. First, KEGG pathway enrichment of upregulated differentially expressed genes and gene set enrichment analysis of the ketogenic diet and normal diet groups indicated that a ketogenic diet significantly improved the steroid anabolic pathway in rats with spinal cord injury. Through cluster analysis, protein-protein interaction analysis and visualization of iPath metabolic pathways, it was determined that Sqle, Sc5d, Cyp51, Dhcr24, Msmo1, Hsd17b7, and Fdft1 expression changed significantly. Second, through weighted gene co-expression network analysis showed that rats fed a ketogenic diet showed a significant reduction in the expression of genes involved in immune-related pathways, including those associated with immunity and infectious diseases. A ketogenic diet may improve the immune microenvironment and myelin growth in rats with spinal cord injury through reprogramming of steroid metabolism.

Glioma is the most common malignant brain tumor in central nervous system. Despite advances in the treatment of glioma such as surgery and chemoradiotherapy, most patients are easy to relapse, resulting in adverse clinical outcomes. Hence, effective molecular-targeting treatment may be one of attractive strategies for glioma therapy. The dysregulated microRNAs (miRNAs), one of the candidates of therapeutic targets, are believed to play an important role in the progression of glioma. In this study, we aimed to examine the expression profile of miRNAs in glioma and provide a reference for glioma therapy. Firstly, expression profile of miRNAs in 5 normal brain tissues, 5 low-grade glioma (LGG) tissues and 5 glioblastoma (GBM) tissues was detected by RNA sequencing (RNA-seq). Next, the target genes of differentially expressed miRNAs (DEmiRNAs) were predicted and then GO enrichment and KEGG pathway analysis performed by bioinformatics. Finally, 10 miRNAs which were significantly up- or down-regulated both in GBM and LGG were validated by real-time quantitative PCR (qRT-PCR). RNA-seq results indicated a number of DEmiRNAs in glioma. There were 64 up-regulated miRNAs and 17 down-regulated miRNAs in LGG, and 181 up-regulated miRNAs and 124 down-regulated miRNAs in GBM, respectively. Bioinformatics analysis showed that the target genes of these DEmiRNAs were enriched in various biological processes and signaling pathways such as cell metabolic and developmental process. Selected DEmiRNAs were further confirmed by qRT-PCR. miRNA-10b-5p, miRNA-92b-3p and miRNA-455-5p were significantly up-regulated in both GBM and LGG; while miRNA-542-3p was significantly up-regulated in LGG; miRNA-184 and miRNA-206 were significantly down-regulated in both GBM and LGG; miRNA-766-5p and miRNA-1-3p were significantly down-regulated in GBM. The subject of our study demonstrated several dysregulated miRNAs may serve as a potential therapeutic target for glioma.

Although vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are under development, the antigen epitopes on the virus and their immunogenicity are poorly understood. Here, we simulate the 3D structures and predict the B cell epitopes on the spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins of SARS-CoV-2 using structure-based approaches and validate epitope immunogenicity by immunizing mice. Almost all 33 predicted epitopes effectively induce antibody production, six of these are immunodominant epitopes in individuals, and 23 are conserved within SARS-CoV-2, SARS-CoV, and bat coronavirus RaTG13. We find that the immunodominant epitopes of individuals with domestic (China) SARS-CoV-2 are different from those of individuals with imported (Europe) SARS-CoV-2, which may be caused by mutations on the S (G614D) and N proteins. Importantly, we find several epitopes on the S protein that elicit neutralizing antibodies against D614 and G614 SARS-CoV-2, which can contribute to vaccine design against coronaviruses., Competing Interests: Declaration of interests R.-t.L, S.L., and X.-x.X. have filed a provisional patent on epitopes for designing a coronavirus vaccine., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Context: The Traditional Chinese herb medicine Dalbergia odorifera T. Chen (Fabaceae), exerted a protective effect on myocardial ischaemia. Latifolin is a neoflavonoid extracted from Dalbergia odorifera . It has been reported to have the effects of anti-inflammation and cardiomyocyte protection., Objective: To investigate whether latifolin can improve myocardial infarction (MI) through attenuating myocardial inflammatory and to explore its possible mechanisms., Materials and Methods: Left coronary artery was ligated to induce a rat model of MI, and the rats were treated with sodium carboxymethyl cellulose (CMC-Na) or different doses of latifolin (25, 50, 100 mg/kg/d) by oral gavage for 28 days. Serum contents of myocardial enzyme were measured at seven and fourteen days after treatment. Cardiac function, infarct size, histopathological changes and inflammatory cells infiltration was assessed at 28 days after treatment. Western blotting was used to investigate the underlying mechanisms., Results: Latifolin treatment markedly decreased the contents of myocardial enzymes, and increased left ventricular ejection fraction (85.27% vs. 59.11%) and left ventricular fractional shortening (62.71% vs. 45.53%). Latifolin was found to significantly reduced infarction size (27.78% vs. 39.07%), myocardial fibrosis and the numbers of macrophage infiltration (436 cells/mm 2 vs. 690 cells/mm 2 ). In addition, latifolin down-regulated the expression levels of hypoxia-inducible factor-1α (0.95-fold), phospho-nuclear factor-κB (0.2-fold) and interleukin-6 (1.11-fold)., Discussion and Conclusions: Latifolin can protect against myocardial infarction by improving myocardial inflammation through the HIF-1α/NF-κB/IL-6 signalling pathway. Accordingly, latifolin may be a promising drug for pharmacological treatment of ischaemic cardiovascular disease.

α-synuclein (α-syn) is a protein associated with the pathogenesis of Parkinson's disease (PD), the second most common neurodegeneration disease with no effective treatment. However, how α-syn drives the pathology of PD remains elusive. Recent studies suggest that α-syn oligomers are the primary cause of neurotoxicity and play a critical role in PD. In this review, we discuss the process of α-syn oligomers formation and the current understanding of the structures of oligomers. We also describe seed and propagation effects of oligomeric forms of α-syn. Then, we summarize the mechanism by which α-syn oligomers exert neurotoxicity and promote neurodegeneration, including mitochondrial dysfunction, endoplasmic reticulum stress, proteostasis dysregulation, synaptic impairment, cell apoptosis and neuroinflammation. Finally, we investigate treatment regimens targeting α-syn oligomers at present. Further research is needed to understand the structure and toxicity mechanism of different types of oligomers, so as to provide theoretical basis for the treatment of PD.