Search

Background: The favorable results of Pemberton acetabuloplasty in children with developmental dysplasia of the hip have been well reported. We reviewed our long-term results related to osteonecrosis of the femoral head after this surgery, especially with regard to the effect of excessive inferior displacement of the femoral head.Methods: From 1993 to 1997, we performed 167 Pemberton acetabuloplasties in patients with developmental dysplasia of the hip who were eighteen months of age or older. Patients who had had prior treatment or developmental dysplasia of the hip due to neuromuscular disease were excluded. We selected patients who had unilateral developmental dysplasia of the hip, had undergone simultaneous open reduction and Pemberton acetabuloplasty between the ages of eighteen and thirty-six months, and had been followed for a minimum of ten years. Forty-nine patients met these criteria. The patients were divided into osteonecrosis-absent and osteonecrosis-present groups according to the criteria described by Kalamchi and MacEwen. Preoperative, interim follow-up and final radiographs were available for evaluation, as were the results of clinical examination. We used the femoral head inferior displacement percentage, measured on the radiographs, to quantify the amount of excessive correction postoperatively. Outcomes were measured with use of the McKay criteria and the Severin criteria.Results: The mean age at the time of surgery was 20.8 months, and the mean duration of follow-up was 134.6 months. Twenty-four patients (49%) were classified as not having osteonecrosis (the osteonecrosis-absent group) and twenty-five patients (51%), as having osteonecrosis (the osteonecrosis-present group). There were no significant differences between the two groups in terms of sex, age, laterality, Tönnis grade, or preoperative acetabular index. Seven of the cases of osteonecrosis were type I, thirteen were type II, one was type III, and four were type IV. The inferior displacement percentage revealed significant differences between the two groups (p < 0.0001). In the osteonecrosis-absent group, 96% of the patients had a radiographically satisfactory result (Severin class I or II); however, only 76% of the patients in the osteonecrosis-present group had a radiographically satisfactory result (p < 0.0001). According to the McKay criteria, there were significant clinical differences between the groups (p < 0.0001).Conclusions: Our results showed significant correlation between excessive reduction of the femoral head and the development of osteonecrosis. In light of the high prevalence of type-II osteonecrosis, we postulated that the lateral epiphyseal branch of the medial circumflex artery was vulnerable to compression with increased inferior displacement of the femoral head. The latest radiographic and functional results corresponded to the severity of the osteonecrosis. [ABSTRACT FROM AUTHOR]

Amphiphilic block copolymer (a-BCP) micelles offer morphological diversity and dimensional tunability, making them suitable for the fabrication of perovskite nanocrystals. However, precise control over the nucleation and growth of perovskite nanocrystals using a-BCP colloidal templates remains underexplored. This study investigates the effects of toluene, methanol, and polystyrene- block -poly(2-vinylpyridine) (PS- b -P2VP) on the formation of cesium lead bromide (CsPbBr 3 ) nanocrystals. The process involves four stages: (i) PS- b -P2VP micellization, (ii) PbBr 2 complexation, (iii) coordination interaction with P2VP, and (iv) burst nucleation of CsPbBr 3 nanocrystals. Toluene, a good solvent for PS but a nonsolvent for P2VP, PbBr 2 , and CsBr, facilitates the formation of PS- b -P2VP spherical micelles. Adding PbBr 2 to these micelles in toluene results in multiple emulsion, dispersing PbBr 2 microstructures (microemulsion) and forming [PbBr 3 ] - complexes encapsulated by the micelles (nanoemulsion). Prolonged stirring enhances this nanoemulsion. CsBr, insoluble in toluene, must be dissolved in methanol before being mixed with micelle-encapsulated complexes, promoting quick crystal nucleation. However, excess methanol weakens micellization, leading to the formation of fused micelles and irregular nanocrystals. At a high methanol content, [PbBr 4 ] 2- complexes also form, driving CsPbBr 3 to CsPb 2 Br 5 transformation via Ostwald ripening, resulting in large CsPb 2 Br 5 microcrystals that precipitate due to gravitational forces overcoming Brownian motion, destabilizing their dispersion in the solution.

Background: Mild cognitive impairment (MCI) may lead to difficulty maintaining postural stability and balance during locomotion. This heightened susceptibility to falls is particularly evident during tasks such as obstacle negotiation, which demands efficient motor planning and reallocation of attentional resources. This study proposed a multi-objective optimal control (MOOC) technique to assess the changes in motor control strategies during obstacle negotiation in older people affected by amnestic MCI., Methods: Motion data from 12 older adults with MCI and 12 controls when crossing obstacles were measured using a motion capture system, and used to obtain the control strategy of obstacle-crossing as the best compromise between the conflicting objectives of the MOOC problem, i.e., minimising mechanical energy expenditure and maximising foot-obstacle clearance. Comparisons of the weighting sets between groups and obstacle heights were performed using a two-way analysis of variance with a significance level of 0.05., Results: Compared to the controls, the MCI group showed significantly lower best-compromise weightings for mechanical energy expenditure but greater best-compromise weightings for both heel- and toe-obstacle clearances. This altered strategy involved a trade-off, prioritising maximising foot-obstacle clearance at the expense of increased mechanical energy expenditure. The MCI group could successfully navigate obstacles with a normal foot-obstacle clearance but at the cost of higher mechanical energy expenditure., Conclusions: MCI alters the best-compromise strategy between minimising mechanical energy expenditure and maximising foot-obstacle clearances for obstacle-crossing in older people. These findings provide valuable insights into how MCI impacts motor tasks and offer potential strategies for mitigating fall risks in individuals with MCI. Moreover, this approach could serve as an assessment tool for early diagnosis and a more precise evaluation of disease progression. It may also have applications for individuals with impairments in other cognitive domains., (© 2024. The Author(s).)

The main protease (M pro ) of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) represents a promising target for antiviral drugs aimed at combating COVID-19. Consequently, the development of M pro inhibitor is an ideal strategy for combating the virus. In this study, we identified twenty-two dithiocarbamates (1 a-h), dithiocarbamate-Cu(II) complexes (2 a-hCu) and disulfide derivatives (2 a-e, 2 i) as potent inhibitors of M pro , with IC 50 value range of 0.09-0.72, 0.9-24.7, and 15.1-111 μM, respectively, through FRET screening. The enzyme kinetics, inhibition mode, jump dilution, and DTT assay revealed that 1 g may be a partial reversible inhibitor, while 2 d and 2 f-Cu are the irreversible and dose- and time-dependent inhibitors, potentially covalently binding to the target. Binding of 2 d, 2 f-Cu, and 1 g to M pro was found to decrease the stability of the protein. Additionally, DTT assays and thermal shift assays indicated that 2 f-Cu and 2 d are the nonspecific and promiscuous cysteine protease inhibitor. ICP-MS implied that the inhibitory activity of 2 f-Cu may stem from the uptake of Cu(II) by the enzyme. Cytotoxicity assays demonstrated that 2 d and 1 g exhibit low cytotoxicity, whereas 2 f-Cu show certain cytotoxicity in L929 cells. Overall, this work presents two promising scaffolds for the development of M pro inhibitors to combat COVID-19., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Nonalcoholic steatohepatitis (NASH), a chronic liver disease characterized by the accumulation of fat in the liver, is highly prevalent on a global scale. In this study, we investigated the effects of total glucosides of Picrorhizae Rhizome (TGPR), the primary active ingredients in traditional Chinese herbal medicine derived from Picrorhiza scrophulariiflora Pennell. TGPR is known for its efficiency in attenuating NASH, in mouse models induced by methionine-choline deficient (MCD) diet or high-fat diet (HFD). Our findings indicated that TGPR exhibited efficacy in reducing hepatic steatosis and lowering serum lipid levels, specifically triglyceride and total cholesterol in the NASH model. Meanwhile, TGPR exhibited a suppressive effect on the production of pro-inflammatory cytokines. Mechanistically, we identified acyl-CoA oxidase 1 (Acox1) as a crucial cellular target of TGPR, influencing lipid metabolism and ATP production to treat NASH. Additionally, we found that the major components of TGPR, including Picroside I, Picroside II, and Picroside IV, exhibit significant binding abilities to the target Acox1 at its catalytic C-terminal α-domain, stabilizing its protein expression. TGPR binding to Acox1 facilitated the degradation of fatty acids via the Acox1-mediated MAPK signaling pathways, and consequently plays a role in regulating energy metabolism and reducing liver inflammation. In summary, our study demonstrates that TGPR effectively counteracts NASH by specifically targeting Acox1, thereby providing a significant clinical solution for the treatment of NASH., Competing Interests: The 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., (© 2024 The Authors. Published by Elsevier Ltd.)

Objective: Although percutaneous kyphoplasty (PKP) under C-arm guidance is an effective treatment for osteoporotic vertebral compression fractures (OVCF), obtaining high-definition images in patients with OVCF and spinal deformities can be challenging or insufficient using traditional C-arm guidance, prompting our institution to adopt the O-arm navigation system-which offers comprehensive 3D imaging and precise navigation-and this study compares its safety and efficacy with conventional C-arm-assisted PKP., Methods: This was a retrospective study. From February 2019 to February 2022, we enrolled 28 patients with OVCF (44 vertebrae) with spinal deformity treated with O-arm navigation-assisted PKP and 30 patients with OVCF (42 vertebrae) with spinal deformity treated with C-arm-guided PKP. We recorded puncture times, single-segment operation time, number of cases with bone cement leakage, and length of stay. The visual analog scales (VASs), Oswestry disability indexes (ODIs), recovery of Cobbs angle, and vertebral height were used to assess treatment effect before the operation, on the first day postoperation, the first month postoperation, and at the final follow-up. The chi-squared test was utilized for comparing discrete variables, an independent samples t-test was used for continuous variables, and Pearson's chi-squared test and Fisher's exact test were applied for categorical data., Results: Demographic features were comparable between the groups. The O-arm navigation group showed a significant reduction in puncture adjustment per vertebrae, single-segment operation time, and the rate of trocar needle malposition compared to the C-arm guidance group. The rate of cement leakage was decreased in the O-arm-guided PKP group, and other complications did not differ between the two groups. Intragroup comparisons revealed significant improvements in VAS scores and ODI on the first day, first month, and final follow-up after the operation (p < 0.05). The VAS score was significantly lower in the O-arm navigation-assisted PKP group than in the C-arm-guided PKP group on the first day postoperatively (p = 0.049). However, no significant differences in VAS scores were observed between the groups at the first month postoperatively or at the final follow-up. In each follow-up period, there was no significant difference in ODI, Cobb angle, and the percent of anterior vertebral height (AVH %) between the groups., Conclusion: O-arm navigation-assisted PKP demonstrates better clinical safety and efficacy than C-arm-guided PKP, marking it as a minimally invasive, safe, and effective procedure for treating patients with OVCF with spinal deformity., (© 2024 The Author(s). Orthopaedic Surgery published by Tianjin Hospital and John Wiley & Sons Australia, Ltd.)

This study reported an effective method for the degradation of Chieh-qua (Benincasa hispida var. Chieh-qua How) polysaccharides (BHCP) by a hydrogen peroxide-ascorbic acid oxidation (H 2 O 2 -V C ) system. The degradation conditions were optimized using a Box-Behnken response surface design as concentration of H 2 O 2 -V C 19.5 mM, degradation temperature 46.4 °C and degradation time 1.0 h. The average molecular weight was decreased and total sugar content was raised of the degraded polysaccharide (DBHCP). Two refined degraded polysaccharides (DBHCP-1, DBHCP-2) were purified and prepared, and their structures were analyzed by chemical and spectral analysis. The in vitro experiments showed that degraded polysaccharides (DBHCP and DBHCP-1) have better antioxidant and anti-tyrosinase activity than natural polysaccharide BHCP. These findings support the potential application of Chieh-qua polysaccharides in the food and medical industries., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

The N7-methylguanosine (m7G) methyltransferase Mettl1 has been recently implicated in cardiac repair and fibrosis. In this study we investigated the role of Mettl1 in mouse cardiomyocytes injury and the underlying mechanisms. Cardiac ischemia/reperfusion (I/R) I/R model was established in mice by ligation of the left anterior descending coronary artery (LAD) for 45 min followed by reperfusion for 24 h. We showed the mRNA and protein levels of Mettl1 were significantly upregulated in mouse I/R hearts and H 2 O 2 -treated neonatal mouse cardiomyocytes (NMCMs). Mettl1 knockdown markedly ameliorated cardiac I/R injury, evidenced by decreased infarct size, apoptosis, and improved cardiac function. Overexpression of Mettl1 triggered cardiomyocytes apoptosis in vivo and in vitro. By performing RNA sequencing combined with m7G methylated RNA sequencing in Mettl1-overexpressing mouse hearts, we revealed that Mettl1 catalyzed m7G modification of the deubiquitinase cylindromatosis (CYLD) mRNA to increase the expression of CYLD, which enhanced the stability of P53 via abrogating its ubiquitination degradation. Vice versa, P53 served as a transcriptional factor to positively regulate Mettl1 expression during I/R injury. Knockdown of CYLD mitigated cardiomyocytes apoptosis induced by Mettl1 overexpression or oxidative stress. From the available drug-targets databases and literature, we identified 4 small molecule inhibitors of m7G modification. Sinefungin, one of the Mettl1 inhibitors exerted profound protection against cardiac I/R injury in vivo and in vitro. Collectively, this study has identified Mettl1 as a key regulator of cardiomyocyte apoptosis, and targeting the Mettl1-CYLD-P53 positive feedback circuit may represent a novel therapeutic avenue for alleviating cardiac I/R injury., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Electronic cigarettes (e-cigarettes) have been advertised as a healthier alternative to traditional cigarettes; however, their exact effects on the bronchial epithelium are poorly understood. Air-liquid interface culture human bronchial epithelium (ALI-HBE) contains various cell types, including basal cell, ciliated cell and secretory cell, providing an in vitro model that simulates the biological characteristics of normal bronchial epithelium. Multiplex single-cell RNA sequencing of ALI-HBE was used to reveal previously unrecognized transcriptional heterogeneity within the human bronchial epithelium and cell type-specific responses to acute exposure to e-cigarette aerosol (e-aerosol) containing distinct components (nicotine and/or flavoring). The findings of our study show that nicotine-containing e-aerosol affected gene expression related to transformed basal cells into secretory cells after acute exposure; inhibition of secretory cell function by down-regulating genes related to epithelial cell differentiation, calcium ion binding, extracellular exosomes, and secreted proteins; and enhanced interaction between secretory cells and other cells. On the other hand, flavoring may alter the growth pattern of epithelial cells and make basal cells more susceptible to SARS-CoV infection. Besides, the data also indicate factors that may promote SARS-CoV-2 infection and suggest therapeutic targets for restoring normal bronchial epithelium function after e-cigarette use. In summary, the current study offered fresh perspectives on alterations in the cellular landscape and cell type-specific responses in human bronchial epithelium that are brought about by e-cigarette use., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Wing-Hung Ko reports financial support was provided by Research Grant Council General Research Fund. Wing-Hung Ko reports financial support was provided by Health and Medical Research Fund, Food and Health Bureau, Government of the Hong Kong Special Administrative Region. Xiaofan Mao reports financial support was provided by 10.13039/501100001809National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Pyroptosis is an identified programmed cell death that has been highly linked to endoplasmic reticulum (ER) dynamics. However, the crucial proteins for modulating dynamic ER membrane curvature change that trigger pyroptosis are currently not well understood. In this study, a biotin-labeled chemical probe of potent pyroptosis inducer α-mangostin (α-MG) was synthesized. Through protein microarray analysis, reticulon-4 (RTN4/Nogo), a crucial regulator of ER membrane curvature, was identified as a target of α-MG. We observed that chemically induced proteasome degradation of RTN4 by α-MG through recruiting E3 ligase UBR5 significantly enhances the pyroptosis phenotype in cancer cells. Interestingly, the downregulation of RTN4 expression significantly facilitated a dynamic remodeling of ER membrane curvature through a transition from tubules to sheets, consequently leading to rapid fusion of the ER with the cell plasma membrane. In particular, the ER-to-plasma membrane fusion process is supported by the observed translocation of several crucial ER markers to the "bubble" structures of pyroptotic cells. Furthermore, α-MG-induced RTN4 knockdown leads to PKM2-dependent conventional caspase-3/GSDME cleavages for pyroptosis progression. In vivo, we observed that chemical or genetic RTN4 knockdown significantly inhibited cancer cells growth, which further exhibited an antitumor immune response with anti-PD-1. In translational research, RTN4 high expression was closely correlated with the tumor metastasis and death of patients. Taken together, RTN4 plays a fundamental role in inducing pyroptosis through the modulation of ER membrane curvature remodeling, thus representing a prospective druggable target for anticancer immunotherapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of Higher Education Press.)

The human malaria parasite Plasmodium falciparum (P. falciparum) continues to pose a significant public health challenge, leading to millions of fatalities globally. Halofuginone (HF) has shown a significant anti-P. falciparum effect, suggesting its potential as a therapeutic agent for malaria treatment. In this study, we synthesized a photoaffinity labeling probe of HF to identify its direct target in P. falciparum. Our results reveal that ubiquitin carboxyl-terminal hydrolase 3 (PfUCHL3) acts as a crucial target protein of HF, which modulates parasite growth in the intraerythrocytic cycle. In particular, we discovered that HF potentially forms hydrogen bonds with the Leu10, Glu11, and Arg217 sites of PfUCHL3, thereby inducing an allosteric effect by promoting the embedding of the helix 6' region on the protein surface. Furthermore, HF disrupts the expression of multiple functional proteins mediated by PfUCHL3, specifically those that play crucial roles in amino acid biosynthesis and metabolism in P. falciparum. Taken together, this study highlights PfUCHL3 as a previously undisclosed druggable target of HF, which contributes to the development of novel anti-malarial agents in the future., (© 2024 Wiley-VCH GmbH.)

End-ischemic normothermic mechanical perfusion (NMP) could provide a curative treatment to reduce cholestatic liver injury from donation after circulatory death (DCD) in donors. However, the underlying mechanism remains elusive. Our previous study demonstrated that air-ventilated NMP could improve functional recovery of DCD in a preclinical NMP rat model. Here, metabolomics analysis revealed that air-ventilated NMP alleviated DCD- and cold preservation-induced cholestatic liver injury, as shown by the elevated release of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and γ-glutamyl transferase (GGT) in the perfusate (p < .05) and the reduction in the levels of bile acid metabolites, including ω-muricholic acid, glycohyodeoxycholic acid, glycocholic acid, and glycochenodeoxycholate (GCDC) in the perfused livers (p < .05). In addition, the expression of the key bile acid metabolism enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1), which is predominantly expressed in hepatocytes, was substantially elevated in the DCD rat liver, followed by air-ventilated NMP (p < .05), and in vitro, this increase was induced by decreased GCDC and hypoxia-reoxygenation in the hepatic cells HepG2 and L02 (p < .05). Knockdown of UGT1A1 in hepatic cells by siRNA aggravated hepatic injury caused by GCDC and hypoxia-reoxygenation, as indicated by the ALT and AST levels in the supernatant. Mechanistically, UGT1A1 is transcriptionally regulated by peroxisome proliferator-activator receptor-γ (PPAR-γ) under hypoxia-physoxia. Taken together, our data revealed that air-ventilated NMP could alleviate DCD- and cold preservation-induced cholestatic liver injury through PPAR-γ/UGT1A1 axis. Based on the results from this study, air-ventilated NMP confers a promising approach for predicting and alleviating cholestatic liver injury through PPAR-γ/UGT1A1 axis., (© 2024 Federation of American Societies for Experimental Biology.)

We conducted a retrospective population-based, matched cohort study using the National Health Insurance Research Database to estimate healthcare resource utilisation (HRU) and costs in patients with newly diagnosed AL amyloidosis in Taiwan. Cases were matched 10:1 by age, sex, and area of residence to patients without AL amyloidosis (comparators) randomly selected from the database during the same time period. Annual all-cause HRU and costs for 3 years were quantified. AL amyloidosis-attributable costs were obtained by subtracting all-cause HRU costs incurred by comparators from cases. The mean age of all patients was 60.78 years and 59.07% were male. Co-morbidities were more frequent in cases than comparators. By 6 months after diagnosis, 12.1% of cases had died versus 0.9% of comparators. In the first year, cases had 103% more outpatient visits, 177% more emergency room visits, were hospitalised 4-times more frequently, and spent 5.5-times more days in hospital than comparators, and total healthcare costs were > sixfold higher. Costs incurred during the first year after diagnosis accounted for 55% of the 3-year cumulative cost. High HRU costs associated with delayed diagnosis and end-organ damage indicate a need for earlier diagnosis and more effective treatments for AL amyloidosis., (© 2024. The Author(s).)

Background: Electroacupuncture (EA) has been shown to promote functional recovery after cerebral ischemia-reperfusion (I/R) injury. However, the contribution of mitochondrial dynamics to recovery remains unclear. The aim of this study was to investigate whether mitochondrial dynamics are involved in the effects of EA on cerebral I/R injury., Methods: The rats with cerebral I/R injury were established by the middle cerebral artery occlusion/reperfusion. Subsequently, EA was applied to Baihui (GV20) and Dazhui (GV14) acupoints, with 2 Hz/5 Hz in frequency, 1.0 mA in intensity, 20 min each time, once a day for seven consecutive days. The therapeutic outcomes were assessed by modified neurological severity score (mNSS), 2,3,5-Triphenyte-trazolium chloride (TTC) staining, and hematoxylin-eosin (HE) staining. Mitochondrial morphology was observed under transmission electron microscopy. Adenosine triphosphate (ATP) content and ATP synthases (ATPases) activity were evaluated to measure mitochondrial function using ELISA. Finally, mitochondrial dynamics-related molecules, including dynamin-related protein 1 (Drp1), fission 1 (Fis1), mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), and optic atrophy 1 (OPA1), were detected by Western blot and immunofluorescence staining., Results: Cerebral I/R injury induced neurological dysfunction, cerebral infarction and neuronal injury, all of which were ameliorated by EA . And EA improved mitochondrial morphology and function. Moreover, EA altered the balance of mitochondrial dynamics. Specifically, the data showed a significant decrease in the expression of Drp1 and Fis1, leading to the inhibition of mitochondrial fission. Additionally, Mfn1, Mfn2 and Opa1, which are related to mitochondrial fusion, were effectively promoted after EA treatment. However, sham EA did not show any neuroprotective effects in rats with cerebral I/R injury., Conclusions: In summary, our study indicates that the balance of mitochondrial dynamics is crucial for EA therapy to treat cerebral I/R injury., Competing Interests: The 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., (© 2024 The Authors.)

Case: A 12-year-old boy with Klippel-Trenaunay-Weber syndrome underwent surgery for unstable slipped capital femoral epiphysis who developed pulmonary embolism postoperatively., Conclusion: It is important to be vigilant about pulmonary embolism in children because it is rare but potentially fatal, especially in the presence of risk factors. Early diagnosis and treatment of unstable slipped capital femoral epiphysis are crucial to minimize immobility. Close monitoring of femoral head osteonecrosis is also necessary., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Aims: Despite clear guideline recommendations for initiating four drug classes in all patients with heart failure (HF) with reduced ejection fraction (HFrEF) and the availability of rapid titration schemes, information on real-world implementation lags behind. Closely following the 2021 ESC HF guidelines and 2023 focused update, the TITRATE-HF study started to prospectively investigate the use, sequencing, and titration of guideline-directed medical therapy (GDMT) in HF patients, including the identification of implementation barriers., Methods and Results: TITRATE-HF is an ongoing long-term HF registry conducted in the Netherlands. Overall, 4288 patients from 48 hospitals were included. Among these patients, 1732 presented with de novo, 2240 with chronic, and 316 with worsening HF. The median age was 71 years (interquartile range [IQR] 63-78), 29% were female, and median ejection fraction was 35% (IQR 25-40). In total, 44% of chronic and worsening HFrEF patients were prescribed quadruple therapy. However, only 1% of HFrEF patients achieved target dose for all drug classes. In addition, quadruple therapy was more often prescribed to patients treated in a dedicated HF outpatient clinic as compared to a general cardiology outpatient clinic. In each GDMT drug class, 19% to 36% of non-use in HFrEF patients was related to side-effects, intolerances, or contraindications. In the de novo HF cohort, 49% of patients already used one or more GDMT drug classes for other indications than HF., Conclusion: This first analysis of the TITRATE-HF study reports relatively high use of GDMT in a contemporary HF cohort, while still showing room for improvement regarding quadruple therapy. Importantly, the use and dose of GDMT were suboptimal, with the reasons often remaining unclear. This underscores the urgency for further optimization of GDMT and implementation strategies within HF management., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

There is an urgent requirement to acquire a comprehensive comprehension of novel therapeutic targets for prostate cancer to facilitate the development of medications with innovative mechanisms. In this study, we identified gambogic acid (GBA) as a specific pyroptosis inducer in prostatic cancer cells. By using a thermal proteome profiling (TPP) strategy, we revealed that GBA induces pyroptosis by directly targeting the canopy FGF signaling regulator (CNPY3), which was previously considered "undruggable". Moreover, through the utilization of the APEX2-based proximity labeling method, we found that GBA recruited delactatease SIRT1, resulting in the elimination of lysine lactylation (Kla) on CNPY3. Of note, SIRT1-mediated delactylation influenced the cellular localization of CNPY3 to promote lysosome rupture for triggering pyroptosis. Taken together, our study identified CNPY3 as a distinctive cellular target for pyroptosis induction and its potential application in prostate cancer therapy.

Fibroblast-like synoviocytes (FLS) play an important role in rheumatoid arthritis (RA)-related swelling and bone damage. Therefore, novel targets for RA therapy in FLS are urgently discovered for improving pathologic phenomenon, especially joint damage and dyskinesia. Here, we suggested that pyruvate kinase M2 (PKM2) in FLS represented a pharmacological target for RA treatment by antimalarial drug artemisinin (ART). We demonstrated that ART selectively inhibited human RA-FLS and rat collagen-induced arthritis (CIA)-FLS proliferation and migration without observed toxic effects. In particular, the identification of targets revealed that PKM2 played a crucial role as a primary regulator of the cell cycle, leading to the heightened proliferation of RA-FLS. ART exhibited a direct interaction with PKM2, resulting in an allosteric modulation that enhances the lactylation modification of PKM2. This interaction further promoted the binding of p300, ultimately preventing the nuclear translocation of PKM2 and inducing cell cycle arrest at the S phase. In vivo, ART obviously suppressed RA-mediated synovial hyperplasia, bone damage and inflammatory response to further improve motor behavior in CIA-rats. Taken together, these findings indicate that directing interventions towards PKM2 in FLS could offer a hopeful avenue for pharmaceutical treatments of RA through the regulation of cell cycle via PKM2 lactylation., Competing Interests: Declaration of Competing interest There are no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Neuroinflammation is initiated in response to a variety of endogenous and exogenous sources. As the resident macrophages of the central nervous system, the polarization of microglia into either the M1 pro-inflammatory phenotype or the M2 anti-inflammatory phenotype holds great promise as a therapeutic strategy for neuroinflammation. Natural products, comprising a vital chemical library with distinctive structures and diverse functions, have been extensively employed to modulate microglial polarization for the treatment of neuroinflammation. In this review, we present up-to-date and extensive insights into the therapeutic effects and underlying mechanisms of natural products in the context of neuroinflammation. Furthermore, the review aims to present a new perspective by focusing on the targets of natural compounds, elucidating the molecular mechanisms and guiding the transition from natural-derived lead compounds to potential anti-neuroinflammatory drugs. Additionally, we provide a comprehensive overview of the challenges and limitations associated with the utilization of natural products for neuroinflammation therapy., (© 2024 British Pharmacological Society.)

The genus Hepacivirus comprises a diverse range of genetically distinct viruses that infect both mammalian and non-mammalian hosts, with some posing significant risks to human and animal health. Members of the genus Hepacivirus are typically classified into fourteen species ( Hepacivirus A-N ), with ongoing discoveries of novel hepaciviruses like Hepacivirus P and Hepacivirus Q . In this study, a novel Hepacivirus was identified in duck liver samples collected from live poultry markets in Hunan province, China, using unbiased high-throughput sequencing and meta-transcriptomic analysis. Through sequence comparison and phylogenetic analysis, it was determined that this newly discovered Hepacivirus belongs to a new subspecies of Hepacivirus Q . Moreover, molecular screening revealed the widespread circulation of this novel virus among duck populations in various regions of Hunan province, with an overall prevalence of 13.3%. These findings significantly enhence our understanding of the genetic diversity and evolution of hepaciviruses, emphasizing the presence of genetically diverse hepaciviruses duck populations in China. Given the broad geographical distribution and relatively high positive rate, further investigations are essential to explore any potential associations between Hepacivirus Q and duck-related diseases., 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 © 2024 Chen, Chen, Wu, Yi and Shao.)

Betel-quid chewing addiction is the leading cause of oral submucous fibrosis and oral cancer, resulting in significant socio-economic burdens. Vaccination may serve as a promising potential remedy to mitigate the abuse and combat accidental overdose of betel nut. Hapten design is the crucial factor to the development of arecoline vaccine that determines the efficacy of a candidate vaccine. Herein, we reported that two kinds of novel arecoline-based haptens were synthesized and conjugated to Bovine Serum Albumin (BSA) to generate immunogens, which generated antibodies with high affinity for arecoline but reduced binding for guvacoline and no affinity for arecaidine or guvacine. Notably, vaccination with Arec-N-BSA, which via the N-position on the tetrahydropyridine ring (tertiary amine group), led to a higher antibody affinity compared to Arec-CONH-BSA, blunted analgesia and attenuated hypothermia for arecoline., Competing Interests: Declaration of competing interest The 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 Elsevier Masson SAS. All rights reserved.)

Objective: The pathogenesis of diarrhea-predominant irritable bowel syndrome (IBS-D) is related to damage to the intestinal mucosal barrier function. Based on the Mast cell (MC)/Tryptase/Protease-activated receptor-2 (PAR-2)/Myosin light chain kinase (MLCK) pathway, this study explored the effect of electroacupuncture (EA) on IBS-D rats and its possible mechanism of protecting the intestinal mucosal barrier., Methods: The IBS-D rat model was established by mother-offspring separation, acetic acid enema, and chronic restraint stress. The efficacy of EA on IBS-D rats was evaluated by observing the rate of loose stool (LSP) and the minimum volume threshold of abdominal withdrawal reflex (AWR) in rats. Mast cells and the ultrastructure of intestinal mucosa were observed by H&E staining, toluidine blue staining, and transmission electron microscopy. The expression levels of Tryptase, PAR-2, MLCK, zonula occludens-1 (ZO-1), and Occludin in rats were detected by ELISA, qRT-PCR, and western blot., Results: After 7 days of intervention, compared to the IBS-D group, the loose stool rates of rats in IBS-D + EA group and IBS-D + ketotifen group were decreased ( P < 0.01), the minimum volume thresholds of AWR were improved ( P < 0.01), the inflammation of colon tissue decreased, the number of MCs were decreased ( P < 0.01), the expression of Tryptase, PAR-2, and MLCK were lowered ( P < 0.01, P < 0.05), and the expression of ZO-1 and Occludin were enhanced ( P < 0.01, P < 0.05). Compared to the EA group, there was no significant difference in each index between the ketotifen groups ( P > 0.05)., Conclusion: EA has a good therapeutic effect on IBS-D rats. Regulating the MCs/Tryptase/PAR-2/MLCK pathway may be a mechanism to protect the intestinal mucosal barrier., Competing Interests: None., (AJTR Copyright © 2024.)

Background: Cayratia albifolia C.L.Li (CAC), commonly known as "Jiao-Mei-Gu" in China, has been extensively utilized by the Dong minority for several millennia to effectively alleviate symptoms associated with autoimmune diseases. CAC extract is believed to possess significant anti-inflammatory properties within the context of Dong medicine. However, an in-depth understanding of the specific pharmaceutical effects and underlying mechanisms through which CAC extract acts against rheumatoid arthritis (RA) has yet to be established., Methods: Twenty-four Sprague-Dawley rats were divided into four groups, with six rats in each group. To induce the collagen-induced arthritis (CIA) model, the rats underwent a process of double immunization with collagen and adjuvant. CAC extract (100 mg/kg) was orally administered to rats. The anti-RA effects were evaluated in CIA rats by arthritis score, hind paw volume and histopathology analysis. Pull-down assay was conducted to identify the potential targets of CAC extract from RAW264.7 macrophage lysates. Moreover, mechanism studies of CAC extract were performed by immunofluorescence assays, real-time PCR and Western blot., Results: CAC extract was found to obviously down-regulate hind paw volume of CIA rats, with diminished inflammation response and damage. 177 targets were identified from CAC extract by MS-based pull-down assay. Bioinformatics analysis found that these targets were mainly enriched in macrophage activation and neutrophils extracellular traps (NETs). Additionally, we reported that CAC extract owned significant anti-inflammatory activity by regulating PI3K-Akt-mTOR signal pathway, and inhibited NETosis in response to PMA., Conclusions: We clarified that CAC extract significantly attenuated RA by inactivating macrophage and reducing NETosis via a multi-targets regulation., (© 2024. The Author(s).)

The bacterial infection mediated by β-lactamases MβLs and SβLs has grown into an emergent health threat, however, development of a molecule that dual inhibits both MβLs and SβLs is challenging. In this work, a series of hydroxamates 1a-g, 2a-e, 3a-c, 4a-c were synthesized, characterized by 1 H and 13 C NMR and confirmed by HRMS. Biochemical assays revealed that these molecules dually inhibited MβLs (NDM-1, IMP-1) and SβLs (KPC-2, OXA-48), with an IC 50 value in the range of 0.64-41.08 and 1.01-41.91 μM (except 1a and 1d on SβLs, IC 50  > 50 μM), and 1f was found to be the best inhibitor with an IC 50 value in the range of 0.64-1.32 and 0.57-1.01 μM, respectively. Mechanism evaluation indicated that 1f noncompetitively and irreversibly inhibited NDM-1 and KPC-2, with K i value of 2.5 and 0.55 μM, is a time- and dose-dependent inhibitor of both MβLs and SβLs. MIC tests shown that all hydroxamates increased the antimicrobial effect of MER on E. coli-NDM-1 and E. coli-IMP-1 (expect 1b, 1d, 1g and 2d), resulting in a 2-8-fold reduction in MICs of MER, 1e-g, 2b-d, 3a-c and 4b-c decreased 2-4-fold MICs of MER on E. coli-KPC-2, and 1c, 1f-g, 2a-c, 3b, 4a and 4c decreased 2-16-fold MICs of MER on E. coli-OXA-48. Most importantly, 1f-g, 2b-c, 3b and 4c exhibited the dual synergizing inhibition against both E. coli-MβLs and E. coli-SβLs tested, resulting in a 2-8-fold reduction in MICs of MER, and 1f was found to have the best effect on the drug-resistant bacteria tested. Also, 1f shown synergizing antimicrobial effect on five clinical isolates EC04, EC06, EC08, EC10 and EC24 that produce NDM-1, resulting in a 2-8-fold reduction in MIC of MER, but its effect on E. coli and K. pneumonia-KPC-NDM was not to be observed using the same dose of inhibitor. Mice tests shown that the monotherapy of 1f or 4a in combination with MER significantly reduced the bacterial load of E. coli-NDM-1 and E. coli-OXA-48 cells in liver and spleen, respectively. The discovery in this work offered a promising bifunctional scaffold for creating the specific molecules that dually inhibit MβLs and MβLs, in combating antibiotic-resistant bacteria., Competing Interests: Declaration of competing interest The 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 © 2023 Elsevier Masson SAS. All rights reserved.)

Background: Crohn's disease (CD) is a chronic inflammatory bowel disease with significant morbidity, affecting millions worldwide. The intricacies of immune responses in CD, especially post-treatment, remain a vital area of exploration. While memory T (Tm)-cell subsets play a pivotal role in adaptive immunity, their specific function in patients with CD after treatment is not well-understood. This study aims to investigate the effect and function of Tm-cell subsets in these patients, addressing a crucial knowledge gap in the context of CD therapeutics., Methods: A total of eight patients diagnosed with CD were selected based on predefined inclusion criteria. All patients were treated with either anti-inflammatory agents, immunosuppressive drugs, or a combination of both. For comparison, healthy donors were enrolled based on exclusion of autoimmune or inflammatory diseases. Peripheral blood mononuclear cells (PBMCs) and lymphocytes were isolated from blood and lymph node tissue respectively. The phenotype and cytokine production of T lymphocytes from both CD patients and healthy donors were analyzed using flow cytometry. Statistical comparisons of the outcomes between CD patients and healthy donors were made using Mann-Whitney test (two-tailed) and Student t -test., Results: Post-treatment CD patients exhibited an altered T cell distribution with a notable increase in CD8 + T cells in PBMCs (P=0.0005), and altered frequencies of CD4 + and CD8 + T cells in mesenteric lymph nodes (MLNs). Tm cells showed decreased interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) production, with significant alterations in the frequency of IFN-γ-producing CD8 + stem cell-like Tm (Tscm) cells in lesions of the MLNs from patients with CD (CD-M-Lys) compared to healthy MLNs from patients with CD (N-M-Lys) (P=0.0152). Differences in tissue-resident Tm (Trm)-cell subset frequencies were observed between the MLNs and small intestinal mucosa in CD patients., Conclusions: The treatments with anti-inflammatory agents and/or immunosuppressive drugs have a significant effect on the frequency and function of Tm-cell subsets. Clinically, these findings suggest a potential therapeutic avenue in modulating Tm-cell responses, which might be particularly beneficial for conditions where immune response modulation is crucial. Further clinical studies are warranted to explore the full therapeutic implications of these findings., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-23-21/coif). The authors have no conflicts of interest to declare., (2024 Translational Gastroenterology and Hepatology. All rights reserved.)

Mercury sulfide (HgS) exerts extensive biological effects on neuronal function. To investigate the direct target of HgS in neuronal cells, we developed a biotin-tagged HgS probe (bio-HgS) and employed an affinity purification technique to capture its target proteins. Then, we identified S-phase kinase-associated protein 1 (Skp1) as a potential target of HgS. Unexpectedly, we discovered that HgS covalently binds to Skp1 through a "Cys62-HgS-Cys120" mode. Moreover, our findings revealed that HgS inhibits the ubiquitin-protease system through Skp1 to up-regulate SNAP-25 expression, thereby triggering synaptic vesicle exocytosis to regulate locomotion ability in C. elegans . Collectively, our findings may promote a comprehensive interpretation of the pharmacological mechanism of mercury sulfide on neuroprotective function.

Objectives: To observe the effect of moxibustion intervention on the hypothalamus-spinal cord-colon axis of rats with irritable bowel syndrome with diarrhea (IBS-D) and explore the mechanism of moxibustion in improving visceral hypersensitivity in rats with IBS-D., Methods: A total of 36 SD rats were randomly divided into normal, model, and moxibustion groups, with 12 rats in each group. The IBS-D model was established by maternal separation + acetic acid stimulation + chronic restraint. Rats of the moxibustion group received bilateral moxibustion on "Tianshu" (ST25) and "Shangjuxu" (ST37) for 15 min, once a day for 7 consecutive days. The body weight, loose stool rate, and minimum threshold volume of abdominal withdrawal reflex (AWR) were measured before and after moxibustion intervention, respectively. The histopathological changes in the colon tissue were observed after HE staining. The number of colonic mucosal mast cells (MCs) was measured by toluidine blue staining. The activation of MCs was determined by tryptase positive expression level and examined by immunohistochemical staining. The content, protein and mRNA expression levels and positive expression levels of corticotropin releasing factor (CRF), substance P (SP), and calcitonin gene-related peptide (CGRP) in the hypothalamus, spinal cord and colon tissues were measured by ELISA, Western blot, real-time fluorescent quantitative PCR and immunofluorescence staining, respectively., Results: Compared with the normal group, the loose stool rate was increased ( P <0.01)；the body weight and minimum threshold volume of AWR were decreased ( P <0.01)；the inflammatory infiltration of colon tissues was obvious；the number of MCs and positive expression level of tryptase in the colon tissue were increased ( P <0.01)；the contents, positive expression le-vels, protein and mRNA expression levels of CRF, SP and CGRP in the hypothalamus, spinal cord and colon tissues were increased ( P <0.01, P <0.05) in the model group. After the intervention, compared with the model group, all these indicators showed opposite trends ( P <0.01, P <0.05) in the moxibustion group., Conclusions: Moxibustion can improve visceral hypersensitivity in rats with IBS-D, and its mechanism may be related to regulating the hypothalamic-spinal-colon axis to reduce the release of CRF, SP and CGRP, and thus to inhibite MC in colon tissue.

The hypothalamus plays a fundamental role in controlling lipid metabolism through neuroendocrine signals. However, there are currently no available drug targets in the hypothalamus that can effectively improve human lipid metabolism. In this study, we found that the antimalarial drug artemether (ART) significantly improved lipid metabolism by specifically inhibiting microglial activation in the hypothalamus of high-fat diet-induced mice. Mechanically, ART protects the thyrotropin-releasing hormone (TRH) neurons surrounding microglial cells from inflammatory damage and promotes the release of TRH into the peripheral circulation. As a result, TRH stimulates the synthesis of thyroid hormone (TH), leading to a significant improvement in hepatic lipid disorders. Subsequently, we employed a biotin-labeled ART chemical probe to identify the direct cellular target in microglial cells as protein kinase Cδ (PKCδ). Importantly, ART directly targeted PKCδ to inhibit its palmitoylation modification by blocking the binding of zinc finger DHHC-type palmitoyltransferase 5 (ZDHHC5), which resulted in the inhibition of downstream neuroinflammation signaling. In vivo, hypothalamic microglia-specific PKCδ knockdown markedly impaired ART-dependent neuroendocrine regulation and lipid metabolism improvement in mice. Furthermore, single-cell transcriptomics analysis in human brain tissues revealed that the level of PKCδ in microglia positively correlated with individuals who had hyperlipemia, thereby highlighting a clinical translational value. Collectively, these data suggest that the palmitoylation of microglial PKCδ in the hypothalamus plays a role in modulating peripheral lipid metabolism through hypothalamus-liver communication, and provides a promising therapeutic target for fatty liver diseases., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Antimony selenide (Sb 2 Se 3 ) is a highly promising photovoltaic material thanks to its outstanding optoelectronic properties, as well as its cost-effective and eco-friendly merits. However, toxic CdS is widely used as an electron transport layer (ETL) in efficient Sb 2 Se 3 solar cells, which largely limit their development toward market commercialization. Herein, an effective green Cd-free ETL of SnO x is introduced and deposited by atomic layer deposition method. Additionally, an important post-annealing treatment is designed to further optimize the functional layers and the heterojunction interface properties. Such engineering strategy can optimize SnO x ETL with higher nano-crystallinity, higher carrier density, and less defect groups, modify Sb 2 Se 3 /SnO x heterojunction with better interface performance and much desirable "spike-like" band alignment, and also improve the Sb 2 Se 3 light absorber layer quality with passivated bulk defects and prolonged carrier lifetime, and therefore to enhance carrier separation and transport while suppressing non-radiative recombination. Finally, the as-fabricated Cd-free Mo/Sb 2 Se 3 /SnO x /ITO/Ag thin-film solar cell exhibits a stimulating efficiency of 7.39%, contributing a record value for Cd-free substrate structured Sb 2 Se 3 solar cells reported to date. This work provides a viable strategy for developing and broadening practical applications of environmental-friendly Sb 2 Se 3 photovoltaic devices., (© 2023 Wiley-VCH GmbH.)

MicroRNAs (miRNAs) can regulate the expression of genes involved in the establishment of the window of implantation (WOI) in the endometrium. Recent studies indicated that cell-free miRNAs in uterine fluid and blood samples could act as alternative and non-invasive sample types for endometrial receptivity analysis. In this study, we attempt to systematically evaluate whether the expression levels of cell-free microRNAs in blood samples could be used as non-invasive biomarkers for assessing endometrial receptivity status. We profiled the miRNA expression levels of 111 blood samples using next-generation sequencing to establish a predictive model for the assessment of endometrial receptivity status. This model was validated with an independent dataset ( n = 73). The overall accuracy is 95.9%. Specifically, we achieved accuracies of 95.9%, 95.9%, and 100.0% for the pre-receptive group, the receptive group, and the post-respective group, respectively. Additionally, we identified a set of differentially expressed miRNAs between different endometrial receptivity statuses using the following criteria: p -value < 0.05 and fold change greater than 1.5 or less than -1.5. In conclusion, the expression levels of cell-free miRNAs in blood samples can be utilized in a non-invasive manner to distinguish different endometrial receptivity statuses.

Background: The distal radius fracture is a common orthopedic injury. We aimed to share the surgical steps and investigate the outcomes of treating distal radius fractures with wounds ≤10 mm using a globally accessible locking plate., Methods: We collected 46 patients who underwent surgery via a <10 mm wound, with a control group consisting of 40 patients who underwent conventional procedures. Both groups were treated using the same volar plate. We compared the radiographic reduction quality, including volar tilt angle, radial inclination angle, and ulna variance. Additionally, clinical outcomes, such as pain assessed using VAS, Q-Dash score, and PRWE, were evaluated. Patient satisfaction with the wound was also analyzed. The follow-up time for the clinical outcomes was 24.2 ± 13.47 months., Results: There were no differences in the quality of reduction in parameters such as the volar tilt angle ( p = 0.762), radial inclination angle ( p = 0.986), and ulna variance ( p = 0.166). Both groups exhibited comparable results in pain VAS ( p = 0.684), Q-Dash score ( p = 0.08), and PRWE ( p = 0.134). The ≤10 mm incision group displayed an increase in satisfaction with the wound ( p < 0.001)., Conclusions: Treating distal radius fractures with a <10 mm wound using a non-specialized locking plate is a feasible approach. It does not compromise the quality of fracture reduction or functional scores and improves wound satisfaction.

Hypertension, a primary cause of cardiovascular and cerebrovascular events, has become a major global public health problem and caused a heavy burden of health economics on the society. In &quot;the 20 Most Important and Most Preventable Health Problems&quot; released by the Chinese Academy of Engineering, hypertension was ranked the second. Due to the disease complexity, many hypertension patients need to take antihypertensive drugs for life. Although significant progress has been achieved in blood pressure lowering by western medicines, the problems including adverse reactions, poor compliance due to long-term medication, and ineffective mitigation in clinical symptoms related to hypertension remain to be addressed. In the last decade, the research on traditional Chinese medicine(TCM) treatment of hypertension has received much attention and achieved remarkable progress. The TCM treatment of hypertension is the most active area of research with integrated Chinese and western medicine in China. In addition to lowering blood pressure smoothly, TCM can alleviate clinical symptoms, reverse risk factors, improve the quality of life, and protect target organs from the damage caused by hypertension. This article systematically reviews the research progress of TCM in treating hypertension in the last decade from the following four aspects: consensus on guideline, clinical trial, experimental study, and systematic review/Meta-analysis. It summarized the evidence of TCM in reducing blood pressure and clarified the mechanism of TCM in reducing blood pressure, aiming to provide a reference for the TCM diagnosis and treatment of hypertension and the development of new drugs.

Metallo-carbapenemases-mediated carbapenem-resistant Enterobacterales (CREs) has been acknowledged as "urgent threat" by the World Health Organization. The discovery of new strategies that block metallo-carbapenemases activity to reverse carbapenem resistance is an urgent need. In this study, a coumarin copper complex containing a PEG linker and glucose ligand, GluC-Cu, was used to reverse carbapenem resistance. Interestingly, it could effectively inhibit metallo-carbapenemases (NDM-1, IMP-1 and ImiS) with an IC 50 value in the range of 0.23-1.21 μM, and simultaneously release the green fluorescence signal (GluC), therefore exhibiting self-reported inhibition performance. The inhibition mechanism of oxidizing Zn(II) thiolate site of NDM-1 from Cu 2+ to Cu + was verified by fluorescence assay, HR-MS, and XPS. Moreover, GluC-Cu in combination with meropenem showed excellent synergistic antibacterial effect to effectively combat E. coli expressing metallo-carbapenemases in vitro and in a mice infection model. This bifunctional metallo-carbapenemases inhibitor provides a novel chemical tool to overcome carbapenem resistance., Competing Interests: Declaration of competing interest The 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 © 2023. Published by Elsevier B.V.)

Purpose: Both lipid metabolism reprogramming and lncRNAs exert effects on tumor development. We aimed to predict the prognosis of head and neck squamous cell carcinoma (HNSCC) based on lipid metabolism-related (LR)-lncRNAs., Methods: LR-lncRNAs were determined from the RNA-ref profiles of HNSCC samples in The Cancer Genome Atlas (TCGA). The prognostic model was established by univariate Cox and Lasso regression analysis. Clinical relevance and predictive accuracy were investigated, and external validation was also performed in the Gene Expression Omnibus (GEO) cohort. Tumor immune infiltration and relevant functional analysis, including the association of autophagy with prognostic signatures, were conducted through single-sample gene set enrichment analysis (ssGSEA). The regulatory network of candidate LR-lncRNAs was investigated via coexpression, ceRNA and cis/trans acting interactions. Potential genes were selected through qRT-PCR analysis, and their effects on tumor biological activities and autophagic activity were explored after gene knockdown., Results: A total of 222 LR-lncRNAs were identified. Among the 41 genes with prognostic significance, 17 lncRNAs were eligible for the risk model. Patients in the high-risk group had a poorer prognosis than those in the low-risk group, and the risk score was found to be positively associated with tumor microenvironment infiltration via multiple algorithms. Furthermore, improved prognosis was found in patients with high autophagic scores and low risk scores, and autophagy-related genes such as PINK1 and CCL2 showed significantly lower expression in the low-risk group. The expression of immune checkpoint genes such as CD28, CTLA4 and PDCD1 decreased dramatically in the high-risk group. The target genes of candidate lncRNAs were confirmed, such as ENO2 and PPAR-gamma. Furthermore, MIR4435-2HG was the most significantly overexpressed lncRNA in HNSCC cell lines and tumor samples, which could promote proliferation and migration and inhibit apoptosis. Additionally, MIR4435-2HG silencing activated autophagy by increasing LC3B expression., Conclusion: This study constructed an LR-lncRNA prognostic signature for HNSCC and indicated its relationships with tumor immunity and autophagy, which provides a promising future for LR-lncRNA-oriented prognostic tools and therapeutic targets., Competing Interests: Declaration of Competing Interest The authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aberrant PCK2 overexpression has been linked to an unfavorable prognosis and shorter survival, particularly in hepatocellular carcinoma (HCC). Thus, the inactivation of PCK2 provides a promising strategy for HCC treatment. In this study, we used a chemical genetic strategy to identify a natural-derived small-molecule cucurbitacin B (CuB) as a selective PCK2 inhibitor. CuB covalently bound to PCK2 at a unique Cys63 site, blocking the Ω-loop lid domain formation via a previously undisclosed allosteric mechanism. Additionally, targeted lipidomics analysis also revealed that CuB destroyed mitochondrial membrane integrity, leading to the disruption of mitochondrial fusion-fission dynamics. Taken together, this study highlights the discovery of a small-molecule CuB, which reprograms lipid metabolism for controlling mitochondrial dynamics via targeting PCK2 in cancer cells.

Background: Multiple epiphyseal dysplasia (MED) is a rare congenital bone dysplasia. Patients with MED develop secondary hip osteoarthritis as early as the third to the fourth decade. Currently, there is no consensus on the prevention of the progressive hip osteoarthritis secondary to MED. The Bernese periacetabular osteotomy (PAO) is a joint-preserving surgery to reshape acetabulum and extend femoral head coverage. However, there is no documentary evidence for the effect of the procedure on MED hips., Patients and Methods: We analyzed the preliminary outcomes following the Bernese PAO in 6 MED hips. The average age at the time of surgery was 14.3 years (range from 11.4 to 17.2 years). For our study interest of time efficiency, radiographic parameters were analyzed preoperatively and 1 year postoperatively. The hip function was evaluated by the Harris Hip Score (HHS) before and after surgery., Results: The mean follow-up time was 1.7 years. The mean lateral center-edge angle increased from 3.8° to 47.1° (p = 0.02), anterior center-edge angle increased from 7.3° to 35.1° (p = 0.02), and acetabulum index decreased from 27.8° to 14.6° (p = 0.04). The femoral head coverage ratio increased from 66.8% to 100% (p = 0.02). The post-operative anteroposterior pelvic radiograph demonstrated all preoperative broken Shenton lines were reversed. The mean HHS improved from 67.3 to 86.7 (p = 0.05)., Conclusion: Bernese PAO is a feasible treatment for hip disorders in MED patients. It reshapes acetabular and femoral morphology efficiently. In our study, the preliminary results showed the procedure not only improved radiographic outcomes but also hip function., (© 2023. The Author(s).)

Size exclusion chromatography (SEC) is a foundational analytical method to assess product purity of biological molecules. To ensure accurate and reproducible data that meet regulatory agency standards, it is critical to monitor the chromatographic column with efficient and continuous approaches. In this study, 19 SEC columns (Waters Acquity BEH200) were evaluated using an in-house monoclonal antibody made at Regeneron. System suitability parameters (SSPs) were used to monitor the performance of the SEC assay, including USP resolution, USP plate count, USP tailing factor, asymmetry factor, elution time, peak width, and peak height. A general linear model was built and revealed that elution time, peak width, asymmetry factor, and tailing factor increased with injection number, while peak height, resolution, and plate count decreased. After 1000 injections, tailing factor and peak width increased by more than 10%, while resolution and plate count decreased by more than 10% from their respective starting values., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tse-Hong Chen, Shao-Chun Wang, Kenneth S. Graham, and Mohammed Shameem has patent pending to Tse-Hong Chen, Shao-Chun Wang, Kenneth S. Graham, and Mohammed Shameem employed by Regeneron Pharmaceuticals Inc. (“Regeneron”) and own shares of stock in Regeneron. Regeneron has filed patent applications related to the subject matter of the manuscript. The authors declare no competing financial interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Duchenne muscular dystrophy (DMD) is a genetic disease characterized by progressive muscle weakness with increased neuromechanical challenge and fall risks, especially during obstructed locomotion. This study aimed to identify the kinematic strategies for obstacle-crossing in DMD via synthesizing the changes in the joint kinematics and associated end-point control. Fourteen boys with DMD (age: 9.0 ± 2.5 years) and fourteen typically developed controls (age: 9.0 ± 2.8 years) each crossed obstacles of three different heights (10%, 20% and 30% of leg length) while the angular motions of the trunk-pelvis-leg apparatus and foot-obstacle clearances were measured. Two-way analyses of variance were used to analyze group and obstacle height effects. Compared to the controls, the DMD group crossed obstacles with significantly increased step width, but decreased crossing speed, crossing step length, trailing toe-obstacle clearance and leading heel-obstacle horizontal distance (p < 0.05). When the leading toe was above the obstacle, the patients showed significantly increased pelvic hiking, pelvic and trunk anterior tilt and ankle plantarflexion, but decreased hip flexion in both limbs (p < 0.05). Similar kinematic changes were found during trailing-limb crossing, except for an additional increase in swing-hip abduction and decrease in contralateral trunk side-bending and stance-knee flexion. Patients with DMD crossed obstacles via a specific kinematic strategy with altered end-point control, predisposing them to a greater risk of tripping during trailing-limb crossing. These results suggest that crossing kinematics in DMD should be monitored-especially in the proximal segments of the pelvis-leg apparatus-that may lead to an increased risk of falling., (© 2023. Springer Nature Limited.)

Isocitrate dehydrogenase (IDH) 1 and 2, as essential enzymes in energy metabolism, contribute to the survival and drug resistance of a variety of solid tumors, especially for colorectal cancer (CRC). However, the underlying molecular mechanism still remains unclear. In this study, IDH1 was identified as a crucial cellular target of a natural-derived anti-CRC small molecule lycorine, using the unbiased thermal proteome profiling (TPP) strategy. We found that lycorine directly targeted a unique C-terminal domain of IDH1, and disrupted IDH1 interaction with deacetylase sirtuin 1 (SIRT1), thereby significantly promoting IDH1 acetylation modification. Then, lycorine noticeably triggered oxidative stress in CRC cells to cause mitochondrial membranes injury, and subsequently facilitated mitochondrial fission. Specific knockdown of IDH1 or SIRT1 markedly aggrieved lycorine-mediated oxidative stress and mitochondrial fragmentation in CRC cells. Furthermore, the combination of lycorine and sirtuins blocker nicotinamide (NAM) exhibited a synergic therapeutic effect in CRC cells. Collectively, our results reveal that IDH1 may serve as a promising therapeutic target for CRC via pharmacologically driving oxidative stress-dependent mitochondrial dynamics imbalance., Competing Interests: Declaration of competing interest The 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 © 2023. Published by Elsevier B.V.)

Purpose: How to factor both tumor burden and oncogenic genomic mutations as variables to predict the outcome of endocrine-based therapy (ET) in ER-positive/HER2-negative metastatic breast cancer patients (MBC) remains to be explored., Method: Blood samples prospectively collected from 163 ER-positive/HER2-negative female MBC patients, before ET, were used for cell-free tumor DNA (cfDNA) analysis. cfDNA was subjected to next-generation sequencing (NGS) to interrogate oncogenic PIK3CA hotspot and TP53 DNA-binding domain (DBD) mutations, including single nucleotide variants (SNVs) or small insertions and deletions (InDels). The variant calling threshold was set at 0.5%. Progression-free survival (PFS) was measured from the start of the ET treatment to the time of disease progression of the same treatment regimen., Results: Overall, the median PFS was 8.3 months (95% CI 5.7-11.1 months). The median cfDNA was 38.5 ng (range 4.4-1935 ng). The proportion of patients with PIK3CA and TP53 alterations were 25.1 and 15.3%, respectively. Patients with high total cfDNA (HR 1.74, p = 0.003), PIK3CA mutation (HR 1.74, p = 0.007), and TP53 mutation (HR 1.64, p = 0.047) in liquid biopsy conferred worse outcome after ET. Even for patients with low tumor burden, the detrimental effect of PIK3CA or TP53 mutation remained significant (p < 0.001). For patients with either PIK3CA (p < 0.001) or TP53 mutation (p = 0.004), there was significant positive correlation between allele frequency (AF) and total cfDNA., Conclusion: After adjustment of cfDNA level, PIK3CA and TP53 mutations observed in liquid biopsy exerted detrimental effects on the outcome of ET-based regimens. The AF of PIK3CA or TP53 may be a surrogate marker for PFS., (© 2023. The Author(s).)

Objective: To observe the effect of electroacupuncture（EA）preconditioning on ferroptosis in rats with cerebral ischemia-reperfusion injury （CIRI）, so as to explore the neuroprotective mechanism of EA preconditioning., Methods: Male SD rats were randomly divided into sham operation, model, EA, inhibitor and inducer groups with 20 rats in each group. The CIRI model was established by modified Zea Longa occlusion of the middle cerebral artery. Before modeling, EA treatment （2 Hz/15 Hz, 1-2 mA） was applied to "Baihui"（GV20）, "Fengfu"（GV16） and "Dazhui"（GV14） for rats of the EA group, 20 min a day for 7 consecutive days. Rats of the inhibitor group were intraperitoneally injected with ferristatin-1（25 mg/kg）at a slow and uniform rate. Rats of the inducer group were intraperitoneally injected with Erastin（100 mg/kg） after 7 days of EA preconditioning, once every 2 h for a total of 4 times. The CIRI models were prepared 2 d later after the above interventions finished by thread-occlusion. The degree of neurological impairment was evaluated by modified Zea Longa score. The percentage of infarct size was calculated by TTC staining. The ultrastructure of neurons in hippocampus was observed by transmission electron microscope. The contents of ferrous ion （Fe 2+ ）, malondialdehyde （MDA） and glutathione （GSH） in cerebral tissue and reactive oxygen species （ROS） in serum were determined by biochemical method. The changes of mitochondrial membrane potential in rats brain tissues were detected by flow cytometry. The mRNA and protein expression levels of glutathione peroxidase 4 （GPX4）, acyl-CoA synthetase long-chain family member 4 （ACSL4）, transferrin receptor （TFRC）, 15-lipoxygenase （15-LOX） and cyclooxygenase-2 （COX-2） in the ischemic hippocampal region of CIRI rats were detected by real-time quantitative PCR and Western blot, respectively., Results: Compared with the sham operation group, the neurological impairment score, the percentage of cerebral infarction area, the contents of MDA and Fe 2+ in cerebral tissue as well as ROS in serum, the protein and mRNA expression levels of ACSL4, TFRC, 15-LOX, COX-2 in hippocampal tissue were increased （ P <0.01）, while the content of GSH in cerebral tissue, the protein and mRNA expression levels of GPX4 in hippocampal tissue were decreased （ P <0.01）, and mitochondria in brain tissue were significantly damaged （ P <0.01） in the model group. Compared with the model group, the above indexes were all reversed （ P <0.05, P <0.01） in the EA group and inhibitor group. Compared with the EA group, the neurological impairment score, the percentage of cerebral infarction area, the contents of MDA and Fe 2+ in cerebral tissue as well as ROS in serum, the protein and mRNA expression le-vels of ACSL4, TFRC, 15-LOX, COX-2 in hippocampal tissue were increased （ P <0.05, P <0.01）, while the content of GSH in cerebral tissue, the protein and mRNA expression levels of GPX4 in hippocampal tissue were decreased （ P <0.01, P <0.05）, and mitochondria in brain tissue were significantly damaged （ P <0.05） in the inducer group., Conclusion: EA preconditioning has neuroprotective effect on CIRI rats, which may be related to inhibiting ACSL4/TFRC/15-LOX/COX-2 expression and increasing GSH/GPX4 expression.

This study aims to analysis the structures of polysaccharides isolated from Pteridium revolutum and their antioxidant and antiglycated activities. Three novel water-soluble heteropolysaccharides, named PRP0, PRP1, and PRP2, were isolated from P. revolutum . The average molecular weight was determined by high performance gel permeation chromatography analysis as 1.04 × 10 6 , 8.39 × 10 5 , and 7.37 × 10 5 Da, respectively. Their structures were characterized using physicochemical and spectroscopic methods. The antioxidant and antiglycated activities were assayed in vitro . PRP0, PRP1, and PRP2 consist of l -Ara, l -Rha, d -Man, d -Xyl, d -Fuc, d -Gal, and d -Glc in different proportions. PRP1 mainly has a backbone of (1 → 3,6)-linked d -Man and (1 → 3)-linked d -Gal on main chain. PRP2 is mainly composed of (1 → 2,4)-linked d -Man and (1 → 3)-linked d -Gal on main chain. All polysaccharides have strong scavenging power on 2,2-difenil-1-picril-hidrazil and hydroxyl radicals and significantly antiglycated activity in Bovine serum albumin-Glucose model, which showing that the polysaccharides have potential application value on the functional food., Competing Interests: The 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., (© 2023 The Authors.)

The continuous emergence of multi-drug resistant pathogens co-expressing serine and metallo-carbapenemases seriously threatens the efficacy of carbapenem. Here, we report the first SeCN-derived dual inhibitor of serine and metallo-carbapenemases with IC 50 values ranging from 0.0038 to 1.27 μg mL -1 . The inhibitor was shown to form covalent bonds with Cys221 of NDM-1 and Ser70 of KPC-2, respectively, achieving selective labelling and cross-class inhibition for carbapenemases. Our results provide a potential strategy to develop clinically useful dual inhibitors targeting serine and metallo-carbapenemases to combat superbugs.

We report on a copper-catalyzed three-component reaction for the synthesis of disubstituted nicotinonitriles using 3-bromopropenals, benzoylacetonitriles, and ammonium acetate (NH 4 OAc). The Knoevenagel-type condensation of 3-bromopropenals with benzoylacetonitriles gives δ-bromo-2,4-dienones that contain strategically placed functional groups that react with the ammonia generated in situ to give the corresponding azatrienes. These azatrienes can then be transformed into trisubstituted pyridines under the reaction conditions via a reaction sequence involving 6π-azaelectrocyclization and aromatization.

Objective: To observe the effect of Tongdu Tiaoshen (promoting the circulation of the governor vessel and regulating the spirit) electroacupuncture (EA) pretreatment on pyroptosis mediated by peroxisome proliferators-activated receptor γ (PPARγ) of the cerebral cortex in rats with cerebral ischemia reperfusion injury (CIRI) and explore the potential mechanism of EA for the prevention and treatment of CIRI., Methods: A total of 110 clean-grade male SD rats were randomly divided into a sham-operation group, a model group, an EA group, an EA + inhibitor group and an agonist group, 22 rats in each group. In the EA group, before modeling, EA was applied to "Baihui" (GV 20), "Fengfu" (GV 16) and "Dazhui" (GV 14), with disperse-dense wave, 2 Hz/5 Hz in frequency, 1 to 2 mA in intensity, lasting 20 min; once a day, consecutively for 7 days. On the base of the intervention as the EA group, on the day 7, the intraperitoneal injection with the PPARγ inhibitor, GW9662 (10 mg/kg) was delivered in the EA + inhibitor group. In the agonist group, on the day 7, the PPARγ agonist, pioglitazone hydrochloride (10 mg/kg) was injected intraperitoneally. At the end of intervention, except the sham-operation group, the modified thread embolization method was adopted to establish the right CIRI model in the rats of the other groups. Using the score of the modified neurological severity score (mNSS), the neurological defect condition of rats was evaluated. TTC staining was adopted to detect the relative cerebral infarction volume of rat, TUNEL staining was used to detect apoptosis of cerebral cortical nerve cells and the transmission electron microscope was used to observe pyroptosis of cerebral cortical neural cells. The positive expression of PPARγ and nucleotide-binding to oligomerization domain-like receptor protein 3 (NLRP3) in the cerebral cortex was detected with the immunofluorescence staining. The protein expression of PPARγ, NLRP3, cysteinyl aspartate specific protease-1 (caspase-1), gasdermin D (GSDMD) and GSDMD-N terminal (GSDMD-N) in the cerebral cortex was detected with Western blot. Using the quantitative real-time fluorescence-PCR, the mRNA expression of PPARγ, NLRP3, caspase-1 and GSDMD of the cerebral cortex was detected. The contents of interleukin (IL)-1β and IL-18 in the cerebral cortex of rats were determined by ELISA., Results: Compared with the sham-operation group, the mNSS, the relative cerebral infarction volume and the TUNEL positive cells rate were increased ( P <0.01), pyroptosis was severe, the protein and mRNA expression levels of PPARγ, NLRP3, caspase-1 and GSDMD were elevated ( P <0.01); and the protein expression of GSDMD-N and contents of IL-1β and IL-18 were increased ( P <0.01) in the model group. When compared with the model group, the mNSS, the relative cerebral infarction volume and the TUNEL positive cells rate were decreased ( P <0.01), pyroptosis was alleviated, the protein and mRNA expression levels of PPARγ were increased ( P <0.01), the protein and mRNA expression levels of NLRP3, caspase-1 and GSDMD were decreased ( P <0.01), the protein expression of GSDMD-N was reduced ( P <0.01); and the contents of IL-1β and IL-18 were lower ( P <0.01) in the EA group and the agonist group; while, in the EA + inhibitor group, the protein expression of PPARγ was increased ( P <0.01), the protein and mRNA expression levels of NLRP3 and GSDMD were decreased ( P <0.01, P <0.05), the mRNA expression of caspase-1 was reduced ( P <0.01); and the contents of IL-1β and IL-18 were lower ( P <0.01). When compared with the EA + inhibitor group, the mNSS, the relative cerebral infarction volume and the TUNEL positive cells rate were decreased ( P <0.05, P <0.01), pyroptosis was alleviated, the protein and mRNA expression levels of PPARγ were increased ( P <0.01), the protein and mRNA expression levels of NLRP3, caspase-1 and GSDMD were decreased ( P <0.01), the protein expression of GSDMD-N was reduced ( P <0.01); and the contents of IL-1β and IL-18 were declined ( P <0.01) in the EA group. Compared with the agonist group, in the EA group, the relative cerebral infarction volume and the TUNEL positive cells rate were increased ( P <0.05, P <0.01), the mRNA expression of PPARγ was decreased ( P <0.01) and the protein expression of GSDMD-N was elevated ( P <0.05); and the contents of IL-1β and IL-18 were higher ( P <0.01)., Conclusion: Tongdu Tiaoshen EA pretreatment can attenuate the neurological impairment in the rats with CIRI, and the underlying mechanism is related to the up-regulation of PPARγ inducing the inhibition of NLRP3 in the cerebral cortex of rats so that pyroptosis is affected.

Obesity is strongly associated with insulin sensitivity in type 2 diabetes (T2D), mainly because free fatty acids (FFAs) are released from excess fat tissue. Long-term exposure to high levels of FFAs and glucose leads to glucolipotoxicity, causing damage to pancreatic β-cells, thus accelerating the progression of T2D. Therefore, the prevention of β-cell dysfunction and apoptosis is essential to prevent the development of T2D. Unfortunately, there are currently no specific clinical strategies for protecting β-cells, highlighting the need for effective therapies or preventive approaches to improve the survival of β-cells in T2D. Interestingly, recent studies have shown that the monoclonal antibody denosumab (DMB), used in osteoporosis, displays a positive effect on blood glucose regulation in patients with T2D. DMB acts as an osteoprotegerin (OPG) by inhibiting the receptor activator of the NF-κB ligand (RANKL), preventing the maturation and function of osteoclasts. However, the exact mechanism by which the RANK/RANKL signal affects glucose homeostasis has not been fully explained. The present study used human 1.4 × 10 7 β-cells to simulate the T2D metabolic condition of high glucose and free fatty acids (FFAs), and it investigated the ability of DMB to protect β-cells from glucolipotoxicity. Our results show that DMB effectively attenuated the cell dysfunction and apoptosis caused by high glucose and FFAs in β-cells. This may be caused by blocking the RANK/RANKL pathway that reduced mammalian sterile 20-like kinase 1 (MST1) activation and indirectly increased pancreatic and duodenal homeobox 1 (PDX-1) expression. Furthermore, the increase in inflammatory cytokines and ROS caused by the RANK/RANKL signal also played an important role in glucolipotoxicity-induced cytotoxicity, and DMB can also protect β-cells by reducing the mechanisms mentioned above. These findings provide detailed molecular mechanisms for the future development of DMB as a potential protective agent of β-cells.