Design, synthesis and biological evaluation of a novel PSMA-PI3K small molecule drug conjugate.

Small molecule drug conjugates are an emerging targeted therapy for cancer treatment. Building upon the overexpressed prostate-specific membrane antigen (PSMA) in prostate cancer, we herein report the design and synthesis of a novel PSMA-PI3K small molecule drug conjugate 1. Conjugate 1 demonstrates potent inhibition against PI3K with an IC50 value of 0.40 nM and simultaneously targets PSMA, giving rise to selective growth inhibition activity for PSMA-positive cancer cells. Conjugate 1 also potently inhibits the phosphorylation of PI3K main downstream effectors and arrests the cell cycle in the G0/G1 phase in PSMA-positive 22Rv1 prostate cancer cells. Further in vivo evaluation shows that conjugate 1 has favorable efficacy and tolerability in a 22Rv1 xenograft model, demonstrating its potential application in targeted cancer therapy.

Outcome and Survival Analysis of Multicenter Lung Metastasectomy for Primary Liver Tumor with Pulmonary Metastasis.

Oligopulmonary metastases from primary liver tumors are typically treated surgically. We evaluated the clinical outcomes after lung metastasectomy in patients with pulmonary metastases from primary liver tumors. We retrospectively enrolled 147 consecutive patients with lung metastases from liver cancer who had undergone pulmonary metastasectomies at three medical centers between February 2007 and December 2020. All patients were pathologically confirmed to have lung metastases from liver cancer. Among the 147 patients, 110, 17, and 20 initially underwent surgical resection, radiofrequency ablation, and transcatheter arterial embolization, respectively. The 5-year overall survival (OS) in the study cohort was 22%. Univariate analysis revealed four factors associated with better OS: surgical resection as the initial primary liver tumor treatment (p = 0.004), a disease-free interval exceeding 12 months after the initial liver surgery (p = 0.036), a lower Model for End-Stage Liver Disease (MELD)-Na score (≤20) for liver cirrhosis (p = 0.044), and the absence of local liver tumor recurrence at the time of pulmonary metastasectomy (p = 0.004). Multivariate analysis demonstrated that surgical resection as the initial primary liver tumor treatment and lower MELD-Na scores significantly correlated with better OS. Our findings can assist thoracic surgeons in selecting suitable patients for surgery and predicting surgical outcomes.

Promotion of polyhydroxyalkanoates-producing granular sludge formation by lactic acid using anaerobic dynamic feeding process.

To promote the formation of granular sludge with high polyhydroxyalkanoates (PHAs) synthesis ability, an anaerobic dynamic feeding process (AnDF) was proposed. This process combines the feast-famine mode with an anaerobic plug flow feeding process and involving variations in cycle length and settling time. The effects of lactic acid (LA) content (0 %, 20 %, and 40 % COD) on sludge granulation and PHAs production were investigated using three AnDF reactors (R1, R2, and R3). The results showed that the AnDF process feeding with LA not only effectively promoted sludge granulation but also improved its PHAs synthesis ability. The granules were quickly observed in R3 after 50 days of cultivation, with an average diameter of 0.69 mm. The maximum PHAs content reached 47.0 wt% in R3, representing a 30.09 % increase compared to R1. Additionally, extracellular polymeric substances (EPS)-producing bacteria observed in granular sludge may be the prime drivers of the formation of PHAs-producing granular sludge (PHAGS), which was defined as granular sludge with an average particle size larger than 0.30 mm and PHAs content above 40 % cell dry weight (CDW) of sludge samples.

Effect of phosphate-mineralized bacteria on multi-metals migration behavior in vanadium tailing slags: Coexistence of immobilization and mobilization.

Biomineralization techniques have been utilized to remediate heavy metals (HMs) contaminated environments. However, the effect of microbial-induced phosphate precipitation (MIPP) on HMs behavior in vanadium tailing slags has not been revealed. This study is the first to report the influence of MIPP on multiple HMs including Cd, Cu, Pb and Zn in the slags with and without soil mixing. The results showed that MIPP exhibited excellent ability for Cd immobilization, Cd immobilization rate reached 43.41 % under the optimal parameters within 7 days. Cd immobilization performance was significantly improved and sustained after the slags were covered with soil, resulting from better colonization of phosphate mineralizing bacteria in slag-soil mixtures. Surprisingly, DTPA-Cu, Zn and Pb contents in slags were all increased to varying degrees after MIPP treatment. Leaching solution mineralization tests further suggested that MIPP significantly reduced the concentration of Cd2+, Pb2+, Ca2+, Mg2+ and Al3+, but barely changed Cu2+ and Zn2+ concentrations. Characterization analysis confirmed that formation of phosphates including Cd(PO4)2 and dissolution of minerals including PbZnSiO2 were the reason for HMs immobilization and mobilization in vanadium tailing slags. This study provides new insights for understanding biomineralization technology and using MIPP to remediate HMs contaminated mine waste.

Quaternary Chiral Phthalides Enabled by Dirhodium(II)/Phosphine Catalyzed Asymmetric Carbonyl Addition Cascade.

The catalytic asymmetric synthesis of chiral phthalides has garnered considerable interest. However, the construction of phthalides with a chiral quaternary carbon stereocenter still remains challenging. In this study, we developed a new strategy toward catalytic asymmetric synthesis of chiral 3,3-disubstituted phthalides via a dirhodium(II)/phosphine-catalyzed carbonyl addition cascade, yielding phthalides with up to 97% ee values. The reaction proceeded through dirhodium(II)/phosphine-catalyzed asymmetric carbonyl addition of arylboronic acids to isoquinoline-1,3,4(2H)-triones, followed by base-mediated ring contraction.

For aqueous/soil cadmium immobilization under acid attack, does the hydroxyapatite converted from Pseudochrobactrum sp. DL-1 induced vaterite necessarily show higher stability?

Microbial induced carbonate precipitation (MICP) technology was widely applied to immobilize heavy metals, but its long-term stability is tough to maintain, particularly under acid attack. This study successfully converted Pseudochrobactrum sp. DL-1 induced vaterite (a rare crystalline phase of CaCO3) to hydroxyapatite (HAP) at 30 â„ƒ. The predominant conversion mechanism was the dissolution of CdCO3-containing vaterite and the simultaneous recrystallization of Ca4.03Cd0.97(PO4)3(OH)-containing HAP. For aqueous Cd immobilization, stability test at pH 2.0-10.0 showed that the Cd2+ desorption rate of Cd-adsorbed vaterite (3.96-4.35 ‱) were 7.13-20.84 times greater than that of Cd-adsorbed HAP (0.19-0.61 ‱). For soil Cd immobilization under 60 days of acid-rain erosion, the highest immobilization rate (51.00 %) of exchangeable-Cd and the lowest dissolution rate (-0.18 %) of carbonate-Cd were achieved with 2 % vaterite, while the corresponding rates were 16.78 % and 1.31 % with 2 % HAP, respectively. Furthermore, vaterite outperformed HAP in terms of soil ecological thorough evaluation. In conclusion, for Cd immobilization by MICP under acid attack, DL-1 induced vaterite displayed direct application value due to its exceptional stability in soil and water, while the mineral conversion strategy we presented is useful for further enhancing the stability in water.

Clinical efficacy and immune response of neoadjuvant camrelizumab plus chemotherapy in resectable locally advanced oesophageal squamous cell carcinoma: a phase 2 trial.

BACKGROUND: Neoadjuvant immunotherapy is under intensive investigation for esophageal squamous cell carcinoma (ESCC). This study assesses the efficacy and immune response of neoadjuvant immunochemotherapy (nICT) in ESCC. METHODS: In this phase II trial (ChiCTR2100045722), locally advanced ESCC patients receiving nICT were enrolled. The primary endpoint was the pathological complete response (pCR) rate. Multiplexed immunofluorescence, RNA-seq and TCR-seq were conducted to explore the immune response underlying nICT. RESULTS: Totally 42 patients were enrolled, achieving a 27.0% pCR rate. The 1-year, 2-year DFS and OS rates were 89.2%, 64.4% and 97.3%, 89.2%, respectively. RNA-seq analysis highlighted T-cell activation as the most significantly enriched pathway. The tumour immune microenvironment (TIME) was characterised by high CD4, CD8, Foxp3, and PD-L1 levels, associating with better pathological regression (TRS0/1). TIME was categorised into immune-infiltrating, immune-tolerant, and immune-desert types. Notably, the immune-infiltrating type and tertiary lymphoid structures correlated with improved outcomes. In the context of nICT, TIM-3 negatively influenced treatment efficacy, while elevated TIGIT/PD-1 expression post-nICT correlated positively with CD8+ T cell levels. TCR-seq identified three TCR rearrangements, underscoring the specificity of T-cell responses. CONCLUSIONS: Neoadjuvant camrelizumab plus chemotherapy is effective for locally advanced, resectable ESCC, eliciting profound immune response that closely associated with clinical outcomes.

Cross-modal group-relation optimization for visible-infrared person re-identification.

Visible-infrared person re-identification (VIPR) plays an important role in intelligent transportation systems. Modal discrepancies between visible and infrared images seriously confuse person appearance discrimination, e.g., the similarity of the same class of different modalities is lower than the similarity between different classes of the same modality. Worse still, the modal discrepancies and appearance discrepancies are coupled with each other. The prevailing practice is to disentangle modal and appearance discrepancies, but it usually requires complex decoupling networks. In this paper, rather than disentanglement, we propose to measure and optimize modal discrepancies. We explore a cross-modal group-relation (CMGR) to describe the relationship between the same group of people in two different modalities. The CMGR has great potential in modal invariance because it considers more stable groups rather than individuals, so it is a good measurement for modal discrepancies. Furthermore, we design a group-relation correlation (GRC) loss function based on Pearson correlations to optimize CMGR, which can be easily integrated with the learning of VIPR's appearance features. Consequently, our CMGR model serves as a pivotal constraint to minimize modal discrepancies, operating in a manner similar to a loss function. It is applied solely during the training phase, thereby obviating the need for any execution during the inference phase. Experimental results on two public datasets (i.e., RegDB and SYSU-MM01) demonstrate that our CMGR method is superior to state-of-the-art approaches. In particular, on the RegDB dataset, with the help of CMGR, the rank-1 identification rate has improved by more than 7% compared to the case of not using CMGR.

Eu/Tb-MOF as fluorescence sensors for the detection homocysteine in human serum performance and mechanistic investigation.

Abnormal homocysteine (Hcy) levels in human serum have been associated with serious or vital diseases, making the reliable and easy detection of Hcy important to clinical analysis and biological study. In this work, five phosphorescent Ir(C^N)2(N^N) complexes (Irn) having aldehyde group were synthesized as probes (C^N and N^N denoted ligands). A discussion was conducted on their molecular structure, electronic structure, photophysical parameters, and Hcy sensing ability, revealing the correlations between their molecular structures and performances. Irn emission was enhanced (by âˆ¼ two folds) and blue-shifted (by 100 nm) after meeting Hcy (free state), via a cyclization reaction between the -CHO group (from Irn) and Hcy. In addition, using RE(BTC) as a supporting material (RE = Tb and Eu), the Ir(III) probe was loaded onto a supporting material of RE(BTC) (H3BTC = 1, 3, 5-benzenetricarboxylic acid). The emission color was changed by increasing Hcy concentration. Straight working curves were obtained with LOD (limit of detection) of 1.9 µM and a response time of ∼200 s. The novelty of this work was the combination of Irn with RE(BTC), which offered enhanced and blue-shifted emission upon Hcy via a cyclization reaction. This demonstrated a high level of sensitivity towards homocysteine detection.

Catalpol attenuates hepatic glucose metabolism disorder and oxidative stress in triptolide-induced liver injury by regulating the SIRT1/HIF-1α pathway.

Triptolide (TP), known for its effectiveness in treating various rheumatoid diseases, is also associated with significant hepatotoxicity risks. This study explored Catalpol (CAT), an iridoid glycoside with antioxidative and anti-inflammatory effects, as a potential defense against TP-induced liver damage. In vivo and in vitro models of liver injury were established using TP in combination with different concentrations of CAT. Metabolomics analyses were conducted to assess energy metabolism in mouse livers. Additionally, a Seahorse XF Analyzer was employed to measure glycolysis rate, mitochondrial respiratory functionality, and real-time ATP generation rate in AML12 cells. The study also examined the expression of proteins related to glycogenolysis and gluconeogenesis. Using both in vitro SIRT1 knockout/overexpression and in vivo liver-specific SIRT1 knockout models, we confirmed SIRT1 as a mechanism of action for CAT. Our findings revealed that CAT could alleviate TP-induced liver injury by activating SIRT1, which inhibited lysine acetylation of hypoxia-inducible factor-1α (HIF-1α), thereby restoring the balance between glycolysis and oxidative phosphorylation. This action improved mitochondrial dysfunction and reduced glucose metabolism disorder and oxidative stress caused by TP. Taken together, these insights unveil a hitherto undocumented mechanism by which CAT ameliorates TP-induced liver injury, positioning it as a potential therapeutic agent for managing TP-induced hepatotoxicity.

Enhancing H2-driven CO2 biomethanation performance in bidirectional flow tidal bioreactor by reducing liquid film resistance and heterogeneity.

This study presents a bidirectional flow tidal bioreactor designed to enhance H2-driven CO2 biomethanation. The bioreactor alternated biofilms between immersion in nutrient solution and exposure to H2/CO2, creating alternating dry and wet states. This tidal operation minimized liquid film thickness during dry periods and ensured uniform nutrient distribution during wet periods. Bidirectional H2/CO2 supply was used to reduce biofilm thickness heterogeneity across the reactor height. CO2 biomethanation remained stable with an empty bed residence time of 9.7 min, achieving a methane (CH4) formation rate of 26.8 Nm3 CH4/(m3·d). The product gas contained 95.0 ± 2.5 % CH4, with a H2/CO2 conversion efficiency of 90.8 %. Tidal operation mitigated the buildup of dissolved and suspended organics, such as organic acids and detached biofilms. Dominant bacteria in biofilms included fermentative species like Petrimonas and H2-utilizing homoacetogens like Sporomusa. Enriched hydrogenotrophic methanogens, particularly Methanobacterium, were observed. Overall, this study highlights the bioreactor's effectiveness in improving CO2 biomethanation.

Gastric cancer prevention by community eradication of Helicobacter pylori: a cluster-randomized controlled trial.

Gastric cancer is a leading cause of cancer-related deaths in China. Affecting more than 40% of the world's population, Helicobacter pylori is a major risk factor for gastric cancer. While previous clinical trials indicated that eradication of H. pylori could reduce gastric cancer risk, this remains to be shown using a population-based approach. We conducted a community-based, cluster-randomized, controlled, superiority intervention trial in Linqu County, China, with individuals who tested positive for H. pylori using a 13C-urea breath test randomly assigned to receiving either (1) a 10-day, quadruple anti-H. pylori treatment (comprising 20 mg of omeprazole, 750 mg of tetracycline, 400 mg of metronidazole and 300 mg of bismuth citrate) or (2) symptom alleviation treatment with a single daily dosage of omeprazole and bismuth citrate. H. pylori-negative individuals did not receive any treatment. We examined the incidence of gastric cancer as the primary outcome. A total of 180,284 eligible participants from 980 villages were enrolled over 11.8 years of follow-up, and a total of 1,035 cases of incident gastric cancer were documented. Individuals receiving anti-H. pylori therapy showed a modest reduction in gastric cancer incidence in intention-to-treat analyses (hazard ratio 0.86, 95% confidence interval 0.74-0.99), with a stronger effect observed for those having successful H. pylori eradication (hazard ratio 0.81, 95% confidence interval 0.69-0.96) than for those who failed treatment. Moderate adverse effects were reported in 1,345 participants during the 10-day treatment. We observed no severe intolerable adverse events during either treatment or follow-up. The findings suggest the potential for H. pylori mass screening and eradication as a public health policy for gastric cancer prevention. Chinese Clinical Trial Registry identifier: ChiCTR-TRC-10000979 .

Integrative Omics Uncovers Low Tumorous Magnesium Content as A Driver Factor of Colorectal Cancer.

Magnesium (Mg) deficiency is associated with increased risk and malignancy in colorectal cancer (CRC), yet the underlying mechanisms remain elusive. Here, we used genomic, proteomic, and phosphoproteomic data to elucidate the impact of Mg deficiency on CRC. Genomic analysis identified 160 genes with higher mutation frequencies in Low-Mg tumors, including key driver genes such as KMT2C and ERBB3. Unexpectedly, initiation driver genes of CRC, such as TP53 and APC, displayed higher mutation frequencies in High-Mg tumors. Additionally, proteomic and phosphoproteomic data indicated that low Mg content in tumors may activate epithelial-mesenchymal transition (EMT) by modulating inflammation or remodeling the phosphoproteome of cancer cells. Notably, we observed a negative correlation between the phosphorylation of DBN1 at S142 (DBN1S142p) and Mg content. A mutation in S142 to D (DBN1S142D) mimicking DBN1S142p upregulated MMP2 and enhanced cell migration, while treatment with MgCl2 reduced DBN1S142p, thereby reversing this phenotype. Mechanistically, Mg2+ attenuated the DBN1-ACTN4 interaction by decreasing DBN1S142p, which in turn enhanced the binding of ACTN4 to F-actin and promoted F-actin polymerization, ultimately reducing MMP2 expression. These findings shed new light on the crucial role of Mg deficiency in CRC progression and suggest that Mg supplementation may be a promising preventive and therapeutic strategy for CRC.

Development and Clinical Applications of Therapeutic Cancer Vaccines with Individualized and Shared Neoantigens.

Neoantigens, presented as peptides on the surfaces of cancer cells, have recently been proposed as optimal targets for immunotherapy in clinical practice. The promising outcomes of neoantigen-based cancer vaccines have inspired enthusiasm for their broader clinical applications. However, the individualized tumor-specific antigens (TSA) entail considerable costs and time due to the variable immunogenicity and response rates of these neoantigens-based vaccines, influenced by factors such as neoantigen response, vaccine types, and combination therapy. Given the crucial role of neoantigen efficacy, a number of bioinformatics algorithms and pipelines have been developed to improve the accuracy rate of prediction through considering a series of factors involving in HLA-peptide-TCR complex formation, including peptide presentation, HLA-peptide affinity, and TCR recognition. On the other hand, shared neoantigens, originating from driver mutations at hot mutation spots (e.g., KRASG12D), offer a promising and ideal target for the development of therapeutic cancer vaccines. A series of clinical practices have established the efficacy of these vaccines in patients with distinct HLA haplotypes. Moreover, increasing evidence demonstrated that a combination of tumor associated antigens (TAAs) and neoantigens can also improve the prognosis, thus expand the repertoire of shared neoantigens for cancer vaccines. In this review, we provide an overview of the complex process involved in identifying personalized neoantigens, their clinical applications, advances in vaccine technology, and explore the therapeutic potential of shared neoantigen strategies.

Enhancing high-efficient cadmium biosorption of Escherichia coli via cell surface displaying metallothionien CUP1.

Cadmium (Cd) is one of the common heavy metal pollutants in soil, which can induce various diseases and pose a serious threat to human health. Metallothioneins (MTs) are well-known for their excellent metal binding ability due to a high content of cysteine, which has great potential for heavy metal chelation. In this study, we used the Escherichia coli (E. coli) surface display system LPP-OmpA to construct a recombinant plasmid pBSD-LCF encoding LPP-OmpA-CUP1-Flag fusion protein. Then we displayed the metallothionein CUP1 from Saccharomyces cerevisiae on E. coli DH5α surface for Cd removing. The feasibility of surface display of metallothionein CUP1 in recombinant E. coli DH5α (pBSD-LCF) by Lpp-OmpA system was proved by flow cytometry and western blot analysis, and the specificity of the fusion protein in the recombinant strain was also verified. The results showed that the Cd2+ resistance capacity of DH5α (pBSD-LCF) was highly enhanced by about 200%. Fourier-transform infrared spectroscopy showed that sulfhydryl and sulfonyl groups were involved in Cd2+ binding to cell surface of DH5α (pBSD-LCF). Meanwhile, Cd removal rate by DH5α (pBSD-LCF) was promoted to 95.2%. Thus, the recombinant strain E. coli DH5α (pBSD-LCF) can effectively chelate environmental metals, and the cell surface expression of metallothionein on E. coli can provide new ideas and directions for heavy metals remediation.

Intrauterine fetal death due to rupture of umbilical vessels: a rare case of furcate cord insertion.

Furcate cord insertion refers to the separation of umbilical vessels before reaching the placenta, where the branching vessels normally attach at the edge of the placental parenchyma or near the placental membranes. This is an extremely rare abnormal umbilical cord insertion. This paper reported a case of a furcate cord insertion, where the rupture of exposed umbilical vessels led to intrauterine fetal death at full term. Through literature review, we analyzed the prenatal ultrasound characteristics and pregnancy outcomes of furcate cord insertions, with the aim to improve detection rates and reduce the risk of adverse pregnancy outcomes.

Inhibition of inflammation and apoptosis through the cyclic GMP-AMP synthase-stimulator of interferon genes pathway by stress granules after ALKBH5 demethylase activation during diabetic myocardial ischaemia-reperfusion injury.

AIM: Post-transcriptional modifications and their specific mechanisms are the focus of research on the regulation of myocardial damage. Stress granules (SGs) can inhibit the inflammatory response by inhibiting the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. This study investigated whether alkylation repair homologue protein 5 (ALKBH5) could affect myocardial inflammation and apoptosis during diabetic myocardial ischaemia-reperfusion injury (IRI) through the cGAS-STING pathway via SGs. METHODS: A diabetes ischaemia-reperfusion rat model and a high glucose hypoxia/reoxygenation cell model were established. Adeno-associated virus (AAV) and lentivirus (LV) were used to overexpress ALKBH5, while the SG agonist arsenite (Ars) and the SG inhibitor anisomycin were used as interventions. Then, the levels of apoptosis and related indicators in the cell and rat models were measured. RESULTS: In the in vivo experiment, compared with the normal sham group, the degree of myocardial tissue damage, creatine kinase-MB and cardiac troponin I in serum, and myocardial apoptosis, the infarcted area of myocardium, and the level of B-cell lymphoma 2 associated X protein, cGAS-STING pathway and inflammatory factors in the diabetes ischaemia-reperfusion group were significantly increased. However, the expression of SGs and the levels of ALKBH5, rat sarcoma-GTPase-activating protein-binding protein 1, T-cell intracellular antigen-1 and Bcl2 were significantly decreased. After AAV-ALKBH5 intervention, the degree of myocardial tissue damage, degree of myocardial apoptosis, and extent of myocardial infarction in myocardial tissue were significantly decreased. In the in vitro experiment, compared with those in the normal control group, the levels of lactate dehydrogenase, inflammation and apoptosis were significantly greater, and cell viability and the levels of ALKBH5 and SGs were decreased in the high glucose and hypoxia/reoxygenation groups. In the high glucose hypoxia/reoxygenation cell model, the degree of cell damage, inflammation, and apoptosis was greater than those in the high glucose and hypoxia/reoxygenation models, and the levels of ALKBH5 and SGs were further decreased. LV-ALKBH5 and Ars alleviated the degree of cell damage and inhibited inflammation and cell apoptosis. The inhibition of SGs could partly reverse the protective effect of LV-ALKBH5. The cGAS agonist G140 antagonized the inhibitory effects of the SG agonist Ars on cardiomyocyte apoptosis, inflammation and the cGAS-STING pathway. CONCLUSION: Both ALKBH5 and SGs inhibited myocardial inflammation and apoptosis during diabetic myocardial ischaemia-reperfusion. Mechanistically, ALKBH5 might inhibit the apoptosis of cardiomyocytes by promoting the expression of SGs through the cGAS-STING pathway.

Negotiating and Struggling for a New Life: Stigma, Spirituality, and Coping Strategies of People Living with HIV in Myanmar.

Although enacted and internalized stigma is a continuing problem for people living with HIV (PLWH) in Southeast Asia, there is little understanding of how PLWH cope with discrimination, exclusion, and other negative outcomes caused by HIV-related stigmatization. This article aims to bridge this gap by analyzing the lived experiences of HIV-related stigmatization and coping strategies among 30 people with HIV in Myanmar, a country heavily influenced by religion, especially Buddhism. Among the 30 study participants, 20 were female and 10 were male, with ages ranging from 18 to 50 years. Through the lens of Bourdieu's concepts of habitus, field, and capital, this article first elucidates the various forms of stigmatization in family, work, social, and other settings as symbolic violence on people with HIV. The present article shows that spirituality serves as a perceptual and action framework for people with HIV to generate reflexivity toward their HIV infection and related stigmatization and to further engage in agentic responses. More importantly, this article demonstrates how people with HIV draw on spirituality to support peers in reclaiming control over their lives and how they are perceived by society. The findings indicate that the local context, especially cultural and religious resources, should be considered when developing interventions to mitigate HIV-related stigmatization in Southeast Asia.

Qualifying P-glycoprotein in drug-resistant ovarian cancer cells: a dual-mode aptamer probe approach.

Drug resistance presents a significant obstacle in treating human ovarian cancer. The development of effective methods for detecting drug-resistant cancer cells is pivotal for tailoring personalized therapies and prognostic assessments. In this investigation, we introduce a dual-mode detection technique employing a fluorogenic aptamer probe for the qualification of P-glycoprotein (P-gp) in drug-resistant ovarian cancer cells. The probe, initially in an "off" state due to the proximity of a quencher to the fluorophore, exhibits increased fluorescence intensity upon binding with the target. The fluorescence enhancement shows a linear correlation with both the concentration of P-gp and the presence of P-gp in drug-resistant ovarian cancer cells. This correlation is quantifiable, with detection limits of 1.56 nM and 110 cells per mL. In an alternate mode, the optimized fluorophores, attached to the aptamer, form larger complexes upon binding to the target protein, which diminishes the rotation speed, thereby augmenting fluorescence polarization. The alteration in fluorescence polarization enables the quantitative analysis of P-gp in the cells, ranging from 100 to 1500 cells per milliliter, with a detection limit of 40 cells per mL. Gene expression analyses, protein expression studies, and immunofluorescence imaging further validated the reliability of our aptamer-based probe for its specificity towards P-gp in drug-resistant cancer cells. Our findings underscore that the dual-mode detection approach promises to enhance the diagnosis and treatment of multidrug-resistant ovarian cancer.

THBru attenuates diabetic cardiomyopathy by inhibiting RAGE-dependent inflammation.

Diabetic cardiomyopathy (DCM) is a complication of diabetes mellitus characterized by heart failure and cardiac remodeling. Previous studies show that tetrahydroberberrubine (THBru) retrogrades cardiac aging by promoting PHB2-mediated mitochondrial autophagy and prevents peritoneal adhesion by suppressing inflammation. In this study we investigated whether THBru exerted protective effect against DCM in db/db mice and potential mechanisms. Eight-week-old male db/db mice were administered THBru (25, 50 mg·kg-1·d-1, i.g.) for 12 weeks. Cardiac function was assessed using echocardiography. We showed that THBru administration significantly improved both cardiac systolic and diastolic function, as well as attenuated cardiac remodeling in db/db mice. In primary neonatal mouse cardiomyocytes (NMCMs), THBru (20, 40 µM) dose-dependently ameliorated high glucose (HG)-induced cell damage, hypertrophy, inflammatory cytokines release, and reactive oxygen species (ROS) production. Using Autodock, surface plasmon resonance (SPR) and DARTS analyses, we revealed that THBru bound to the domain of the receptor for advanced glycosylation end products (RAGE), subsequently leading to inactivation of the PI3K/AKT/NF-κB pathway. Importantly, overexpression of RAGE in NMCMs reversed HG-induced inactivation of the PI3K/AKT/NF-κB pathway and subsequently counteracted the beneficial effects mediated by THBru. We conclude that THBru acts as an inhibitor of RAGE, leading to inactivation of the PI3K/AKT/NF-κB pathway. This action effectively alleviates the inflammatory responses and oxidative stress in cardiomyocytes, ultimately leading to ameliorated DCM.