Liver cancer is one of the world's serious diseases today because of its high frequency and fatality rate, genetic differences, and limited effectiveness of late-stage therapy. Although chemotherapy, targeted therapy, immunotherapy, ablation and transarterial chemoembolisation (TACE) have improved the disease control of some patients, recurrence and acquired resistance are still common, especially for tumors that are hypoxic, nutrient-deprived, acidic-stressed, vascularly insufficient and exposed to repeated drug pressure. A bad environment will cause a change in the quality-control system and metabolism of cancer cells, and as a result, lysosomes have started to alter. In addition to the above catabolic functions of lysosomes, they also take part in autophagic flux, substrate recycling, iron and lipid metabolism, nutrient sensing, drug distribution, membrane repair and cell death signalling. Under the stress of therapy in liver cancer cells, increased lysosomal acidification and enhanced terminal degradation lead to prolonged autophagy; TFEB/TFE3 promotes the formation of new lysosomes and lysophagosomes to sequester weakly basic drugs, thereby reducing the concentration of active drugs and mitigating proteotoxicity and oxidative stress to promote cell survival. The above processes produce a lysosome-dependent resistant phenotype that is particularly relevant to sorafenib and doxorubicin and other drugs whose effectiveness can be reduced by protective autophagy or changes in intracellular location. Conversely, the same dependency on lysosomal homeostasis is also a vulnerability. Natural products and monomeric compounds derived from Chinese herbal medicines have various structures, multiple target regulation capabilities, and the potential to act on several lysosome-related nodes simultaneously. Based on the evidence in this review, it is believed that such compounds may sensitise liver cancer cells by inhibiting V-ATPase-mediated acid hydrolysis, obstructing late-stage autophagy-mediated degradation, disrupting lysosomal calcium or membrane homeostasis, causing lysosomal membrane permeabilisation, reducing compensatory lysosomal biogenesis, promoting ferritin degradation and ferroptosis, or enhancing acid-responsive intracellular delivery. Agents that impair lysosomal function and protective autophagy, compounds that convert enlarged or drug-sequestering lysosomes into lethal targets, and nanodelivery systems that exploit the acidic environment of endolysosomes to co-deliver natural products with chemotherapeutic drugs are examples. Lysosome-targeted intervention will have different effects under different circumstances; for example, inhibiting autophagy may result in an increase in cytotoxic stress in some areas, whereas overstimulation of autophagy or iron release from lysosomes may induce autophagic cell death or ferroptosis in other areas. Therefore, the design of therapy should take into account the status of the tumour microenvironment, autophagic flux, lysosomal pH, TFEB/TFE3 activity, drug sequestration capacity, ferroptosis sensitivity, dosing sequence and delivery route. This review systematically examines the lysosomal homeostasis in the microenvironment of liver cancer, the mechanisms through which lysosomal adaptation contributes to chemoresistance, and the rationale for combining natural products with standard agents such as sorafenib and doxorubicin. Based on basic lysosome biology, pharmacodynamic and delivery data have also been collected; as a result, some applications for future studies have been proposed, such as dynamic monitoring of autophagy flux, in vivo spatial measurements of lysosomal functions, rational optimisation of combination therapy timings, and safety assessments in immunocompetent liver cancer models prior to clinical translation. Translation difficulties are also evident, such as insufficient tumour selectivity, pharmacokinetic limitations, compensatory lysosomal regeneration, toxicity to normal liver and immune cells, and a lack of validated predictive biomarkers. A new way will be found to use biomarkers to divide the patient group, optimize nanoparticles for better delivery, design specific schedules for combined treatments based on the problem they cause within the cell, etc., thereby overcoming drug resistance and reducing the harm patients suffer from toxic treatments. This system can help select biomarkers and rational drug pairs for the next round of lysosome-centred precision trials.

BACKGROUND:It has been shown that Gushukang affects bone metabolism by regulating nucleotide and amino acid metabolism and immune mechanisms.Current research on the mechanism of Gushukang in the treatment of osteoporosis primarily focuses on osteoblast regulation and requires further improvement from the perspective of osteoclasts. OBJECTIVE:To investigate the mechanism by which Gushukang interferes with osteoclasts in the treatment of osteoporosis using RAW264.7 cells as the research model. METHODS:Twenty-four 8-week-old female Sprague-Dawley rats were randomly divided into four groups(n=6 per group):the three experimental groups were given 1,2 and 4 g/kg osteoporosis solution by gavage(2 times per day),and the control group was given an equal amount of distilled water by gavage(2 times per day).After 7 days of intragastric administration,aortic blood samples were extracted to collect serum samples using centrifugation,and serum samples from the same groups were combined to obtain the low-,medium-,and high-concentration Gushukang-containing and normal sera for the subsequent experiments.(1)RAW264.7 cells were cultured in six groups:normal serum was added to the control group;low,medium,and high concentration groups were added with low,medium,and high concentrations of Gushukang-containing serum,respectively;ML385,a nuclear factor erythroid 2-related factor 2(Nrf2)inhibitor was given in the Nrf2 inhibitor group;and t-BHQ,a Nrf2 activator,was added in the Nrf2 activator group.Cell viability was detected using the cell counting kit-8 assay.(2)The 3rd generation RAW 264.7 cells were cultured and divided into five groups:the blank control group was added with normal serum,the osteoclast group was added with receptor activator of nuclear factor κB ligand(RANKL),and the low-,medium-,and high-concentration groups were added with low-,medium-,and high-concentration Gushukang-containing serum based on the addition of RANKL.Tartrate-resistant acid phosphate staining was performed after 5 days of culture.(3)RAW264.7 cells were cultured and divided into five groups:blank control group was cultured with normal serum,osteoclast group cultured with normal serum and RANKL,high concentration+osteoclast group cultured with RANKL+high concentration Gushukang-containing serum,osteoclast+Nrf2 agonist group cultured with RANKL+t-BHQ,and high concentration+osteoclast+Nrf2 inhibitor group cultured with RANKL+high concentration Gushukang-containing serum+ML385.Western blot assay and determination of reactive oxygen content were performed after 5 days of culture. RESULTS AND CONCLUSION:The cell counting kit-8 results indicated that Gushukang-containing serum,NRF2 inhibitor or agonist had no significant effect on RAW264.7 cell viability.Tartrate-resistant acid phosphate staining results demonstrated that Gushukang-containing serum exhibited a concentration-dependent inhibitory effect on osteoclast differentiation.Western blot analysis and determination of reactive oxygen species revealed that compared with the blank control group,Nrf2 protein expression was decreased in the osteoclast group(P<0.05),while c-Fos and NFATc1 protein expression and reactive oxygen species content were elevated(P<0.05);compared with the osteoclast group,Nrf2 protein expression was elevated and reactive oxygen species content was decreased in the high-concentration+osteoclast group,osteoclast+Nrf2 agonist group,and high-concentration+osteoclast+Nrf2 inhibitor group(P<0.05),while c-Fos and NFATc1 protein expression was decreased in the high concentration+osteoclast group and osteoclast+Nrf2 agonist group(P<0.05);compared with the high concentration+osteoclast group,Nrf2 protein expression was decreased(P<0.05)and reactive oxygen species content was elevated(P<0.05)in the high concentration+osteoclast+Nrf2 inhibitor group.To conclude,Gushukang reduces reactive oxygen species production by activating Nrf2,thereby inhibiting downstream of the c-Fos/NFATc1 pathway and suppressing osteoclast differentiation.

Hypochlorous acid/hypochlorite(HClO/ClO-)plays a key role in biological processes and is commonly used as a disinfectant in drinking water.However,excessive intake of HClO/ClO-can oxidize biomolecules like DNA,RNA,and proteins,causing organ damage.Diseases such as rheumatoid arthritis and Alzheimer's disease can also lead to overproduction of HClO/ClO-.Therefore,accurately detecting HClO/ClO-levels is crucial.In this study,an HClO/ClO-fluorescent probe,NC-TPA-PPh3,was designed and synthesized,with a triphenylamine core as the fluorescent unit,carbon-carbon double bonds as recognition sites,and a quaternary ammonium salt for mitochondria targeting,forming a D-π-A structure.This probe had a fluorescence lifetime of 3.71 ns and a fluorescence quantum yield of 0.51.Upon exposure to HClO/ClO-,the maximum fluorescence emission wavelength of the probe in DMSO/H2O(9∶1,V/V,pH=7.4)solution(20 μmol/L)shifted from 550 nm to 430 nm,with a fluorescence intensity increase of 35.7 times compared to blank probe solution,allowing for selective recognition of HClO/ClO-.The probe also exhibited a large Stokes shift(130 nm)and a low limit of detection(LOD)of 9.16×10-8 mol/L.Based on characterization by proton nuclear magnetic resonance(1H NMR),electrospray ionization-mass spectrometry(ESI-MS),scanning electron microscopy(SEM)and theoretical calculations,it was speculated that NC-TPA-PPh3 recognized HClO/ClO-through oxidative cleavage of the C=C bond in the probe,generating TPA-CHO with lower water solubility and a smaller conjugated structure.This disrupted the D-π-A structure,blocking intramolecular charge transfer(ICT),causing the fluorescence emission peak to blue-shift from 550 nm to 430 nm.Additionally,this process induced an aggregation-induced fluorescence effect,significantly enhancing the fluorescence intensity at 430 nm.

OBJECTIVE: To investigate the effect of inverted-Y urethral function-preserving holmium laser enucleation of the prostate (HoLEP) on stress urinary incontinence after surgery in patients with BPH. METHODS: We retrospectively analyzed the clinical data on 109 cases of BPH treated in our hospital from June 2022 to May 2023 by traditional HoLEP with preservation of the apical prostatic urethral valve (group A, n = 52) or inverted-Y urethral function-preserving HoLEP (group B, n = 57). We recorded the intra- and post-operative parameters, evaluated the urinary incontinence status and post-void symptoms according to the International Continence Society standards, and analyzed the effect of inverted-Y versus traditional HoLEP in improving the postoperative urinary incontinence of the patients. RESULTS: The incidence rate of stress urinary incontinence after catheter removal was significantly lower in group B than in A (10.52% vs 26.92%, P = 0.027), and so was it at 2 weeks after surgery (1.75% vs 11.54%, P = 0.037), and at 1 month postoperatively (0% vs 7.69%, P = 0.033). CONCLUSION For the treatment of BPH, inverted-Y urethral function-preserving HoLEP is superior to traditional HoLEP with preservation of the apical prostatic urethral valve in improving stress urinary incontinence after surgery.
Humans ; Male ; Retrospective Studies ; Lasers, Solid-State/therapeutic use* ; Prostatic Hyperplasia/surgery* ; Urethra/surgery* ; Postoperative Complications/prevention & control* ; Urinary Incontinence, Stress/etiology* ; Prostatectomy/adverse effects* ; Aged ; Urinary Incontinence ; Prostate/surgery*

The aim of this study was to investigate the contribution of lung zinc ions to pathogenesis of lung ischemia/reperfusion (I/R) injury in rats. Male Sprague Dawley (SD) rats were randomly divided into control group, lung I/R group (I/R group), lung I/R + low-dose zinc chloride group (LZnCl₂+I/R group), lung I/R + high-dose ZnCl₂ group (HZnCl₂+I/R group), lung I/R + medium-dose ZnCl₂ group (MZnCl₂+I/R group) and TPEN+MZnCl₂+I/R group (n = 8 in each group). Inductively coupled plasma mass spectrometry (ICP-MS) was used to measure the concentration of zinc ions in lung tissue. The degree of lung tissue injury was analyzed by observing HE staining, alveolar damage index, lung wet/dry weight ratio and lung tissue gross changes. TUNEL staining was used to detect cellular apoptosis in lung tissue. Western blot and RT-qPCR were used to determine the protein expression levels of caspase-3 and ZIP8, as well as the mRNA expression levels of zinc transporters (ZIP, ZNT) in lung tissue. The mitochondrial membrane potential (MMP) of lung tissue was detected by JC-1 MMP detection kit. The results showed that, compared with the control group, the lung tissue damage, lung wet/dry weight ratio and alveolar damage index were significantly increased in the I/R group. And in the lung tissue, the concentration of Zn²⁺ was markedly decreased, while the cleaved caspase-3/caspase-3 ratio and apoptotic levels were significantly increased. The expression levels of ZIP8 mRNA and protein were down-regulated significantly, while the mRNA expression of other zinc transporters remained unchanged. There was also a significant decrease in MMP. Compared with the I/R group, both MZnCl₂+I/R group and HZnCl₂+I/R group exhibited significantly reduced lung tissue injury, lung wet/dry weight ratio and alveolar damage index, increased Zn²⁺ concentration, decreased ratio of cleaved caspase-3/caspase-3 and apoptosis, and up-regulated expression levels of ZIP8 mRNA and protein. In addition, the MMP was significantly increased in the lung tissue. Zn²⁺ chelating agent TPEN reversed the above-mentioned protective effects of medium-dose ZnCl₂ on the lung tissue in the I/R group. The aforementioned results suggest that exogenous administration of ZnCl₂ can improve lung I/R injury in rats.
Animals ; Reperfusion Injury/pathology* ; Male ; Rats, Sprague-Dawley ; Rats ; Chlorides/administration & dosage* ; Lung/pathology* ; Zinc Compounds/administration & dosage* ; Apoptosis/drug effects* ; Caspase 3/metabolism* ; Cation Transport Proteins/metabolism*

Ginsenoside Rg_2(GRg2) is a triterpenoid compound found in Panax notoginseng. This study explored its effects and mechanisms on diabetic retinopathy and angiogenesis. The study employed endothelial cell models induced by glucose or vascular endothelial growth factor(VEGF), the chorioallantoic membrane(CAM) model, the oxygen-induced retinopathy(OIR) mouse model, and the db/db mouse model to evaluate the therapeutic effects of GRg2 on diabetic retinopathy and angiogenesis. Transwell assays and endothelial tube formation experiments were conducted to assess cell migration and tube formation, while vascular area measurements were applied to detect angiogenesis. The impact of GRg2 on the retinal structure and function of db/db mice was evaluated through retinal thickness and electroretinogram(ERG) analyses. The study investigated the mechanisms of GRg2 by analyzing the activation of Yes-associated protein(YAP) and Toll-like receptors(TLRs) pathways. The results indicated that GRg2 significantly reduced cell migration numbers and tube formation lengths in vitro. In the CAM model, GRg2 exhibited a dose-dependent decrease in the vascular area ratio. In the OIR model, GRg2 notably decreased the avascular and neovascular areas, ameliorating retinal structural disarray. In the db/db mouse model, GRg2 increased the total retinal thickness and enhanced the amplitudes of the a-wave, b-wave, and oscillatory potentials(OPs) in the ERG, improving retinal structural disarray. Transcriptomic analysis revealed that the TLR signaling pathway was significantly down-regulated following YAP knockdown, with PCR results consistent with the transcriptome sequencing findings. Concurrently, GRg2 downregulated the expression of Toll-like receptor 4(TLR4), TNF receptor-associated factor 6(TRAF6), and nuclear factor-kappaB(NF-κB) proteins in high-glucose-induced endothelial cells. Collectively, GRg2 inhibits cell migration and tube formation and significantly reduces angiogenesis in CAM and OIR models, improving retinal structure and function in db/db mice, with its pharmacological mechanism likely involving the down-regulation of YAP expression.
Animals ; Ginsenosides/pharmacology* ; Diabetic Retinopathy/physiopathology* ; Mice ; YAP-Signaling Proteins ; Humans ; Male ; Signal Transduction/drug effects* ; Cell Movement/drug effects* ; Adaptor Proteins, Signal Transducing/genetics* ; Mice, Inbred C57BL ; Neovascularization, Pathologic/metabolism* ; Drugs, Chinese Herbal/administration & dosage* ; Panax notoginseng/chemistry* ; Endothelial Cells/metabolism* ; Transcription Factors/genetics* ; Angiogenesis

Emodin is a hydroxyanthraquinone compound that is widely distributed and has multiple pharmacological activities, including anti-diarrheal, anti-inflammatory, and liver-protective effects. Research indicates that emodin may be one of the main components responsible for inducing hepatotoxicity. However, studies on the mechanisms of liver injury are relatively limited, particularly those related to bile acids(BAs) metabolism. This study aims to systematically investigate the effects of different dosages of emodin on BAs metabolism, providing a basis for the safe clinical use of traditional Chinese medicine(TCM)containing emodin. First, this study evaluated the safety of repeated administration of different dosages of emodin over a 5-week period, with a particular focus on its impact on the liver. Next, the composition and content of BAs in serum and liver were analyzed. Subsequently, qRT-PCR was used to detect the mRNA expression of nuclear receptors and transporters related to BAs metabolism. The results showed that 1 g·kg~(-1) emodin induced hepatic damage, with bile duct hyperplasia as the primary pathological manifestation. It significantly increased the levels of various BAs in the serum and primary BAs(including taurine-conjugated and free BAs) in the liver. Additionally, it downregulated the mRNA expression of farnesoid X receptor(FXR), retinoid X receptor(RXR), and sodium taurocholate cotransporting polypeptide(NTCP), and upregulated the mRNA expression of cholesterol 7α-hydroxylase(CYP7A1) in the liver. Although 0.01 g·kg~(-1) and 0.03 g·kg~(-1) emodin did not induce obvious liver injury, they significantly increased the level of taurine-conjugated BAs in the liver, suggesting a potential interference with BAs homeostasis. In conclusion, 1 g·kg~(-1) emodin may promote the production of primary BAs in the liver by affecting the FXR-RXR-CYP7A1 pathway, inhibit NTCP expression, and reduce BA reabsorption in the liver, resulting in BA accumulation in the peripheral blood. This disruption of BA homeostasis leads to liver injury. Even doses of emodin close to the clinical dose can also have a certain effect on the homeostasis of BAs. Therefore, when using traditional Chinese medicine or formulas containing emodin in clinical practice, it is necessary to regularly monitor liver function indicators and closely monitor the risk of drug-induced liver injury.
Emodin/administration & dosage* ; Bile Acids and Salts/metabolism* ; Animals ; Male ; Liver/injuries* ; Chemical and Drug Induced Liver Injury/genetics* ; Drugs, Chinese Herbal/adverse effects* ; Humans ; Rats, Sprague-Dawley ; Mice ; Rats

OBJECTIVE: To describe survival trends and global patterns of esophageal cancer (EC) using survival data from population-based cancer registries. METHODS: We systematically searched PubMed, EMBASE, Web of Science, SEER, and SinoMed databases for articles published up to 31 December 2023. Eligible EC survival estimates were evaluated according to country or region, period, sex, age group, pathology, and disease stage. RESULTS: After 2010, Jordan exhibited the highest age-standardized 5-year relative survival rates (RSRs)/net survival rates (NSRs) at 41.1% between 2010 and 2014, while India had the lowest, at 4.1%. Survival rates generally improved with diagnostic age across most countries, with significant increases in South Korea and China, of 12.7% and 10.5% between 2000 and 2017, respectively. Survival was higher among women compared to men, ranging from 0.4%-10.9%. Survival rates for adenocarcinoma and squamous cell carcinoma were similar, differing by about 4%. In China, the highest age-standardized RSRs/NSRs was 33.4% between 2015 and 2017. Meanwhile, the lowest was 5.3%, in Qidong (Jiangsu province) between 1992-1996. CONCLUSION Global EC survival rates have improved significantly in recent decades, but substantial geographical, sex, and age disparities still exist. In Asia, squamous cell carcinoma demonstrated superior survival rates compared to adenocarcinoma, while the opposite trend was observed in Western countries. Future research should clarify the prognostic factors influencing EC survival and tailor prevention and screening strategies to the changing EC survival patterns.
Humans ; Esophageal Neoplasms/mortality* ; Registries ; Male ; Female ; Survival Analysis ; Middle Aged ; Survival Rate ; Aged ; Global Health

Objective To examine the changing prevalence and antimicrobial resistance profiles of Burkholderia cepacia in 52 hospitals across China from 2015 to 2021.Methods A total of 9 261 strains of B.cepacia were collected from 52 hospitals between January 1,2015 and December 31,2021.Antimicrobial susceptibility of the strains was tested using Kirby-Bauer method or automated antimicrobial susceptibility testing systems according to a unified protocol.The results were interpreted according to the breakpoints released in the Clinical & Laboratory Standards Institute(CLSI)guidelines(2023 edition).Results A total of 9 261 strains of B.cepacia were isolated from all age groups,especially elderly patients.The proportion was 11.1％(1 032 strains)in children,significantly lower than the proportion in adults.About half(46.5％,4 310/9 261)of the strains were isolated from patients at least 60 years old and 42.3％(3 919/9 261)of the strains were isolated from young adults.Most isolates(71.1％)were isolated from sputum and respiratory secretions,followed by urine(10.7％)and blood samples(8.1％).B.cepacia isolates were highly susceptible to the five antimicrobial agents recommended in the CLSI M100 document(33rd edition,2023).B.cepacia isolates showed relatively higher resistance rates to meropenem and levofloxacin.However,the resistance rates to ceftazidime,trimethoprim-sulfamethoxazole,and minocycline remained below 8.1％.The percentage of B.cepacia strains resistant to levofloxacin was the highest compared to other antibiotics in any of the three age groups(from 12.4％in the patients＜18 years old to 20.6％in the patients aged 60 years or older).Conclusions B.cepacia is one of the clinically important non-fermenting gram-negative bacteria.Accurate and timely reporting of antimicrobial susceptibility test results and ongoing antimicrobial resistance surveillance are helpful for rational prescription of antimicrobial agents and proper prevention and control of nosocomial infections.

AIM To evaluate the quality of Gegen Formula Granules.METHODS Linear calibration with two reference substances(LCTRS)was adopted in the predicting of retention time with puerarin and daidzein as internal standards.UPLC characteristic chromatograms were established.The contents of 3'-hydroxy puerarin,puerarin(internal standard),3'-methoxy puerarin,puerarin 6"-O-xyloside,puerarin apioside and daidzin were determined by quantitative determination analysis multi-components by a single marker(QAMS),after which their transfer rates were calculated.RESULTS Compared with relative retention time method,LCTRS demonstrated higher positional accuracy for characteristic peaks and wider application range for columns.There were 9 characteristic peaks in the characteristic chromatograms for 14 batches of formula granules and 15 batches of standard decoctions with the similarities of more than 0.95.The contents and transfer rates of various constituents in formula granules and standard decoctions were basically consistent.CONCLUSION The chemical constituents in formula granules and their standard decoctions of Puerariae lobatae Radix display good consistency,reliable preparation process is observable in the former.