Tibetan Mesenchymal Stem Cell-derived Exosomes Alleviate Pulmonary Vascular Remodeling in Hypoxic Pulmonary Hypertension Rats.

Hypoxic pulmonary hypertension (HPH) is characterized by progressive pulmonary vasoconstriction, vascular remodeling, and right ventricular hypertrophy, causing right heart failure. This study aimed to investigate the therapeutic effects of exosomes from Tibetan umbilical cord mesenchymal stem cells on HPH via the TGF-ß1/Smad2/3 pathway, comparing them with exosomes from Han Chinese individuals. An HPH rat model was established in vivo, and a hypoxia-induced injury in the rat pulmonary artery smooth muscle cells (rPASMCs) was simulated in vitro. Exosomes from human umbilical cord mesenchymal stem cells were administered to HPH model rats or added to cultured rPASMCs. The therapeutic effects of Tibetan-mesenchymal stem cell-derived exosomes (Tibetan-MSC-exo) and Han-mesenchymal stem cell-derived exosomes (Han-MSC-exo) on HPH were investigated through immunohistochemistry, Western blotting, EdU, and Transwell assays. The results showed that Tibetan-MSC-exo significantly attenuated pulmonary vascular remodeling and right ventricular hypertrophy in HPH rats compared with Han-MSC-exo. Tibetan-MSC-exo demonstrated better inhibition of hypoxia-induced rPASMCs proliferation and migration. Transcriptome sequencing revealed upregulated genes (Nbl1, Id2, Smad6, and Ltbp1) related to the TGFß pathway. Nbl1 knockdown enhanced hypoxia-induced rPASMCs proliferation and migration, reversing Tibetan-MSC-exo-induced downregulation of TGFß1 and p-Smad2/3. Furthermore, TGFß1 overexpression hindered the therapeutic effects of Tibetan-MSC-exo and Han-MSC-exo on hypoxic injury. These findings suggest that Tibetan-MSC-exo favors HPH treatment better than Han-MSC-exo, possibly through the modulation of the TGFß1/Smad2/3 pathway via Nbl1.

Activation of secondary metabolite gene clusters in Chaetomium olivaceum via the deletion of a histone deacetylase.

Histone acetylation modifications in filamentous fungi play a crucial role in epigenetic gene regulation and are closely linked to the transcription of secondary metabolite (SM) biosynthetic gene clusters (BGCs). Histone deacetylases (HDACs) play a pivotal role in determining the extent of histone acetylation modifications and act as triggers for the expression activity of target BGCs. The genus Chaetomium is widely recognized as a rich source of novel and bioactive SMs. Deletion of a class I HDAC gene of Chaetomium olivaceum SD-80A, g7489, induces a substantial pleiotropic effect on the expression of SM BGCs. The C. olivaceum SD-80A ∆g7489 strain exhibited significant changes in morphology, sporulation ability, and secondary metabolic profile, resulting in the emergence of new compound peaks. Notably, three polyketides (A1-A3) and one asterriquinone (A4) were isolated from this mutant strain. Furthermore, our study explored the BGCs of A1-A4, confirming the function of two polyketide synthases (PKSs). Collectively, our findings highlight the promising potential of molecular epigenetic approaches for the elucidation of novel active compounds and their biosynthetic elements in Chaetomium species. This finding holds great significance for the exploration and utilization of Chaetomium resources. KEY POINTS: • Deletion of a class I histone deacetylase activated secondary metabolite gene clusters. • Three polyketides and one asterriquinone were isolated from HDAC deleted strain. • Two different PKSs were reported in C. olivaceum SD-80A.

Cadmium phytoremediation potential of Houttuynia cordata: Insights from growth, uptake, and rhizosphere mechanisms.

Cadmium (Cd) pollutes 7.0 % of China's land area. This study examined the potential of Houttuynia cordata for Cd phytoremediation because of its ability to accumulate Cd in its growth matrix. H. cordata were planted in plastic pots filled with paddy field soils having low (LCd), medium (MCd), and high (HCd) Cd levels of 0.19, 0.69, and 2.91 mg/kg, respectively. After six months of growth, harvested plant parts were evaluated for Cd uptake and tolerance mechanisms. Metabolomics and metagenomics approaches were employed to investigate the soil rhizosphere mechanism. Results showed that the average plant biomass increased as soil Cd increased. The biomass Cd contents surpassed the allowable Cd limits for food (≤ 0.2 mg/kg) and medicinal uses (≤ 0.3 mg/kg). Cd contents were higher in H. cordata roots (30.59-86.27 mg/kg) than in other plant parts (0.63-2.90 mg/kg), with significantly increasing values as Cd soil level increased. Phenolic acids, lipids, amino acids and derivatives, organic acids, and alkaloids comprised the majority (69 in MCd vs HCd and 73 % in LCd vs HCd) of the shared upregulated metabolites. In addition, 13 metabolites specific to H. cordata root exudates were significantly increased. The top two principal metabolic pathways were arginine and proline metabolism, and beta-alanine metabolism. H. cordata increased the abundance of Firmicutes and Glomeromycota across all three Cd levels, and also stimulated the growth of Patescibacteria, Rozellomycota, and Claroideoglomus in HCd. Accordingly, H. cordata demonstrated potential for remediation of Cd-contaminated soils, and safety measures for its production and food use must be highly considered.

Maternal F-53B exposure during pregnancy and lactation affects bone growth and development in male offspring.

6:2 Chlorinated polyfluoroalkyl ether sulfonate (F-53B) is a new type of perfluorinated and polyfluoroalkyl substance (PFAS) that is used extensively in industry and manufacturing. F-53B causes damage to multiple mammalian organs. However, the impacts of F-53B on bone are unknown. Maternal exposure to F-53B is of particular concern because of the vulnerability of the developing fetus and newborn to contaminants from the mother. The goal of this study was to examine the impacts of maternal F-53B exposure on bone growth and development in offspring and to explore its underlying mechanisms. Herein, C57BL/6 J mice were given free access to deionized water containing 0, 0.57, or 5.7 mg/L F-53B during pregnancy and lactation. F-53B exposure resulted in impaired liver function, decreased IGF-1 secretion, dysregulation of bone metabolism and disruption of the dynamic balance between osteoblasts and osteoclasts in male offspring. F-53B inhibits longitudinal bone growth and development and causes osteoporosis in male offspring. F-53B may affect the growth and development of offspring bone via the IGF-1/OPG/RANKL/CTSK signaling pathway. This study provides new insights for the study of short stature and bone injury caused by F-53B.

Qualitative and quantitative analysis of chemical constituents in goupi plaster prepared by various extraction methods using UPLC-Q-Exactive-MS and UPLC-MS/MS.

Goupi plaster, a representative preparation of black plaster, has demonstrated promising effects in treating knee osteoarthritis. However, high temperature used in traditional frying extraction may cause decomposition of its effective components, thus limiting the efficacy. This study aimed to explore the scientific nature of the traditional preparation technology of Goupi plaster, and to compare the effects of different extraction methods on the types of chemical components and the content of index components. The UPLC-Q-Exactive-MS and UPLC-MS/MS technologies which have high efficiency, sensitivity and accuracy, were used to qualitatively and quantitatively analyze the chemical components of Goupi plaster under different preparation processes. The results show that the extraction solvent approach is different from the traditional frying extraction method, and has a positive effect. However, the mechanism of action of Goupi plaster is complex and its pharmacological effects are diverse. Future studies should explore whether it necessary to change the frying extraction method. This experiment provides a theoretical basis that will guide further scientific discussion and research into the frying extraction of Goupi plaster.

A Methylation-Gated DNAzyme Circuit for Spatially Controlled Imaging of MicroRNA in Cells and Animals.

Epigenetic modification plays an indispensable role in regulating routine molecular signaling pathways, yet it is rarely used to modulate molecular self-assembly networks. Herein, we constructed a bioorthogonal demethylase-stimulated DNA circuitry (DSC) system for high-fidelity imaging of microRNA (miRNA) in live cells and mice by eliminating undesired off-site signal leakage. The simple and robust DSC system is composed of a primary cell-specific circuitry regulation (CR) module and an ultimate signal-transducing amplifier (SA) module. After the modularly designed DSC system was delivered into target live cells, the DNAzyme of the CR module was site-specifically activated by endogenous demethylase to produce fuel strands for the subsequent miRNA-targeting SA module. Through the on-site and multiply guaranteed molecular recognitions, the lucid yet efficient DSC system realized the reliably amplified in vivo miRNA sensing and enabled the in-depth exploration of the demethylase-involved signal pathway with miRNA in live cells. Our bioorthogonally on-site-activated DSC system represents a universal and versatile biomolecular sensing platform via various demethylase regulations and shows more prospects for more different personalized theragnostics.

Development of a Fluorescent Assay and Imidazole-Containing Inhibitors by Targeting SARS-CoV-2 Nsp13 Helicase.

Nsp13, a non-structural protein belonging to the coronavirus family 1B (SF1B) helicase, exhibits 5'-3' polarity-dependent DNA or RNA unwinding using NTPs. Crucially, it serves as a key component of the viral replication-transcription complex (RTC), playing an indispensable role in the coronavirus life cycle and thereby making it a promising target for broad-spectrum antiviral therapies. The imidazole scaffold, known for its antiviral potential, has been proposed as a potential scaffold. In this study, a fluorescence-based assay was designed by labeling dsDNA substrates with a commercial fluorophore and monitoring signal changes upon Nsp13 helicase activity. Optimization and high-throughput screening validated the feasibility of this approach. In accordance with the structural characteristics of ADP, we employed a structural-based design strategy to synthesize three classes of imidazole-based compounds through substitution reaction. Through in vitro activity research, pharmacokinetic parameter analysis, and molecular docking simulation, we identified compounds A16 (IC50 = 1.25 µM) and B3 (IC50 = 0.98 µM) as potential lead antiviral compounds for further targeted drug research.

Hydronidone induces apoptosis in activated hepatic stellate cells through endoplasmic reticulum stress-associated mitochondrial apoptotic pathway.

BACKGROUND AND AIM: Hydronidone (HDD) is a novel pirfenidone derivative developed initially to reduce hepatotoxicity. Our previous studies in animals and humans have demonstrated that HDD treatment effectively attenuates liver fibrosis, yet the underlying mechanism remains unclear. This study aimed to investigate whether HDD exerts its anti-fibrotic effect by inducing apoptosis in activated hepatic stellate cells (aHSCs) through the endoplasmic reticulum stress (ERS)-associated mitochondrial apoptotic pathway. METHODS: The carbon tetrachloride (CCl4)- and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced liver fibrosis models were used for in vivo studies. In vitro studies were conducted using the human hepatic stellate cell line LX-2. The apoptotic effect of HDD on aHSCs was examined using TUNEL and flow cytometry assays. The small interfering RNA (siRNA) technique was employed to downregulate the expression of interest genes. RESULTS: HDD treatment significantly promoted apoptosis in aHSCs in both the CCl4- and DDC-induced liver fibrosis in mice and LX-2 cells. Mechanistic studies revealed that HDD triggered ERS and subsequently activated the IRE1α-ASK1-JNK pathway. Furthermore, the influx of cytochrome c from the mitochondria into the cytoplasm was increased, leading to mitochondrial dysfunction and ultimately triggering apoptosis in aHSCs. Notably, inhibition of IRE1α or ASK1 by siRNA partially abrogated the pro-apoptotic effect of HDD in aHSCs. CONCLUSIONS: The findings of both in vivo and in vitro studies suggest that HDD induces apoptosis in aHSCs via the ERS-associated mitochondrial apoptotic pathway, potentially contributing to the amelioration of liver fibrosis.

[Application of antibiotic bone cement-coated plates internal fixation for primary treating Gustilo type â ¢B tibiofibular open fracture].

Objective: To explore the effectiveness of using antibiotic bone cement-coated plates internal fixation technology as a primary treatment for Gustilo type ⅢB tibiofibular open fractures. Methods: The clinical data of 24 patients with Gustilo type ⅢB tibiofibular open fractures who were admitted between January 2018 and December 2021 and met the selection criteria was retrospectively analyzed. Among them, there were 18 males and 6 females, aged from 25 to 65 years with an average age of 45.8 years. There were 3 cases of proximal tibial fracture, 6 cases of middle tibial fracture, 15 cases of distal tibial fracture, and 21 cases of fibular fracture. The time from injury to emergency surgery ranged from 3 to 12 hours, with an average of 5.3 hours. All patients had soft tissue defects ranging from 10 cm×5 cm to 32 cm×15 cm. The time from injury to skin flap transplantation for wound coverage ranged from 1 to 7 days, with an average of 4.1 days, and the size of skin flap ranged from 10 cm×5 cm to 33 cm×15 cm. Ten patients had bone defects with length of 2-12 cm (mean, 7.1 cm). After emergency debridement, the tibial fracture end was fixed with antibiotic bone cement-coated plates, and the bone defect area was filled with antibiotic bone cement. Within 7 days, the wound was covered with a free flap, and the bone cement was replaced while performing definitive internal fixation of the fracture. In 10 patients with bone defect, all the bone cement was removed and the bone defect area was grafted after 7-32 weeks (mean, 11.8 weeks). The flap survival, wound healing of the affected limb, complications, and bone healing were observed after operation, and the quality of life was evaluated according to the short-form 36 health survey scale (SF-36 scale) [including physical component summary (PCS) and mental component summary (MCS) scores] at 1 month, 6 months after operation, and at last follow-up. Results: All 24 patients were followed up 14-38 months (mean, 21.6 months). All the affected limbs were successfully salvaged and all the transplanted flaps survived. One case had scar hyperplasia in the flap donor site, and 1 case had hypoesthesia (grade S3) of the skin around the scar. There were 2 cases of infection in the recipient area of the leg, one of which was superficial infection after primary flap transplantation and healed after debridement, and the other was sinus formation after secondary bone grafting and was debrided again 3 months later and treated with Ilizarov osteotomy, and healed 8 months later. The bone healing time of the remaining 23 patients ranged from 4 to 9 months, with an average of 6.1 months. The scores of PCS were 44.4±6.5, 68.3±8.3, 80.4±6.9, and the scores of MCS were 59.2±8.2, 79.5±7.8, 90.0±6.6 at 1 month, 6 months after operation, and at last follow-up, respectively. The differences were significant between different time points ( P<0.05). Conclusion: Antibiotic bone cement-coated plates internal fixation can be used in the primary treatment of Gustilo type ⅢB tibiofibular open fractures, and has the advantages of reduce the risk of infection in fracture fixation, reducing complications, and accelerating the functional recovery of patients.

Association of 25-hydroxyvitamin D, lipoprotein-associated phospholipase A2 and asymptomatic coronary artery disease in patients with type 2 diabetes mellitus.

AIM: To evaluate the relationship of 25-hydroxyvitamin D (25(OH)D), lipoprotein-associated phospholipase A2 (Lp-PLA2), and coronary artery disease (CAD) in type 2 diabetes mellitus (T2DM) patients with no history or symptoms of cardiovascular disease. METHODS: The study identified 66 pairs of T2DM patients with and without CAD using propensity score matching. All subjects performed coronary computed tomography angiography (CCTA). Data on 25(OH)D, Lp-PLA2, and metabolic indexes were collected and analyzed. RESULTS: Compared to the patients without CAD, the patients with CAD had lower 25(OH)D levels and the rate of vitamin D sufficiency, but higher Lp-PLA2 levels. Meanwhile, subjects in the vitamin D sufficiency group had a lower prevalence of CAD and Lp-PLA2 levels. Furthermore, 25(OH)D was inversely correlated with Lp-PLA2, Gensini score, Leiden score, segment involvement score, and segment stenosis score (P < 0.05). After adjusting for age, gender, blood lipids and blood pressure, 25(OH)D was associated with a decreased risk of CAD (aOR 0.933, 95 %CI 0.887-0.983, P = 0.009), while Lp-PLA2 was associated with an increased risk of CAD (aOR 1.014, 95 %CI 1.005-1.022, P = 0.002). CONCLUSIONS: Decreased 25(OH)D and increased Lp-PLA2 could identify patients with a high risk of CAD and are associated with the severity of coronary artery stenosis in T2DM.

Study on the Bonding Performance of BFRP Bars with Seawater Sand Concrete.

A total of 66 sets of pullout specimens were prepared to investigate the bonding properties of basalt fiber-reinforced polymer reinforcement (hereinafter referred to as BFRP) with seawater sand concrete (hereinafter referred to as SSC). The volume dosages of mono-doped glass fibers and mono-doped polypropylene fibers were 0.1%, 0.2%, and 0.3%; the total volume dosage was set to be constant at 0.3%; and the doping ratios of the hybrid fibers were 1:2, 1:1, and 2:1. The effect on the bonding performance of BFRP reinforcement with SSC was studied on the condition of the diameter D of the BFRP reinforcement being 12 mm; the bond length of SSC being 3D, 5D, and 7D; and the surface characteristics of the reinforcement being sandblasted and threaded. The research showed that due to internal cracks in the matrix, salt crystals in the pores, chloride salts with high brittleness and expansion, as well as sulfate corrosion products such as "Frederick salts" in SSC, the concrete became brittle, resulting in more brittle splitting failures during the pullout test. Doped fibers can increase the ductility effect of concrete, but the bonding effect between the threaded fiber reinforcement and the SSC was not as good as that of the sandblasting group. When the bond length was 5D, the bonding effect between the BFRP reinforcement and SSC was the best, and the bonding performance of the experimental group with doped fibers was better than that of the threaded group. Finally, by combining the ascending segment of the Malvar model with the descending segment of the improved BPE model, a constitutive relationship model suitable for the bond-slip curve between BFRP reinforcement and SSC was fitted, which laid a theoretical foundation for future research on SSC.

Mediating role of social support in dysphoria, despondency, and quality of life in patients undergoing maintenance hemodialysis.

BACKGROUND: Dysphoria and despondency are prevalent psychological issues in patients undergoing Maintenance Hemodialysis (MHD) that significantly affect their quality of life (QOL). High levels of social support can significantly improve the physical and mental well-being of patients undergoing MHD. Currently, there is limited research on how social support mediates the relationship between dysphoria, despondency, and overall QOL in patients undergoing MHD. It is imperative to investigate this mediating effect to mitigate dysphoria and despondency in patients undergoing MHD, ultimately enhancing their overall QOL. AIM: To investigate the mediating role of social support in relationships between dysphoria, despondency, and QOL among patients undergoing MHD. METHODS: Participants comprised 289 patients undergoing MHD, who were selected using a random sampling approach. The Social Support Rating Scale, Self-Rating Anxiety Scale, Self-Rating Depression Scale, and QOL Scale were administered. Correlation analysis was performed to examine the associations between social support, dysphoria, despondency, and QOL in patients undergoing MHD. To assess the mediating impact of social support on dysphoria, despondency, and QOL in patients undergoing MHD, a bootstrap method was applied. RESULTS: Significant correlations among social support, dysphoria, despondency, and quality in patients undergoing MHD were observed (all P < 0.01). Dysphoria and despondency negatively correlated with social support and QOL (P < 0.01). Dysphoria and despondency had negative predictive impacts on the QOL of patients undergoing MHD (P < 0.05). The direct effect of dysphoria on QOL was statistically significant (P < 0.05). Social support mediated the relationship between dysphoria and QOL, and this mediating effect was significant (P < 0.05). Similarly, the direct effect of despondency on QOL was significant (P < 0.05). Moreover, social support played a mediating role between despondency and QOL, with a significant mediating effect (P < 0.05). CONCLUSION: These findings suggest that social support plays a significant mediating role in the relationship between dysphoria, despondency, and QOL in patients undergoing MHD.

Improving therapeutic outcomes in heart failure with reduced nonvalvular ejection fraction: A clinical study of heart failure education intervention.

OBJECTIVE: The current study delves into the impact of heart failure education intervention on improving therapeutic outcomes for heart failure (HF) patients with reduced nonvalvular ejection fraction. METHODS: There involved a total of 60 HF patients with non-valvular ejection fraction reduction who met the inclusion requirements. Patients enrolled were randomly distributed into an observation group and a control group. The observation group received heart failure education intervention, while the control group received conventional intervention. The therapeutic effect, changes in physical indicators, cardiac function indicators, coagulation function, self-management scale scores, and the incidence of adverse cardiovascular events were meticulously evaluated. RESULTS: The total effective proportion in the observation group was 96.67%, which was significantly higher than the control group's proportion of 76.67% (p < .05). After treatment, several parameters in the observation group showed significant improvements compared to the control group: hs-CRP, IL-6, LVEDV value, LVESV value, PT value, APTT value, and TT value were all evidently lower in the observation group. Additionally, the cardiac index, LVEF value, and heart failure self-management scale fraction were significantly higher in the observation group compared to the control group (p < .05). Furthermore, the incidence of adverse cardiovascular events in the observation group was only 6.67%, which was significantly lower than the control group's incidence of 20.00% (p < .05). CONCLUSION: Heart failure education intervention demonstrates effectiveness in improving the therapeutic outcomes for HF patients and reduced nonvalvular ejection fraction. Additionally, it enhances patients' self-management abilities. Given these positive results, it is highly recommended to promote and implement HF education intervention in clinical practice.

Masquelet combined with free-flap technique versus the Ilizarov bone transport technique for severe composite tibial and soft-tissue defects.

BACKGROUND: The treatment of bone and soft-tissue defects after open fractures remains challenging. This study aimed to evaluate the clinical efficacy of the Masquelet technique combined with the free-flap technique (MFFT) versus the Ilizarov bone transport technique (IBTT) for the treatment of severe composite tibial and soft-tissue defects. METHODS: We retrospectively analysed the data of 65 patients with tibial and soft-tissue defects and Gustilo type IIIB/C open fractures treated at our hospital between April 2015 and December 2021. The patients were divided into two groups based on the treatment method: group A (n = 35) was treated with the MFFT and internal fixation, and group B (n = 30) was treated with the IBTT. RESULTS: The mean follow-up period was 28 months (range 13-133 months). Complete union of both soft-tissue and bone defects was achieved in all cases. The mean bone-union times were 6 months (range 3-12 months) in group A and 11 months (range 6-23 month) in group B, with a significant difference between the two groups (Z = -4.11, P = 0.001). The mean hospital stay was 28 days (range 14-67 d) in group A which was significantly longer than the mean stay of 18 days (range 10-43 d) in group B (Z = -2.608, P = 0.009). There were no significant differences in the infection rate between group A (17.1 %) and group B (26.7%) (χ2 = 0.867, P = 0.352). The Total Physical Health Scores were 81.51 ± 6.86 (range 67-90) in group A and 75.83±16.14 (range 44-98) in group B, with no significant difference between the two groups (t = 1.894, P = 0.063). The Total Mental Health Scores were significantly higher in group A (90.49 ± 6.37; range 78-98) than in group B (84.70 ± 13.72; range 60-98) (t = 2.232, P = 0.029). CONCLUSION: Compared with IBTT, MFFT is a better choice of treatment for open tibial and soft-tissue defects with Gustilo IIIB/C fractures. IBTT is the preferred option when the tibial bone defect is large or if the surgeon's expertise in microsurgery is limited.

Synergistic Inhibitions of Gram-Negative Bacteria by Combination Treatment with Ciprofloxacin and a Novel Glucolipid.

Psychrophilic fungus Pseudogymnoascus sp. OUCMDZ-4032 derived from Antarctica was cultivated under 16 °C to produce a new glucolipid compound (1). Its structure was elucidated by analysis of detailed spectroscopic data, acid hydrolysis and 1-phenyl-3-methyl-5-pyrazolone precolumn derivatization, and 13C NMR quantum chemical calculations. Though compound 1 did not show inhibitory activity against bacteria, it can reduce the minimum inhibitory concentration (MIC) of ciprofloxacin against Gram-negative bacteria Pseudomonas aeruginosa, Escherichia coli, and Salmonella paratyphi by 1024, 256 and 256-fold. Compound 1 showed potential as a synergistically inhibiting adjuvant in co-administration with antibiotic to enhance antibacterial activities.

Age at Diagnosis of Diabetes in Young Men is Associated with Albuminuria.

Background: Early-onset diabetes appears to be an aggressive phenotype of type 2 diabetes (T2D). The impact of the age of onset of T2D on albuminuria, especially high urinary albumin excretion, remains to be investigated. Objective: To determine whether adults diagnosed with T2D between the ages of 18 and 45 more aggressively develop albuminuria. Methods: Conducted at Taizhou People's Hospital from November 2018 to August 2020, this cross-sectional study enrolled T2D patients. Anthropometric measures, metabolic profiles, and urinary albumin creatinine ratio were examined. Patients were categorized into early-onset (≤45 years) and late-onset (> 45 years) groups. Univariate and multivariate analyses were performed to identify albuminuria risk factors. Subgroups were formed based on age at diabetes diagnosis and gender. Multivariate ordinal logistic regression analysis was then conducted to identify distinct risk factors within each subgroup. Results: Analyzing 1900 T2D patients, it was found significantly higher albuminuria prevalence in early-onset patients (35.08% vs 29.92%, P = 0.022). The risk of albuminuria in early-onset patients was 1.509 times higher than that in late-onset patients, especially among male patients, where the risk increased to 1.980. For late-onset patients, disease duration and glycated hemoglobin (HbA1c) were identified as risk factors, whereas for early-onset patients, body-mass index (BMI) and systolic blood pressure were associated with increased risk. Among male patients, age at diagnosis of diabetes, blood pressure, and BMI were identified as risk factors, while for female patients, disease duration and HbA1c played a significant role. Additionally, high-density lipoprotein cholesterol was found to be a protective factor against albuminuria. Conclusion: Individuals diagnosed with T2D before 45 face heightened albuminuria risk, especially males. Risk factors vary by gender and onset age, highlighting the need for tailored management strategies.

EP300-ZNF384 transactivates IL3RA to promote the progression of B-cell acute lymphoblastic leukemia.

The EP300-ZNF384 fusion gene is an oncogenic driver in B-cell acute lymphoblastic leukemia (B-ALL). In the present study, we demonstrated that EP300-ZNF384 substantially induces the transcription of IL3RA and the expression of IL3Rα (CD123) on B-ALL cell membranes. Interleukin 3 (IL-3) supplementation promotes the proliferation of EP300-ZNF348-positive B-ALL cells by activating STAT5. Conditional knockdown of IL3RA in EP300-ZF384-positive cells inhibited the proliferation in vitro, and induced a significant increase in overall survival of mice, which is attributed to impaired propagation ability of leukemia cells. Mechanistically, the EP300-ZNF384 fusion protein transactivates the promoter activity of IL3RA by binding to an A-rich sequence localized at -222/-234 of IL3RA. Furthermore, forced EP300-ZNF384 expression induces the expression of IL3Rα on cell membranes and the secretion of IL-3 in CD19-positive B precursor cells derived from healthy individuals. Doxorubicin displayed a selective killing of EP300-ZNF384-positive B-ALL cells in vitro and in vivo. Collectively, we identify IL3RA as a direct downstream target of EP300-ZNF384, suggesting CD123 is a potent biomarker for EP300-ZNF384-driven B-ALL. Targeting CD123 may be a novel therapeutic approach to EP300-ZNF384-positive patients, alternative or, more likely, complementary to standard chemotherapy regimen in clinical setting.

Metabolic profile of Phellodendron amurense Rupr. in vivo of rat and its metabolomic study on intervention in rheumatoid arthritis.

To analyze the metabolites (blood, urine and feces) in normal rats after intragastric administration of the decoction of Phellodendri Amurensis Cortex (PAC) and to map the metabolic profile of PAC in vivo of rat; meanwhile, to evaluate the anti-rheumatoid arthritis (RA) effect of PAC by blood metabolomics technique and to explore its mechanism. Performing on UPLC-Q-TOF-MS technology with a Waters ACQUITY UPLC BEH-C18 column (100 mm × 2.1 mm, 1.7 µm), the mobile phase was acetonitrile-0.1% formic acid aqueous solution (gradient elution). Prior to and following the administration of the decoction of PAC, the samples of blood, urine, and fecal were collected from the rats, in the positive ion mode, pharmacogenic metabolites in each biological sample were identified according to the accurate mass, fragment ions, retention time, metabolic reaction type, comparison of reference substance and retrieval of Pub Med database; The adjuvant-type arthritis (AA) rat model was established, and blood metabonomics method was used to study the improvement effect of rheumatoid arthritis after drug intervention with PAC, and its mechanism was preliminarily explored through analysis of metabolic pathway. A total of 72 exogenous components were identified, including 17 prototype components and 55 metabolites; 14 biomarkers were screened by blood metabolomics techniques combined with multivariate statistical analysis, and PAC significantly improved symptoms of rheumatoid arthritis in rats, and the metabolic pathway analysis mainly involves 5 metabolic pathways. The components in the aqueous decoction of PAC mainly undergo phase I metabolic reactions in rats, such as oxidation, reduction, dehydrogenation, demethylation, and phase II metabolic reactions, such as acetylation, glucuronidation, methylation; PAC has anti-rheumatoid arthritis effects, and its mechanism of action may be related to biosynthesis of aminoacyl-tRNA, metabolism of phenylalanine, metabolism of tryptophan, degradation of valine, leucine and isoleucine and biosynthesis of pantothenic acid and coenzyme A, providing a scientific basis for the study of the pharmacodynamic substances and the action mechanism of PAC against RA.

Portable Detection of Lysine Acetyltransferase Activity in Lung Cancer Cells Based on a Miniature Electrochemical Sensor.

The detection of lysine acetyltransferases is crucial for diagnosing and treating lung cancer, highlighting the necessity for highly efficient detection methods. We developed a portable, highly accurate, and sensitive technique using fast-scan cyclic voltammetry (FSCV) to determine the activity of the lysine acetyltransferase TIP60, employing a novel miniature electrochemical sensor. This approach involves a compact electrochemical cell, merely 3 mm in diameter, that holds solutions up to 50 µL, equipped with a conductive indium tin oxide working electrode. Uniquely, this system operates on a two-electrode model compatible with the FSCV, obviating the traditional requirement for a reference electrode. The system detects TIP60 activity through the continuous generation of CoA molecules that engage in reactions with Cu(II), thereby significantly improving the accuracy of the acetylation analysis. Remarkably, the detection limit achieved for TIP60 is notably low at 3.3 pg/mL (S/N = 3). The results show that the reversible dynamic acetylation can be effectively regulated by inhibitor incubation and glucose stimulation. This cutting-edge strategy enhances the analysis of a broad spectrum of biomarkers by modifying the responsive unit, and its miniaturization and portability significantly amplify its applicability in biomedical research, promising it to be a versatile tool for early diagnostic and therapeutic interventions in lung cancer.

Radiofrequency hyperthermia enhances the effect of OK-432 for Hepatocellular carcinoma by activating of TLR4-cGAS-STING pathway.

Radiofrequency ablation (RFA) has been used as an alternative to surgical management of early-stage hepatocellular carcinoma (HCC). However, when large and irregular HCCs are subjected to RFA, a safety margin is usually difficult to obtain, thus causing a sublethal radiofrequency hyperthermia (RFH) at the ablated tumor margin. This study investigated the feasibility of using RFH to enhance the effect of OK-432 on HCC, with the aim to generate a tumor-free margin during RFA of HCC. Our results showed OK-432 could activate the cGAS-STING pathway, and RFH could further enhance the activation. Meanwhile, RFH could induce a high expression of TLR4, and TLR4 might be an upstream molecular of the cGAS-STING pathway. The combined therapy of RFH with OK-432 resulted in a better tumor response, and a prolonged survival compared to the other three treatments. In conclusion, RFH in combination with OK-432 might reduce the residual and recurrent tumor after RFA of large and irregular HCCs, and serve as a new option for other solid malignancies treated by RFA.