Broadening Horizons: Exploring the Cathepsin Family as Therapeutic Targets for Alzheimer's Disease.

Alzheimer's disease (AD) is an intricate neurodegenerative disorder characterized by the accumulation of misfolded proteins, including beta-amyloid (Aß) and tau, leading to cognitive decline. Despite decades of research, the precise mechanisms underlying its onset and progression remain elusive. Cathepsins are a family of lysosomal enzymes that play vital roles in cellular processes, including protein degradation and regulation of immune responses. Emerging evidence suggests that cathepsins may be involved in AD pathogenesis. Cathepsins can influence the activation of microglia and astrocytes, the resident immune cells in the brain. However, cathepsin dysfunction may lead to the accumulation of misfolded proteins, notably Aß and tau. In addition, dysregulated cathepsin activity may induce an exaggerated immune response, promoting chronic inflammation and neuronal dysfunction in patients with AD. By unraveling the classification, functions, and roles of cathepsins in AD's pathogenesis, this review sheds light on their intricate involvement in this devastating disease. Targeting cathepsin activity could be a promising and novel approach for mitigating the pathological processes that contribute to AD, providing new avenues for its treatment and prevention.

Advancements in understanding substantia nigra hyperechogenicity via transcranial sonography in Parkinson's disease and its clinical implications.

Amidst rising Parkinson's disease (PD) incidence in an aging global population, the need for non-invasive and reliable diagnostic methods is increasingly critical. This review evaluates the strategic role of transcranial sonography (TCS) in the early detection and monitoring of PD. TCS's ability to detect substantia nigra hyperechogenicity offers profound insights into its correlation with essential neuropathological alterations-namely, iron accumulation, neuromelanin depletion, and glial proliferation-fundamental to PD's pathophysiology. Our analysis highlights TCS's advantages, including its non-invasiveness, cost-effectiveness, and ease of use, positioning it as an invaluable tool for early diagnosis and continual disease progression monitoring. Moreover, TCS assists in identifying potential risk and protective factors, facilitating tailored therapeutic strategies to enhance clinical outcomes. This review advocates expanding TCS utilization and further research to maximize its diagnostic and prognostic potential in PD management, contributing to a more nuanced understanding of the disease.

Luteolin-7-diglucuronide, a novel PTP1B inhibitor, ameliorates hepatic stellate cell activation and liver fibrosis in mice.

Liver fibrosis, one of the leading causes of morbidity and mortality worldwide, lacks effective therapy. The activation of hepatic stellate cells (HSCs) is the dominant event in hepatic fibrogenesis. Luteolin-7-diglucuronide (L7DG) is the major flavonoid extracted from Perilla frutescens and Verbena officinalis. Their beneficial effects in the treatment of liver diseases were well documented. In this study we investigated the anti-fibrotic activities of L7DG and the potential mechanisms. We established TGF-ß1-activated mouse primary hepatic stellate cells (pHSCs) and human HSC line LX-2 as in vitro liver fibrosis models. Co-treatment with L7DG (5, 20, 50 µM) dose-dependently decreased TGF-ß1-induced expression of fibrotic markers collagen 1, α-SMA and fibronectin. In liver fibrosis mouse models induced by CCl4 challenge alone or in combination with HFHC diet, administration of L7DG (40, 150 mg·kg-1·d-1, i.g., for 4 or 8 weeks) dose-dependently attenuated hepatic histopathological injury and collagen accumulation, decreased expression of fibrogenic genes. By conducting target prediction, molecular docking and enzyme activity detection, we identified L7DG as a potent inhibitor of protein tyrosine phosphatase 1B (PTP1B) with an IC50 value of 2.10 µM. Further studies revealed that L7DG inhibited PTP1B activity, up-regulated AMPK phosphorylation and subsequently inhibited HSC activation. This study demonstrates that the phytochemical L7DG may be a potential therapeutic candidate for the treatment of liver fibrosis.

Engineered bacteria breach tumor physical barriers to enhance radio-immunotherapy.

Radiotherapy widely applied for local tumor therapy in clinic has been recently reinvigorated by the discovery that radiotherapy could activate systematic antitumor immune response. Nonetheless, the endogenous radio-immune effect is still incapable of radical tumor elimination due to the prevention of immune cell infiltration by the physical barrier in tumor microenvironment (TME). Herein, an engineered Salmonella secreting nattokinase (VNPNKase) is developed to synergistically modulate the physical and immune characteristics of TME to enhance radio-immunotherapy of colon tumors. The facultative anaerobic VNPNKase enriches at the tumor site after systemic administration, continuously secreting abundant NKase to degrade fibronectin, dredge the extracellular matrix (ECM), and inactivate cancer-associated fibroblasts (CAFs). The VNPNKase- dredged TME facilitates the infiltration of CD103+ dendritic cells (DCs) and thus the presentation of tumor-associated antigens (TAAs) after radiotherapy, recruiting sufficient CD8+ T lymphocytes to specifically eradicate localized tumors. Moreover, the pre-treatment of VNPNKase before radiotherapy amplifies the abscopal effect and achieves a long-term immune memory effect, preventing the metastasis and recurrence of tumors. Our research suggests that this strategy using engineered bacteria to breach tumor physical barrier for promoting immune cell infiltration possesses great promise as a translational strategy to enhance the effectiveness of radio-immunotherapy in treating solid tumors.

Conduction system pacing upgrade versus biventricular pacing on pacemaker-induced cardiomyopathy: a retrospective observational study.

Objective: The feasibility of the conduction system pacing (CSP) upgrade as an alternative modality to the traditional biventricular pacing (BiVP) upgrade in patients with pacemaker-induced cardiomyopathy (PICM) remains uncertain. This study sought to compare two modalities of CSP (His bundle pacing (HBP) and left bundle branch pacing (LBBP)) with BiVP and no upgrades in patients with pacing-induced cardiomyopathy. Methods: This retrospective analysis comprised consecutive patients who underwent either BiVP or CSP upgrade for PICM at the cardiac department from 2017 to 2021. Patients with a follow-up period exceeding 12 months were considered for the final analysis. Results: The final group of patients who underwent upgrades included 48 individuals: 11 with BiVP upgrades, 24 with HBP upgrades, and 13 with LBBP upgrades. Compared to the baseline data, there were significant improvements in cardiac performance at the last follow-up. After the upgrade, the QRS duration (127.81 ± 31.89 vs 177.08 ± 34.35 ms, p < 0.001), NYHA class (2.28 ± 0.70 vs 3.04 ± 0.54, p < 0.05), left ventricular end-diastolic diameter (LVEDD) (54.08 ± 4.80 vs 57.50 ± 4.85 mm, p < 0.05), and left ventricular ejection fraction (LVEF) (44.46% ± 6.39% vs 33.15% ± 5.25%, p < 0.001) were improved. There was a noticeable improvement in LVEF in the CSP group (32.15% ± 3.22% vs 44.95% ± 3.99% (p < 0.001)) and the BiVP group (33.90% ± 3.09% vs 40.83% ± 2.99% (p < 0.001)). The changes in QRS duration were more evident in CSP than in BiVP (56.65 ± 11.71 vs 34.67 ± 13.32, p < 0.001). Similarly, the changes in LVEF (12.8 ± 3.66 vs 6.93 ± 3.04, p < 0.001) and LVEDD (5.80 ± 1.71 vs 3.16 ± 1.35, p < 0.001) were greater in CSP than in BiVP. The changes in LVEDD (p = 0.549) and LVEF (p = 0.570) were similar in the LBBP and HBP groups. The threshold in LBBP was also lower than that in HBP (1.01 ± 0.43 vs 1.33 ± 0.32 V, p = 0.019). Conclusion: The improvement of clinical outcomes in CSP was more significant than in BiVP. CSP may be an alternative therapy to CRT for patients with PICM. LBBP would be a better choice than HBP due to its lower thresholds.

[Determination of 13 perfluorinated and polyfluoroalkyl substances in fishes by QuEChERS-ultra-high performance liquid chromatography-tandem mass spectrometry].

Perfluorinated and polyfluoroalkyl substances (PFASs) are compounds characterized by at least one perfluorinated carbon atom in an alkyl chain linked to side-chain groups. Owing to their unique chemical properties, these compounds are widely used in industrial production and daily life. However, owing to anthropogenic activities, sewage discharge, surface runoff, and atmospheric deposition, PFASs have gradually infiltrated the environment and aquatic resources. With their gradual accumulation in environmental waters, PFASs have been detected in fishes and several fish-feeding species, suggesting that they are bioconcentrated and even amplified in aquatic organisms. PFASs exhibit high intestinal absorption efficiencies, and they bioaccumulate at higher trophic levels in the food chain. They can be bioconcentrated in the human body via food (e. g., fish) and thus threaten human health. Therefore, establishing an efficient analytical technique for use in analyzing PFASs in typical fish samples and providing technical support for the safety regulation and risk assessment of fish products is necessary. In this study, by combining solvent extraction and magnetic dispersion-solid phase extraction (d-SPE), an improved QuEChERS method with ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was developed for the determination of 13 PFASs in fish samples. Fe3O4-TiO2 can be used as an ideal adsorbent in the removal of sample matrix interference and a separation medium for the rapid encapsulation of other solids to be isolated from the solution. Based on the matrix characteristics of the fish products and structural properties of the target PFASs, Fe3O4-TiO2 and N-propyl ethylenediamine (PSA) were employed as adsorbents in dispersive purification. The internal standard method was used in the quantitative analyses of the PFASs. To optimize the sample pretreatment conditions of analyzing PFASs, the selection of the extraction solvent and amounts of Fe3O4-TiO2 and PSA were optimized. Several PFASs contain acidic groups that are non-dissociated in acidic environments, thus favoring their entry into the organic phase. In addition, acidified acetonitrile can denature and precipitate the proteins within the sample matrix, facilitating their removal. Finally, 2% formic acid acetonitrile was used as the extraction solvent, and 20 mg Fe3O4-TiO2, 20 mg PSA and 120 mg anhydrous MgSO4 were used as purification adsorbents. Under the optimized conditions, the developed method exhibited an excellent linearity (R≥0.9973) in the range of 0.01-50 µg/L, and the limits of detection (LODs) and quantification (LOQs) ranged from 0.001-0.023 and 0.003-0.078 µg/L, respectively. The recoveries of the 13 PFASs at low, medium, and high spiked levels (0.5, 10, and 100 µg/kg) were 78.1%-118%, with the intra- and inter-day precisions of 0.2%-11.1% and 0.8%-8.7%, respectively. This method was applied in analyzing real samples, and PFASs including perfluorooctanesulfonic acid, perfluorooctanoic acid, perfluoroundecanoic acid, perfluorododecanoic acid, and perfluorotridecanoic acid, were detected in all 11 samples evaluated. This method is simple, sensitive, and suitable for use in analyzing PFASs in fish samples.

One-size-fits-all versus risk-category-based screening interval strategies for cardiovascular disease prevention in Chinese adults: a prospective cohort study.

Background: In non-high-risk individuals, risk-category-based atherosclerotic cardiovascular disease (ASCVD) screening strategies may be more cost-effective than one-size-fits-all approaches. However, current decisions are constrained by a lack of research evidence. We aimed to explore appropriate risk-category-based screening interval strategies for non-high-risk individuals in ASCVD primary prevention in the Chinese population. Methods: We used data from 28,624 participants in the China Kadoorie Biobank (CKB) who had completed at least two field surveys. The risk assessment tools were the 10-year ASCVD risk prediction models developed based on the CKB cohort. We constructed multistate Markov models to model disease progression and estimate transition probabilities between different risk categories. The total person-years spent unidentified in the high-risk state over a 10-year period were calculated for each screening interval protocol. We also estimated the number of ASCVD events prevented, quality-adjusted life years (QALYs) gained, and costs saved when compared to the 3-yearly screening protocol. Findings: When compared to the uniform 3-yearly protocol, most risk-category-based screening interval protocols would identify more high-risk individuals timely, thus preventing more ASCVD events and gaining QALYs. A few of them would reduce total health-care costs. The protocol, which used 6-year, 3-year, and 2-year screening intervals for low-risk, intermediate-low-risk, and intermediate-high risk individuals, was optimal, and would reduce the person-years spent unidentified in the high-risk category by 17.9% (95% CI: 13.1%-21.9%), thus preventing an estimated 113 thousand (95% CI: 83-138) hard ASCVD events for Chinese adults aged 30-79 over a 10-year period. When using a lower cost of statin therapy, more screening protocols would gain QALYs while saving costs. Interpretation: For the primary prevention of ASCVD, risk-category-based screening protocols outperformed the one-size-fits-all approach in the Chinese population. Funding: This work was supported by National Natural Science Foundation of China (82192904, 82388102, 82192900) and grants (2023YFC2509400) from the National Key R&D Program of China. The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up is supported by grants from the UK Wellcome Trust (212946/Z/18/Z, 202922/Z/16/Z, 104085/Z/14/Z, 088158/Z/09/Z), grants (2016YFC0900500) from the National Key R&D Program of China, National Natural Science Foundation of China (81390540, 91846303, 81941018), and Chinese Ministry of Science and Technology (2011BAI09B01).

TAX1BP1 and FIP200 orchestrate non-canonical autophagy of p62 aggregates for mouse neural stem cell maintenance.

Autophagy plays a pivotal role in diverse biological processes, including the maintenance and differentiation of neural stem cells (NSCs). Interestingly, while complete deletion of Fip200 severely impairs NSC maintenance and differentiation, inhibiting canonical autophagy via deletion of core genes, such as Atg5, Atg16l1, and Atg7, or blockade of canonical interactions between FIP200 and ATG13 (designated as FIP200-4A mutant or FIP200 KI) does not produce comparable detrimental effects. This highlights the likely critical involvement of the non-canonical functions of FIP200, the mechanisms of which have remained elusive. Here, utilizing genetic mouse models, we demonstrated that FIP200 mediates non-canonical autophagic degradation of p62/sequestome1, primarily via TAX1BP1 in NSCs. Conditional deletion of Tax1bp1 in fip200 hGFAP conditional knock-in (cKI) mice led to NSC deficiency, resembling the fip200 hGFAP conditional knockout (cKO) mouse phenotype. Notably, reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from tax1bp1-knockout fip200 hGFAP cKI mice but also led to a marked reduction in p62 aggregate accumulation. Conversely, a TAX1BP1 mutant incapable of binding to FIP200 or NBR1/p62 failed to achieve this restoration. Furthermore, conditional deletion of Tax1bp1 in fip200 hGFAP cKO mice exacerbated NSC deficiency and p62 aggregate accumulation compared to fip200 hGFAP cKO mice. Collectively, these findings illustrate the essential role of the FIP200-TAX1BP1 axis in mediating the non-canonical autophagic degradation of p62 aggregates towards NSC maintenance and function, presenting novel therapeutic targets for neurodegenerative diseases.

Trade-offs of reproductive growth and Cd remobilization regulated Cd accumulation in wheat grains (Triticum aestivum L.).

Minimization of cadmium (Cd) accumulation in wheat grain (Triticum aestivum L.) is an important way to prevent Cd hazards to humans. However, little is known about the mechanisms of varietal variation of Cd accumulation in wheat grain. This study explores the physiological mechanisms of Cd bioaccumulation through field and hydroponic experiments on two wheat varieties of low-Cd-accumulating variety (L-6331) and high-Cd-accumulating variety (H-6049). Field study showed that average Cd accumulative rates in spikes of H-6049 were 1.57-fold of L-6331 after flowering, ultimately grain-Cd of H-6049 was 1.70-fold of L-6331 in Cd-contaminated farmland. The hydroponic experiment further confirmed that more vegetative tissues of L-6331 were involved in the remobilization of Cd, which jointly mitigated the process of Cd loaded to grains when leaf-cutting conducted after Cd stress. Additionally, the L1 and N1 of L-6331 play an especially important role in regulating Cd remobilization, and the larger EVB areas in N1 have the morphological feature that facilitates the transfer of Cd to L1. Overall results implied that low-Cd-accumulating variety initiated more trade-offs of reproductive growth and Cd remobilizatoin under Cd-stress after flowering compared with high-Cd-accumulating variety, and provided new insights into the processes of Cd loaded into wheat grains among different varieties.

Incidence and mortality rates of 14 site-specific infectious diseases in 10 diverse areas of China: findings from China Kadoorie Biobank, 2006-2018.

BACKGROUND: Infectious diseases remain a major global health concern, including in China, with an estimated >10 million cases of infectious disease in 2019. We describe the burden of site-specific infectious diseases among Chinese adults. METHODS: From 2004 to 2008, the prospective China Kadoorie Biobank enrolled 512,726 adults aged 30-79 years from 10 diverse areas (5 rural, 5 urban) of China. During the 12 years of follow-up, 101,673 participants were hospitalised for any infectious disease. Descriptive analyses examined standardised incidence, mortality, and case fatality of infections. FINDINGS: The incidence of any infectious disease was 1856 per 100,000 person-years; respiratory tract infections (1069) were most common. The infectious disease mortality rate was 31.8 per 100,000 person years (20.3 and 9.4 for respiratory and non-respiratory infections, respectively) and case fatality was 2.2% (2.6% and 1.6% for respiratory and non-respiratory infections, respectively). Infectious disease incidence and mortality rates were higher at older ages and in rural areas. There were no clear sex-differences in infectious disease incidence rates, but mortality and case fatality rates were twice as high in men as in women. INTERPRETATION: Infectious diseases were common in Chinese adults. The observed burden of, and disparities in, site-specific infections can inform targeted prevention efforts. FUNDING: Kadoorie Foundation, Wellcome Trust, MRC, BHF, CR-UK, MoST, NNSF.

Dual-Drug Nanomedicine Assembly with Synergistic Anti-Aneurysmal Effects via Inflammation Suppression and Extracellular Matrix Stabilization.

Abdominal aortic aneurysm (AAA) represents a critical cardiovascular condition characterized by localized dilation of the abdominal aorta, carrying a significant risk of rupture and mortality. Current treatment options are limited, necessitating novel therapeutic approaches. This study investigates the potential of a pioneering nanodrug delivery system, RAP@PFB, in mitigating AAA progression. RAP@PFB integrates pentagalloyl glucose (PGG) and rapamycin (RAP) within a metal-organic-framework (MOF) structure through a facile assembly process, ensuring remarkable drug loading capacity and colloidal stability. The synergistic effects of PGG, a polyphenolic antioxidant, and RAP, an mTOR inhibitor, collectively regulate key players in AAA pathogenesis, such as macrophages and smooth muscle cells (SMCs). In macrophages, RAP@PFB efficiently scavenges various free radicals, suppresses inflammation, and promotes M1-to-M2 phenotype repolarization. In SMCs, it inhibits apoptosis and calcification, thereby stabilizing the extracellular matrix and reducing the risk of AAA rupture. Administered intravenously, RAP@PFB exhibits effective accumulation at the AAA site, demonstrating robust efficacy in reducing AAA progression through multiple mechanisms. Moreover, RAP@PFB demonstrates favorable biosafety profiles, supporting its potential translation into clinical applications for AAA therapy.

Antifungal Activity of Piperine-based Nanoemulsion Against Candida spp. via In Vitro Broth Microdilution Assay.

Candidemia leaves a trail of approximately 750,000 cases yearly, with a morbidity rate of up to 30%. While Candida albicans still ranks as the most predominantly isolated Candida species, C. glabrata comes in second, with a death rate of 40-50%. Although infections by Candida spp are commonly treated with azoles, the side effects and rise in resistance against it has significantly limited its clinical usage. The current study aims to address the insolubility of piperine and provide an alternative treatment to Candida infection by formulating a stable piperine-loaded O/W nanoemulsion, comprised of Cremophor RH40, Transcutol HP and Capryol 90 as surfactant, co-surfactant, and oil, respectively. Characterization with zetasizer showed the droplet size, polydispersity (PDI) and zetapotential value of the nanoemulsion to be 24.37 nm, 0.453 and -21.10 mV, respectively, with no observable physical changes such as phase separation from thermostability tests. FTIR peaks confirms presence of piperine within the nanoemulsion and TEM imaging visualized the droplet shape and further confirms the droplet size range of 20-24 nm. The MIC90 value of the piperine-loaded nanoemulsion determined with in vitro broth microdilution assay was approximately 20-50% lower than that of the pure piperine in DMSO, at a range of 0.8-2.0 mg/mL across all Candida spp. tested. Overall, the study showed that piperine can be formulated into a stable nanoemulsion, which significantly enhances its antifungal activity compared to piperine in DMSO.

Construction of an Ohmic Contact Cathode by Two Metal Sulfides for efficient Capture and Catalysis of Polysulfide.

The slow reaction kinetics and severe shuttle effect of lithium polysulfide make Li-S battery electrochemical performance difficult to meet the demands of large electronic devices such as electric vehicles. Based on this, an electrocatalyst constructed by metal phase material (MoS2) and semiconductor phase material (SnS2) with ohmic contact is designed for inhibiting the dissolution of lithium polysulfide with improving the reaction kinetics. According to the density-functional theory calculations, it is found that the heterostructured samples with ohmic contacts can effectively reduce the reaction-free energy of lithium polysulfide to accelerate the sulfur redox reaction, in addition to the excellent electron conduction to reduce the overall activation energy. The metallic sulfide can add more sulfophilic sites to promote the capture of polysulfide. Thanks to the ohmic contact design, the carbon nanotube-MoS2-SnS2 achieved a specific capacity of 1437.2 mAh g-1 at 0.1 C current density and 805.5 mAh g-1 after 500 cycles at 1 C current density and is also tested as a pouch cell, which proves to be valuable for practical applications. This work provides a new idea for designing an advanced and efficient polysulfide catalyst based on ohmic contact.

Hsp47 promotes biogenesis of multi-subunit neuroreceptors in the endoplasmic reticulum.

Protein homeostasis (proteostasis) deficiency is an important contributing factor to neurological and metabolic diseases. However, how the proteostasis network orchestrates the folding and assembly of multi-subunit membrane proteins is poorly understood. Previous proteomics studies identified Hsp47 (Gene: SERPINH1), a heat shock protein in the endoplasmic reticulum lumen, as the most enriched interacting chaperone for gamma-aminobutyric acid type A (GABAA) receptors. Here, we show that Hsp47 enhances the functional surface expression of GABAA receptors in rat neurons and human HEK293T cells. Furthermore, molecular mechanism study demonstrates that Hsp47 acts after BiP (Gene: HSPA5) and preferentially binds the folded conformation of GABAA receptors without inducing the unfolded protein response in HEK293T cells. Therefore, Hsp47 promotes the subunit-subunit interaction, the receptor assembly process, and the anterograde trafficking of GABAA receptors. Overexpressing Hsp47 is sufficient to correct the surface expression and function of epilepsy-associated GABAA receptor variants in HEK293T cells. Hsp47 also promotes the surface trafficking of other Cys-loop receptors, including nicotinic acetylcholine receptors and serotonin type 3 receptors in HEK293T cells. Therefore, in addition to its known function as a collagen chaperone, this work establishes that Hsp47 plays a critical and general role in the maturation of multi-subunit Cys-loop neuroreceptors.

Intriguing steroid glycosides for cancer therapy by suppressing the DNA damage response and mTOR/S6K signaling pathways.

Two rare 8-hydroxysteroid glycosides (6-7), and their downstream metabolites (1-5) with an unprecedented 6/6/5/5/5-pentacyclic scaffold, together with seven known analogues (8-14) were isolated from the twigs and leaves of Strophanthus divaricatus. Their structures were fully assigned by analysis of the spectroscopic and ECD data, NMR calculations, X-ray crystallographic study, and chemical methods. In addition, the inhibitory effects of 1-14 on liver and lung cancer cell lines were evaluated, and preliminary structure-activity relationship was discussed. Data-independent acquisition (DIA)-based quantitative proteomic analysis and biological verification of H1299 cells suggested that this family of compounds may play an anticancer role by suppressing both DNA damage response (DDR) and mTOR/S6K signaling pathways.

Cinobufacini Inhibits Survival and Metastasis of Hepatocellular Carcinoma via c-Met Signaling Pathway.

OBJECTIVE: To investigate the anti-tumor effects of cinobufacini (CINO) on hepatocellular carcinoma (HCC) induced by des-gamma-carboxy-prothrombin (DCP) and to uncover the underlying mechanisms. METHODS: The inhibitory effect of CINO on HCC cell proliferation was evaluated using the cell counting kit-8 method, and the apoptosis rate was quantified using flow cytometry. Immunofluorescence and Western blot analyses were used to investigate the differential expression of proteins associated with cell growth, apoptosis, migration, and invasion pathways after CINO treatment. The therapeutic potential of CINO for HCC was confirmed, and the possibility of combining cinobufacini with c-Met inhibitor for the treatment of primary HCC was further validated by in vivo experiments. RESULTS: Under the induction of DCP, CINO inhibited the activity of HCC cells, induced apoptosis, and inhibited migration and invasion. Upon the induction of DCP, CINO regulated c-Met activation and the activation of the phosphatidylinositol-3 kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathways. In a mouse model of HCC, CINO exhibited significant antitumor effects by inhibiting the phosphorylation of c-Met and the downstream PI3K/AKT and MEK/ERK pathways in tumor tissues. CONCLUSIONS: CINO inhibited HCC cell growth, promoted apoptosis, and suppressed HCC cell invasion and migration by targeting c-Met and PI3K/AKT and MEK/ERK signaling pathways under DCP induction.

Spicy food consumption and risk of vascular disease: Evidence from a large-scale Chinese prospective cohort of 0.5 million people.

BACKGROUND: Spicy food consumption has been reported to be inversely associated with mortality from multiple diseases. However, the effect of spicy food intake on the incidence of vascular diseases in the Chinese population remains unclear. This study was conducted to explore this association. METHODS: This study was performed using the large-scale China Kadoorie Biobank (CKB) prospective cohort of 486,335 participants. The primary outcomes were vascular disease, ischemic heart disease (IHD), major coronary events (MCEs), cerebrovascular disease, stroke, and non-stroke cerebrovascular disease. A Cox proportional hazards regression model was used to assess the association between spicy food consumption and incident vascular diseases. Subgroup analysis was also performed to evaluate the heterogeneity of the association between spicy food consumption and the risk of vascular disease stratified by several basic characteristics. In addition, the joint effects of spicy food consumption and the healthy lifestyle score on the risk of vascular disease were also evaluated, and sensitivity analyses were performed to assess the reliability of the association results. RESULTS: During a median follow-up time of 12.1 years, a total of 136,125 patients with vascular disease, 46,689 patients with IHD, 10,097 patients with MCEs, 80,114 patients with cerebrovascular disease, 56,726 patients with stroke, and 40,098 patients with non-stroke cerebrovascular disease were identified. Participants who consumed spicy food 1-2 days/week (hazard ratio [HR] = 0.95, 95% confidence interval [95% CI] = [0.93, 0.97], P <0.001), 3-5 days/week (HR = 0.96, 95% CI = [0.94, 0.99], P = 0.003), and 6-7 days/week (HR = 0.97, 95% CI = [0.95, 0.99], P = 0.002) had a significantly lower risk of vascular disease than those who consumed spicy food less than once a week (Ptrend <0.001), especially in those who were younger and living in rural areas. Notably, the disease-based subgroup analysis indicated that the inverse associations remained in IHD (Ptrend = 0.011) and MCEs (Ptrend = 0.002) risk. Intriguingly, there was an interaction effect between spicy food consumption and the healthy lifestyle score on the risk of IHD (Pinteraction = 0.037). CONCLUSIONS: Our findings support an inverse association between spicy food consumption and vascular disease in the Chinese population, which may provide additional dietary guidance for the prevention of vascular diseases.

Isoindoline-based fluorogenic probes bearing a self-immolative linker for the sensitive and selective detection of O-GlcNAcase activity.

O-GlcNAcase (OGA) is implicated in several important biological and disease-relevant processes. Here, we synthesized fluorogenic probes for OGA by grafting GlcNAc directly or using a self-immolative linker to the hydroxyl position of 4-hydroxylisoindoline (BHID), a typical excited-state intramolecular proton transfer (ESIPT) probe. The probe was used for a fluorogenic assay to determine the half maximal inhibitory concentration of a known OGA inhibitor and differentiate between OGA and hexosaminidase when GlcNAc is replaced by GlcNPr, where a propionyl group is used instead of an acetyl group.