CRISPR screens unveil nutrient-dependent lysosomal and mitochondrial nodes impacting intestinal tissue-resident memory CD8+ T cell formation.

Nutrient availability and organelle biology direct tissue homeostasis and cell fate, but how these processes orchestrate tissue immunity remains poorly defined. Here, using in vivo CRISPR-Cas9 screens, we uncovered organelle signaling and metabolic processes shaping CD8+ tissue-resident memory T (TRM) cell development. TRM cells depended on mitochondrial translation and respiration. Conversely, three nutrient-dependent lysosomal signaling nodes-Flcn, Ragulator, and Rag GTPases-inhibited intestinal TRM cell formation. Depleting these molecules or amino acids activated the transcription factor Tfeb, thereby linking nutrient stress to TRM programming. Further, Flcn deficiency promoted protective TRM cell responses in the small intestine. Mechanistically, the Flcn-Tfeb axis restrained retinoic acid-induced CCR9 expression for migration and transforming growth factor ß (TGF-ß)-mediated programming for lineage differentiation. Genetic interaction screening revealed that the mitochondrial protein Mrpl52 enabled early TRM cell formation, while Acss1 controlled TRM cell development under Flcn deficiency-associated lysosomal dysregulation. Thus, the interplay between nutrients, organelle signaling, and metabolic adaptation dictates tissue immunity.

The impact of processing voltage of wire electric discharge machining on the performance of Mo doped V-VO0.2 based Archimedean micro-supercapacitors.

Vanadium oxide-based electrode materials have attracted increasing attention owing to their extraordinary capacitance and prolonged lifespan, excellent conductivity and outstanding electrochemical reversibility. However, the development of vanadium oxide-based integrated electrodes with outstanding capacitive performance is an enduring challenge. This research reports a facile method for structuring 3D Archimedean micro-supercapacitors (AMSCs) composed of Mo doped V-VO0.2 (Mo@V-VO0.2) based integrated electrodes with designable geometric shape, using computer-aided wire electric discharge machining (WEDM). The performance of Mo@V-VO0.2 based AMSCs manufactured by different processing voltages of 60 V, 80 V and 100 V were evaluated. It was found that 80 V is the optimal processing voltage for manufacturing Mo@V-VO0.2 based AMSCs with the best electrochemical performance. This device demonstrates superior capacitive behavior even at an ultra-high scan rate of 50, 000 mV s-1, and achieves a good capacitance retention rate of 94.4% after 2000 cycles. Additionally, the characteristics of electric field distribution were also simulated for optimizing the geometric structure of the microdevices. This WEDM fabrication technique, which is easy, secure, patternable, efficient, economical, eco-friendly, and does not require binders or conductive additives, enables the development of high-capacity 3D pseudocapacitive micro-supercapacitors and demonstrates the great potential for metal oxide synthesis and microdevice manufacturing.

YOLO-PBESW: A Lightweight Deep Learning Model for the Efficient Identification of Indomethacin Crystal Morphologies in Microfluidic Droplets.

Crystallization is important to the pharmaceutical, the chemical, and the materials fields, where the morphology of crystals is one of the key factors affecting the quality of crystallization. High-throughput screening based on microfluidic droplets is a potent technique to accelerate the discovery and development of new crystal morphologies with active pharmaceutical ingredients. However, massive crystal morphologies' datum needs to be identified completely and accurately, which is time-consuming and labor-intensive. Therefore, effective morphologies' detection and small-target tracking are essential for high-efficiency experiments. In this paper, a new improved algorithm YOLOv8 (YOLO-PBESW) for detecting indomethacin crystals with different morphologies is proposed. We enhanced its capability in detecting small targets through the integration of a high-resolution feature layer P2, and the adoption of a BiFPN structure. Additionally, in this paper, adding the EMA mechanism before the P2 detection head was implemented to improve network attention towards global features. Furthermore, we utilized SimSPPF to replace SPPF to mitigate computational costs and reduce inference time. Lastly, the CIoU loss function was substituted with WIoUv3 to improve detection performance. The experimental findings indicate that the enhanced YOLOv8 model attained advancements, achieving AP metrics of 93.3%, 77.6%, 80.2%, and 99.5% for crystal wire, crystal rod, crystal sheet, and jelly-like phases, respectively. The model also achieved a precision of 85.2%, a recall of 83.8%, and an F1 score of 84.5%, with a mAP of 87.6%. In terms of computational efficiency, the model's dimensions and operational efficiency are reported as 5.46 MB, and it took 12.89 ms to process each image with a speed of 77.52 FPS. Compared with state-of-the-art lightweight small object detection models such as the FFCA-YOLO series, our proposed YOLO-PBESW model achieved improvements in detecting indomethacin crystal morphologies, particularly for crystal sheets and crystal rods. The model demonstrated AP values that exceeded L-FFCA-YOLO by 7.4% for crystal sheets and 3.9% for crystal rods, while also delivering a superior F1-score. Furthermore, YOLO-PBESW maintained a lower computational complexity, with parameters of only 11.8 GFLOPs and 2.65 M, and achieved a higher FPS. These outcomes collectively demonstrate that our method achieved a balance between precision and computational speed.

Matrix-assisted laser desorption/ionization mass spectrometry for the rapid and high throughput analysis of betaine and trigonelline in Lycium chinense Mill. and trigonelline in coffee.

A rapid, simple, effective, and green method for the determination of betaine and trigonelline from Lycium chinense Mill. (LCM) and the quantification of the trigonelline in coffee was proposed and validated by matrix-assisted laser desorption ionization time-of-flight mass spectrometric (MALDI-TOF MS) detection. Due to without chromatographic separation, the method greatly shortened the detection time. The detection of betaine and trigonelline concentration showed good linearity in the range of 1-100 µg/mL and 0.01-100 µg/mL, with correlation coefficients r2 = 0.9962 and 0.9946, respectively. The good reproducibility and reliability of the method were demonstrated by excellent intraday and interday precisions with RSD <8.3%, and the recovery of betaine and trigonelline ranged from 92.2% to 116.0%. Analysis of LCM and coffee extracts (raw, light-roasted, and dark-roasted coffee beans) gave results in agreement with the literature. The method appeared as a fast and reliable alternative method for routine Lycium chinense and coffee analysis.

Association between gut microbiota and diabetic microvascular complications: a two-sample Mendelian randomization study.

Background: Gut microbiota (GM) homeostasis in the human body is closely associated with health, which can be used as a regulator for preventing the onset and progression of disease. Diabetic microvascular complications bring about not only a huge economic burden to society, but also miserable mental and physical pain. Thus, alteration of the GM may be a method to delay diabetic microvascular complications. Objective: A two-sample Mendelian randomization (MR) analysis was conducted to reveal the causal inference between GM and three core diabetic microvascular complications, namely, diabetic kidney disease (DKD), diabetic retinopathy (DR), and diabetic neuropathy (DNP). Methods: First, genome-wide association study (GWAS) summary statistics for GM from the MiBioGen consortium and three main diabetic microvascular complications acquired from the FinnGen research project were assessed. Second, a forward MR analysis was conducted to assess the causality of GM on the risk of DKD, DR, and DNP. Third, a series of sensitivity studies, such as heterogeneity tests, pleiotropy evaluations, and leave-one-out analyses, were further conducted to assess the accuracy of MR analysis. Finally, Steiger tests and reverse MR analyses were performed to appraise the possibility of reverse causation. Results: A total of 2,092 single-nucleotide polymorphisms related to 196 bacterial traits were selected as instrumental variables. This two-sample MR analysis provided strongly reasonable evidence that 28 genetically predicted abundance of specific GM that played non-negligible roles in the occurrence of DKD, DR, and DNP complications were causally associated with 23 GM, the odds ratio of which generally ranged from 0.9 to 1.1. Further sensitivity analysis indicated low heterogeneity, low pleiotropy, and high reliability of the causal estimates. Conclusion: The study raised the possibility that GM may be a potential target to prevent and delay the progression of diabetic microvascular complications. Further experiments of GM therapy on diabetic microvascular complications are warranted to clarify their effects and specific mechanisms.

Pipette-tip solid-phase extraction coupled with matrix-assisted laser desorption/ionization mass spectrometry enables rapid and high-throughput analysis of antidepressants in rat serum.

Therapeutic drug monitoring is essential for ensuring the efficacy and safety of medications. This study introduces a streamlined approach that combines pipette-tip solid-phase extraction (PT-SPE) with matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), facilitating rapid and high-throughput monitoring of drug concentrations. As a demonstration, this method was applied to the extraction and quantification of antidepressants in serum. Utilizing Zip-Tip C18, the method enabled the extraction of antidepressants from complex biological matrices in less than 2 min, with the subsequent MALDI-MS analysis yielding results in just 1 min. Optimal extraction recoveries were achieved using a sampling solution at pH 9.0 and a 10 µL ethanol desorption solution containing 0.1% phosphoric acid. For MALDI analysis, 2,5-dihydroxybenzoic acid was identified as the most effective matrix for producing the highest signal intensity. The quantification strategy exhibited robust linearities (R2 ≥ 0.997) and satisfactory limits of quantification, ranging from 0.05 to 0.5 µg/mL for a suite of antidepressants. The application for monitoring dynamic concentration changes of antidepressants in rat serum emphasized the method's efficacy. This strategy offers the advantages of high throughput, minimal sample usage, environmental sustainability, and simplicity, providing ideas and a reference basis for the subsequent development of methods for therapeutic drug monitoring.

Integration of Myrica rubra-based N-doped carbon dots with Fe3S4 as excellent peroxidase mimics for colorimetric assay and smartphone-based intelligent sensing of p-aminophenol in waters.

To realize the reutilization of waste Myrica rubra in the analytical field, we synthesized Myrica rubra-based N-doped carbon dots (MN-CDs) and further anchored them onto the surface of Fe3S4 to fabricate Fe3S4@MN-CD nanocomposites. The as-fabricated nanocomposites possessed higher peroxidase-mimetic activity than its two precursors, resulting from the synergistic effect between them, and could catalyze colorless 3,3',5,5'-tetramethylbenzidine (TMB) into deep blue oxTMB with a strong 652-nm absorption. Under optimized conditions (initial solution pH, 3.5; incubation temperature, 35 ℃; Fe3S4@MN-CD concentration, 50 µg mL-1, and 652-nm absorption), Fe3S4@MN-CDs were employed for colorimetric assay of p-aminophenol (p-AP) with wide linear range (LR, 2.9-100 µM), low detection limit (LOD, 0.87 µM), and satisfactory recoveries (86.3-105%) in environmental waters. Encouragingly, this colorimetric assay provided the relative accuracy of 97.0-99.4% as compared with  conventional HPLC-UV detection. A portable smartphone-based colorimetric application was developed by combining the Fe3S4@MN-CD-based visually chromogenic reaction with a "Thing Identify" APP software. Besides, we engineered an image-capturing device feasible for field use, in which the internal-compact sealing prevented external light source from entering photography chamber, thereby reducing light interference, and also the bottom light source enhanced the intensity of blue imaging. This colorimetric platform exhibited satisfactory LR (1-500 µM), low LOD (0.3 µM), and fortification recoveries (86.6-99.6%). In the chromogenic reaction catalyzed by Fe3S4@MN-CDs, ·O2- played a key role in concomitant with the participation of •OH and h+. Both the colorimetric assay and smartphone-based intelligent sensing show great promising in on-site monitoring of p-AP under field conditions.

Myricetin induces M2 macrophage polarization to alleviate renal tubulointerstitial fibrosis in diabetic nephropathy via PI3K/Akt pathway.

BACKGROUND: Development of end-stage renal disease is predominantly attributed to diabetic nephropathy (DN). Previous studies have indicated that myricetin possesses the potential to mitigate the pathological alterations observed in renal tissue. Nevertheless, the precise molecular mechanism through which myricetin influences the progression of DN remains uncertain. AIM: To investigate the effects of myricetin on DN and explore its potential therapeutic mechanism. METHODS: Db/db mice were administered myricetin intragastrically on a daily basis at doses of 50 mg/kg or 100 mg/kg for a duration of 12 wk. Subsequently, blood and urine indexes were assessed, along with examination of renal tissue pathology. Kidney morphology and fibrosis were evaluated using various staining techniques including hematoxylin and eosin, periodic acid-Schiff, Masson's trichrome, and Sirius-red. Additionally, high-glucose culturing was conducted on the RAW 264.7 cell line, treated with 25 mM myricetin or co-administered with the PI3K/Akt inhibitor LY294002 for a period of 24 h. In both in vivo and in vitro settings, quantification of inflammation factor levels was conducted using western blotting, real-time qPCR and ELISA. RESULTS: In db/db mice, administration of myricetin led to a mitigating effect on DN-induced renal dysfunction and fibrosis. Notably, we observed a significant reduction in expressions of the kidney injury markers kidney injury molecule-1 and neutrophil gelatinase associated lipocalin, along with a decrease in expressions of inflammatory cytokine-related factors. Furthermore, myricetin treatment effectively inhibited the up-regulation of tumor necrosis factor-alpha, interleukin-6, and interluekin-1ß induced by high glucose in RAW 264.7 cells. Additionally, myricetin modulated the M1-type polarization of the RAW 264.7 cells. Molecular docking and bioinformatic analyses revealed Akt as the target of myricetin. The protective effect of myricetin was nullified upon blocking the polarization of RAW 264.7 via inhibition of PI3K/Akt activation using LY294002. CONCLUSION: This study demonstrated that myricetin effectively mitigates kidney injury in DN mice through the regulation of macrophage polarization via the PI3K/Akt signaling pathway.

Unraveling spatial metabolome of the aerial and underground parts of Scutellaria baicalensis by matrix-assisted laser desorption/ionization mass spectrometry imaging.

BACKGROUND: Scutellaria baicalensis Georgi, a traditional Chinese medicine, is clinically applied mainly as the dried root of Scutellaria baicalensis, and the aerial parts of Scutellaria baicalensis, its stems and leaves, are often consumed as "Scutellaria baicalensis tea" to clear heat, dry dampness, reduce fire and detoxify, while few comparative analyses of the spatial metabolome of the aerial and underground parts of Scutellaria baicalensis have been carried out in current research. METHODS: In this work, Matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) was used to visualize the spatial imaging of the root, stem, and leaf of Scutellaria baicalensis at a high resolution of 10 µm, respectively, investigating the spatial distribution of the different secondary metabolites in the aerial and underground parts of Scutellaria baicalensis. RESULTS: In the present results, various metabolites, such as flavonoid glycosides, flavonoid metabolites, and phenolic acids, were systematically characterized in Scutellaria baicalensis root, stem, and leaf. Nine glycosides, 18 flavonoids, one organic acid, and four other metabolites in Scutellaria baicalensis root; nine glycosides, nine flavonoids, one organic acid in Scutellaria baicalensis stem; and seven flavonoids and seven glycosides in Scutellaria baicalensis leaf were visualized by MALDI-MSI. In the underground part of Scutellaria baicalensis, baicalein, wogonin, baicalin, wogonoside, and chrysin were widely distributed, while there was less spatial location in the aerial parts. Moreover, scutellarein, carthamidin/isocarthamidin, scutellarin, carthamidin/isocarthamidin-7-O-glucuronide had a high distribution in the aerial parts of Scutellaria baicalensis. In addition, the biosynthetic pathways involved in the biosynthesis of significant flavonoid metabolites in aerial and underground parts of Scutellaria baicalensis were successfully localized and visualized. CONCLUSIONS: MALDI-MSI offers a favorable approach for investigating the spatial distribution and effective utilization of metabolites of Scutellaria baicalensis. The detailed spatial chemical information can not only improve our understanding of the biosynthesis pathways of flavonoid metabolites, but more importantly, suggest that we need to fully exert the overall medicinal value of Scutellaria baicalensis, strengthening the reuse and development of the resources of Scutellaria baicalensis aboveground parts.

Fructose sweetens the adipocyte-T cell alliance against tumors.

Dietary fructose is implicated in tumorigenesis, but whether dietary fructose regulates antitumor immunity remains elusive. In this issue of Cell Metabolism, Zhang et al. show that dietary fructose promotes adipocyte-derived leptin production, which attenuates terminal exhaustion programming and boosts the effector function of CD8+ T cells for improved tumor control.

Single-cell CRISPR screens in vivo map T cell fate regulomes in cancer.

CD8+ cytotoxic T cells (CTLs) orchestrate antitumour immunity and exhibit inherent heterogeneity1,2, with precursor exhausted T (Tpex) cells but not terminally exhausted T (Tex) cells capable of responding to existing immunotherapies3-7. The gene regulatory network that underlies CTL differentiation and whether Tex cell responses can be functionally reinvigorated are incompletely understood. Here we systematically mapped causal gene regulatory networks using single-cell CRISPR screens in vivo and discovered checkpoints for CTL differentiation. First, the exit from quiescence of Tpex cells initiated successive differentiation into intermediate Tex cells. This process is differentially regulated by IKAROS and ETS1, the deficiencies of which dampened and increased mTORC1-associated metabolic activities, respectively. IKAROS-deficient cells accumulated as a metabolically quiescent Tpex cell population with limited differentiation potential following immune checkpoint blockade (ICB). Conversely, targeting ETS1 improved antitumour immunity and ICB efficacy by boosting differentiation of Tpex to intermediate Tex cells and metabolic rewiring. Mechanistically, TCF-1 and BATF are the targets for IKAROS and ETS1, respectively. Second, the RBPJ-IRF1 axis promoted differentiation of intermediate Tex to terminal Tex cells. Accordingly, targeting RBPJ enhanced functional and epigenetic reprogramming of Tex cells towards the proliferative state and improved therapeutic effects and ICB efficacy. Collectively, our study reveals that promoting the exit from quiescence of Tpex cells and enriching the proliferative Tex cell state act as key modalities for antitumour effects and provides a systemic framework to integrate cell fate regulomes and reprogrammable functional determinants for cancer immunity.

Identification and validation of ubiquitination-related signature and subgroups in immune microenvironment of tuberculosis.

BACKGROUND: Mycobacterium tuberculosis (Mtb) is the bacterial pathogen responsible for causing tuberculosis (TB), a severe public health concern that results in numerous deaths worldwide. Ubiquitination (Ub) is an essential physiological process that aids in maintaining homeostasis and contributes to the development of TB. Therefore, the main objective of our study was to investigate the potential role of Ub-related genes in TB. METHODS: Our research entailed utilizing single sample gene set enrichment analysis (ssGSEA) in combination with several machine learning techniques to discern the Ub-related signature of TB and identify potential diagnostic markers that distinguish TB from healthy controls (HC). RESULTS: In summary, we used the ssGSEA algorithm to determine the score of Ub families (E1, E2, E3, DUB, UBD, and ULD). Notably, the score of E1, E3, and UBD were lower in TB patients than in HC individuals, and we identified 96 Ub-related differentially expressed genes (UbDEGs). Employing machine learning algorithms, we identified 11 Ub-related hub genes and defined two distinct Ub-related subclusters. Notably, through GSVA and functional analysis, it was determined that these subclusters were implicated in numerous immune-related processes. We further investigated these Ub-related hub genes in four TB-related diseases and found that TRIM68 exhibited higher correlations with various immune cells in different conditions, indicating that it may play a crucial role in the immune process of these diseases. CONCLUSION: The observed enrichment of Ub-related gene expression in TB patients emphasizes the potential involvement of ubiquitination in the progression of TB. These significant findings establish a basis for future investigations to elucidate the molecular mechanisms associated with TB, select suitable diagnostic biomarkers, and design innovative therapeutic interventions for combating this fatal infectious disease.

No evident causal association between Helicobacter pylori infection and colorectal cancer: a bidirectional mendelian randomization study.

Observational studies have reported a correlation between Helicobacter pylori infection and colorectal cancer (CRC); however, the underlying cause has remained unclear. This research was aimed at determining whether there is a correlation between H. pylori infection and CRC by measuring the prevalence of H. pylori CagA antibodies and VacA antibodies. Using data from many genome-wide association studies (GWAS), we conducted a Mendelian randomization (MR) study with two sample GWAS. Then, we used bidirectional MR to evaluate the association between H. pylori infection and CRC for identifying causation. The most common method of analysis was the inverse variance-weighted technique. In addition, we performed supplementary analyses using the weighted median technique and MR-Egger regression. Horizontal pleiotropic outliers were identified and corrected using the MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) method. Genetically predicted anti-H. pylori IgG seropositivity was not causally associated with CRC [odds ratio (OR): 1.12; 95% confidence interval (CI): 0.98-1.27, P = 0.08] and neither were H. pylori VacA antibody levels (OR = 0.96, 95% CI: 0.90-1.02, P = 0.25) or H. pylori CagA antibody levels (OR = 1.00, 95% CI: 0.93-1.07, P = 0.92). Furthermore, reverse MR analysis did not reveal evidence for a causal effect of CRC on H. pylori infection. The weighted median, the MR-Egger method, and MR-PRESSO yielded identical results. Using genetic data, MR analysis showed there was no evidence for a causal association between seroprevalence of H. pylori infection and CRC. The relationship between H. pylori infection and CRC requires further research.

Effects of Niaoduqing granules on inflammatory response of diabetic kidney disease: A meta­analysis.

Diabetic kidney disease (DKD) is one of the most severe chronic microvascular complications of diabetes and the leading cause of end-stage kidney disease worldwide. The mechanism of inflammation underlying DKD has been attracting attention over recent years, but effective therapeutic strategies have remained elusive. Niaoduqing (NDQ) granules are one of the most commonly used drugs for the treatment of DKD in China, and it has therapeutic effects against inflammation in DKD. Therefore, the aim of the present analysis was to evaluate the inflammatory response outcomes and safety of NDQ granules for the treatment of DKD. The following databases were searched from their inception to 31st of May 2023 to obtain published accounts of relevant randomized controlled trials: China National Knowledge Infrastructure, China Science and Technology Journal, Wanfang, The Chinese Biomedicine, PubMed, Web of Science and Cochrane Library. The 'risk of bias' evaluation tool produced by the Cochrane Collaboration Handbook was used for evaluating the quality, whereas Revman software (version 5.3) was used for meta-analysis. In total, 16 studies were included into the present study according to criteria, with a total of 1,526 patients. Compared with those in the control group, the results of the meta-analysis revealed that the combination of conventional treatment and NDQ granules may further decrease C-reactive protein [standardized mean difference (SMD), -1.33; 95% confidence interval (CI), -1.76, -0.91; P<0.00001], TNF-α (SMD, -1.90; 95% CI, -2.35,-1.45; P<0.00001) and IL-6 (SMD, -1.72; 95% CI, -2.52,-0.91; P<0.0001) levels, whilst increasing the clinical effective rate (risk ratio, 1.22; 95% CI, 1.14,1.29; P<0.00001), in patients with DKD. In terms of safety, a total of 34 and 39 patients included in the intervention and in the control group, respectively, developed adverse reactions. Results from the present analysis suggest that NDQ granules may be beneficial in suppressing inflammation caused by DKD when used in combination with conventional treatment, potentially guiding future directions in clinical practice. However, further high-quality studies are needed to confirm the anti-inflammation response in the future.

Integrated brain and plasma dual-channel metabolomics to explore the treatment effects of Alpinia oxyphyllaFructus on Alzheimer's disease.

Alpinia oxyphylla Fructus, called Yizhi in Chinese, is the dried fruit of Alpinia oxyphylla Miquel. It has been used in traditional Chinese medicine to treat dementia and memory defects of Alzheimer's disease for many years. However, the underlying mechanism is still unclear. In this study, we used a rat Alzheimer's disease model on intrahippocampal injection of aggregated Aß1-42 to study the effects of Alpinia oxyphylla Fructus. A brain and plasma dual-channel metabolomics approach combined with multivariate statistical analysis was further performed to determine the effects of Alpinia oxyphylla Fructus on Alzheimer's disease animals. As a result, in the Morris water maze test, Alpinia oxyphylla Fructus had a clear ability to ameliorate the impaired learning and memory of Alzheimer's disease rats. 11 differential biomarkers were detected in AD rats' brains. The compounds mainly included amino acids and phospholipids; after Alpinia oxyphylla Fructus administration, 9 regulated biomarkers were detected compared with the AD model group. In the plasma of AD rats, 29 differential biomarkers, primarily amino acids, phospholipids and fatty acids, were identified; After administration, 23 regulated biomarkers were detected. The metabolic pathways of regulated metabolites suggest that Alpinia oxyphylla Fructus ameliorates memory and learning deficits in AD rats principally by regulating amino acid metabolism, lipids metabolism, and energy metabolism. In conclusion, our results confirm and enhance our current understanding of the therapeutic effects of Alpinia oxyphylla Fructus on Alzheimer's disease. Meanwhile, our work provides new insight into the potential intervention mechanism of Alpinia oxyphylla Fructus for Alzheimer's disease treatment.

Huobahuagen tablet improves renal function in diabetic kidney disease: a real-world retrospective cohort study.

Objective: We aimed to explore the value of Huobahuagen tablet (HBT) in improving decreased renal function for patients with diabetic kidney disease (DKD) over time. Methods: This was a single-center, retrospective, real-world study on eligible 122 DKD patients who continued to use HBT + Huangkui capsule (HKC) therapy or HKC therapy without interruption or alteration in Jiangsu Province Hospital of Chinese Medicine from July 2016 to March 2022. The primary observation outcomes included estimated glomerular filtration rate (eGFR) at baseline and 1-, 3-, 6-, 9-, and 12-month follow-up visits and changes in eGFR from baseline (ΔeGFR). Propensity score (PS) and inverse probability treatment weighting (IPTW) were used to control for confounders. Results: eGFR was significantly higher in the HBT + HKC group than in the HKC alone group at the 6-, 9-, and 12-month follow-up visits (p = 0.0448, 0.0002, and 0.0037, respectively), indicating the superiority of HBT + HKC over HBT alone. Furthermore, the ΔeGFR of the HBT + HKC group was significantly higher than that of the HKC alone group at the 6- and 12-month follow-up visits (p = 0.0369 and 0.0267, respectively). In the DKD G4 patients, eGFR was higher in the HBT + HKC group at the 1-, 3-, 6-, 9-, and 12-month follow-up visits compared with baseline, with statistically significant differences at the 1-, 3-, and 6- month follow-up visits (p = 0.0256, 0.0069, and 0.0252, respectively). The fluctuations in ΔeGFR ranged from 2.54 ± 4.34 to 5.01 ± 5.55 ml/min/1.73 m2. Change in the urinary albumin/creatinine ratio from baseline did not exhibit a significant difference between the two groups at any of the follow-up visits (p > 0.05 for all). Adverse event incidence was low in both groups. Conclusion: The findings of this study based on real-world clinical practice indicate that HBT + HKC therapy exhibited better efficacy in improving and protecting renal function with a favorable safety profile than HKC therapy alone. However, further large-scale prospective randomized controlled trials are warranted to confirm these results.

Classification and characterisation of extracellular vesicles-related tuberculosis subgroups and immune cell profiles.

Around the world, tuberculosis (TB) remains one of the most common causes of morbidity and mortality. The molecular mechanism of Mycobacterium tuberculosis (Mtb) infection is still unclear. Extracellular vesicles (EVs) play a key role in the onset and progression of many disease states and can serve as effective biomarkers or therapeutic targets for the identification and treatment of TB patients. We analysed the expression profile to better clarify the EVs characteristics of TB and explored potential diagnostic markers to distinguish TB from healthy control (HC). Twenty EVs-related differentially expressed genes (DEGs) were identified, and 17 EVs-related DEGs were up-regulated and three DEGs were down-regulated in TB samples, which were related to immune cells. Using machine learning, a nine EVs-related gene signature was identified and two EVs-related subclusters were defined. The single-cell RNA sequence (scRNA-seq) analysis further confirmed that these hub genes might play important roles in TB pathogenesis. The nine EVs-related hub genes had excellent diagnostic values and accurately estimated TB progression. TB's high-risk group had significantly enriched immune-related pathways, and there were substantial variations in immunity across different groups. Furthermore, five potential drugs were predicted for TB using CMap database. Based on the EVs-related gene signature, the TB risk model was established through a comprehensive analysis of different EV patterns, which can accurately predict TB. These genes could be used as novel biomarkers to distinguish TB from HC. These findings lay the foundation for further research and design of new therapeutic interventions aimed at treating this deadly infectious disease.

Highly efficient nanocomposites based on molecularly imprinted magnetic covalent organic frameworks for selective extraction of bisphenol A from liquid matrices.

Highly efficient nanocomposites, hydrophobic molecularly imprinted magnetic covalent organic frameworks (MI-MCOF), have been farbricated by a facile Schiff-base reaction. The MI-MCOF was based on terephthalaldehyde (TPA) and 1,3,5-tris(4-aminophenyl) benzene (TAPB) as functional monomer and crosslinker, anhydrous acetic acid as catalyst, bisphenol AF as dummy template, and NiFe2O4 as magnetic core. This organic framework significantly reduced the time consumption of conventional imprinted polymerization and avoided the use of traditional initiator and cross-linking agents. The synthesized MI-MCOF exhibited superior magnetic responsivity and affinity, as well as high selectivity and kinetics for bisphenol A (BPA) in water and urine samples. The equilibrium adsorption capacity (Qe) of BPA on the MI-MCOF was 50.65 mg g-1, which was 3-7-fold higher than of its three structural analogues. The imprinting factor of BPA reached up to 3.17, and the selective coefficients of three analogues were all > 2.0, evidencing the excellent selectivity of fabricated nanocomposites to BPA. Based on the MI-MCOF nanocomposites, the magnetic solid-phase extraction (MSPE), combined with HPLC and fluorescence detection (HPLC-FLD), offered superior analytical performance: wide linear range of 0.1-100 µg L-1, high correlation coefficient of 0.9996, low limit of detection of 0.020 µg L-1, good recoveries of 83.5-110%, and relative standard deviations (RSDs) of 0.5-5.7% in environmental water, beverage, and human urine samples. Consequently, the MI-MCOF-MSPE/HPLC-FLD method provides a good prospect in selective extraction of BPA from complex matrices while replacing traditional magnetic separation and adsorption materials.

Classification of tuberculosis-related programmed cell death-related patient subgroups and associated immune cell profiling.

Background: Tuberculosis (TB) is the deadliest communicable disease in the world with the exception of the ongoing COVID-19 pandemic. Programmed cell death (PCD) patterns play key roles in the development and progression of many disease states such that they may offer value as effective biomarkers or therapeutic targets that can aid in identifying and treating TB patients. Materials and methods: The Gene Expression Omnibus (GEO) was used to gather TB-related datasets after which immune cell profiles in these data were analyzed to examine the potential TB-related loss of immune homeostasis. Profiling of differentially expressed PCD-related genes was performed, after which candidate hub PCD-associated genes were selected via a machine learning approach. TB patients were then stratified into two subsets based on the expression of PCD-related genes via consensus clustering. The potential roles of these PCD-associated genes in other TB-related diseases were further examined. Results: In total, 14 PCD-related differentially expressed genes (DEGs) were identified and highly expressed in TB patient samples and significantly correlated with the abundance of many immune cell types. Machine learning algorithms enabled the selection of seven hub PCD-related genes that were used to establish PCD-associated patient subgroups, followed by the validation of these subgroups in independent datasets. These findings, together with GSVA results, indicated that immune-related pathways were significantly enriched in TB patients exhibiting high levels of PCD-related gene expression, whereas metabolic pathways were significantly enriched in the other patient group. Single cell RNA-seq (scRNA-seq) further highlighted significant differences in the immune status of these different TB patient samples. Furthermore, we used CMap to predict five potential drugs for TB-related diseases. Conclusion: These results highlight clear enrichment of PCD-related gene expression in TB patients and suggest that this PCD activity is closely associated with immune cell abundance. This thus indicates that PCD may play a role in TB progression through the induction or dysregulation of an immune response. These findings provide a foundation for further research aimed at clarifying the molecular drivers of TB, the selection of appropriate diagnostic biomarkers, and the design of novel therapeutic interventions aimed at treating this deadly infectious disease.

Pharmacokinetic comparison of sitagliptin and metformin HCl extended-release tablets versus JANUMET® XR in healthy volunteers under fasting and fed conditions.

Background and Objectives: Janumet® XR is the combination of sitagliptin and extended metformin hydrochloride produced by Merck Sharp & Dohme. It is specially designed for diabetes mellitus patients taking both drugs already. Janumet® XR exhibited clinically significant blood glucose lowering efficacy and long-term use safety. However, no generic form of Janumet® XR has been approved in western countries. The relatively high cost made the medication less prescribed. A more affordable form of this drug may benefit an immense diabetes mellitus population. The current study compared the bioequivalence (BE) of sitagliptin 100 mg and metformin 1000 mg produced by Nanjing Chia-Tai Tianqing Pharmaceutical Company to Janumet® XR in healthy Chinese subjects. Methods: Twenty-eight healthy Chinese subjects were enrolled in Study 1 and 2, respectively. Both studies were conducted with an open, randomized, two-period crossover design using the test (T) or the reference (R) drug. Study 1 is conducted under the fasting state, and Study 2 is under the fed state. Subjects received an oral dose of sitagliptin 100 mg and metformin 1000 mg, and plasma concentrations of sitagliptin and metformin were determined up to 72 h post-dose. Pharmacokinetic (PK) parameters, including maximum serum concentration (Cmax) and area under the concentration-time curve up to the last quantifiable concentration (AUC0-t) of both sitagliptin and metformin, were calculated and compared between the T and R treatments. Results: In the fasting study, the geometric mean ratios of Cmax, AUC0-t, and AUC0-∞ for sitagliptin were 109.42%, 101.93%, and 101.95%, respectively; the corresponding ratios for metformin were 98.69%, 94.12%, and 93.42%, respectively. In the fed study, the geometric mean ratios of Cmax, AUC0-t, and AUC0-∞ for sitagliptin were 98.41%, 100.30%, and 100.24%, respectively; the corresponding ratios for metformin were 97.79%, 99.28%, and 100.69%, respectively. The 90% CIs of Cmax, AUC0-t, and AUC0-∞ in both studies were all within acceptance limits (80.00%-125.00%). Conclusion: The results demonstrated for the first time that sitagliptin 100 mg and metformin 1000 mg produced by Nanjing Chia-Tai Tianqing Pharmaceutical Company was bioequivalent to the branded Janumet® XR, and both drugs were well tolerated.