Fatty acid metabolism in neutrophils promotes lung damage and bacterial replication during tuberculosis.

Mycobacterium tuberculosis (Mtb) infection induces a marked influx of neutrophils into the lungs, which intensifies the severity of tuberculosis (TB). The metabolic state of neutrophils significantly influences their functional response during inflammation and interaction with bacterial pathogens. However, the effect of Mtb infection on neutrophil metabolism and its consequent role in TB pathogenesis remain unclear. In this study, we examined the contribution of glycolysis and fatty acid metabolism on neutrophil responses to Mtb HN878 infection using ex-vivo assays and murine infection models. We discover that blocking glycolysis aggravates TB pathology, whereas inhibiting fatty acid oxidation (FAO) yields protective outcomes, including reduced weight loss, immunopathology, and bacterial burden in lung. Intriguingly, FAO inhibition preferentially disrupts the recruitment of a pathogen-permissive immature neutrophil population (Ly6Glo/dim), known to accumulate during TB. Targeting carnitine palmitoyl transferase 1a (Cpt1a)-a crucial enzyme in mitochondrial ß-oxidation-either through chemical or genetic methods impairs neutrophils' ability to migrate to infection sites while also enhancing their antimicrobial function. Our findings illuminate the critical influence of neutrophil immunometabolism in TB pathogenesis, suggesting that manipulating fatty acid metabolism presents a novel avenue for host-directed TB therapies by modulating neutrophil functions.

Using a novel PSMA-PET and PSA-based model to enhance the diagnostic accuracy for clinically significant prostate cancer and avoid unnecessary biopsy in men with PI-RADS ≤ 3 MRI.

INTRODUCTION: The diagnostic evaluation of men with suspected prostate cancer (PCa) yet inconclusive MRI (PI-RADS ≤ 3) presents a common clinical challenge. [68Ga]Ga-labelled prostate-specific membrane antigen ([68Ga]Ga-PSMA) positron emission tomography/computed tomography (PET/CT) has shown promise in identifying clinically significant PCa (csPCa). We aim to establish a diagnostic model incorporating PSMA-PET to enhance the diagnostic process of csPCa in PI-RADS ≤ 3 men. MATERIALS AND METHODS: This study retrospective included 151 men with clinical suspicion of PCa and PI-RADS ≤ 3 MRI. All men underwent [68Ga]Ga-PSMA PET/CT scans and ultrasound/MRI/PET fusion-guided biopsies. csPCa was defined as Grade Group ≥ 2. PRIMARY-scores from PSMA-PET scans were evaluated. A diagnostic model incorporating PSMA-PET and prostate-specific antigen (PSA)-derived parameters was developed. The discriminative performance and clinical utility were compared with conventional methods. Internal validation was conducted using a fivefold cross-validation with 1000 iterations. RESULTS: In this PI-RADS ≤ 3 cohort, areas-under-the-curve (AUCs) for detecting csPCa were 0.796 (95%CI, 0.738-0.853), 0.851 (95%CI, 0.783-0.918) and 0.806 (95%CI, 0.742-0.870) for PRIMARY-score, SUVmax and routine clinical PSMA-PET assessment, respectively. The diagnostic model comprising PRIMARY-score, SUVmax and serum free PSA/total PSA (fPSA/tPSA) achieved a significantly higher AUC of 0.906 (95%CI, 0.851-0.961) compared to strategies based on PRIMARY-score or SUVmax (P < 0.05) and markedly superior to conventional strategies typically based on PSA density (P < 0.001). The average fivefold cross-validated AUC with 1000 iterations was 0.878 (95%CI, 0.820-0.954). Theoretically, using a threshold of 21.6%, the model could have prevented 78% of unnecessary biopsies while missing only 7.8% of csPCa cases in this cohort. CONCLUSIONS: A novel diagnostic model incorporating PSMA-PET derived metrics-PRIMARY-score and SUVmax-along with serum fPSA/tPSA, has been developed and validated. The integrated model may assist clinical decision-making with enhanced diagnostic accuracy over the individual conventional metrics. It has great potential to reduce unnecessary biopsies for men with PI-RADS ≤ 3 MRI results and warrants further prospective and external evaluations.

Characterization, expression and functional analysis of Hsp40 during LPS challenge in blood parrot Amphilophus citrinellus ×Vieja melanura.

Heat shock protein 40 belonging to heat shock protein family plays an important role in the immune responses of organisms. In this study, the full length cDNA of Hsp40 was 2426 bp including a 1368 bp open reading frame (ORF) encoding 455 amino acids with a molecular weight of 49.16 kDa and a theoretical isoelectric point of 9.34 in blood parrot Vieja synspila ♀ × Amphilophus citrinellus ♂, an important ornamental fish in China. It had three conserved domains DnaJ, CRR and DnaJ_C. Phylogenetic analysis showed that the sequence of Hsp40 among species was conserved, and the blood parrot Hsp40 was closely related to Neolamprologus brichardi. Blood parrot Hsp40 mRNA could be detected in all of the tissues examined and mainly distributed in the cytoplasm. The expression of Hsp40 was upregulated during lipopolysaccharide (LPS) challenge. Upregulated Hsp40 inhibited the activity of nuclear factor κB (NF-κB) and activated protein 1 (AP-1) and reduced the ratio of Bax/Bcl-2 mRNA expression. This study provides a theoretical basis for further exploring the role of Hsp40 gene in the anti-bacterial immunity of blood parrot.

Study on correlation between Chinese medicine syndromes in stroke and neurological deficits during recovery phase: Perspective.

Stroke is a leading cause of long-term disability and mortality worldwide, necessitating effective rehabilitation strategies for successful recovery. Traditional Chinese medicine (TCM) has gained recognition as a complementary and alternative approach in stroke rehabilitation, owing to its unique syndromes that offer valuable insights for personalized treatment plans. This study aims to elucidate the correlation between TCM syndromes observed during the recovery phase of stroke and the associated neurological deficits. Syndromes such as Blood stasis, Phlegm-dampness, Qi deficiency, and Yin deficiency were systematically examined, while standardized neurological assessments, encompassing motor function, sensory perception, and cognitive abilities, were employed to evaluate the extent of neurological impairment. Rigorous statistical analyses were conducted to discern potential correlations between TCM syndromes and the severity of neurological deficits. The results revealed statistically significant positive associations between certain TCM syndromes, particularly Blood stasis and Phlegm-dampness, and heightened neurological deficits during the recovery phase post-stroke. These findings suggest that these syndromes may serve as indicators of more severe brain injury post-stroke, thereby guiding the development of tailored rehabilitation strategies. By establishing robust connections between TCM syndromes and neurological deficits, this study contributes to advancing our understanding of stroke recovery through an integrated approach that incorporates TCM principles. Moreover, it underscores the potential benefits of integrating TCM into conventional rehabilitation protocols, offering valuable insights for healthcare professionals and potentially improving patient outcomes.

Human 8-oxoguanine glycosylase OGG1 binds nucleosome at the dsDNA ends and the super-helical locations.

The human glycosylase OGG1 extrudes and excises the oxidized DNA base 8-oxoguanine (8-oxoG) to initiate base excision repair and plays important roles in many pathological conditions such as cancer, inflammation, and neurodegenerative diseases. Previous structural studies have used a truncated protein and short linear DNA, so it has been unclear how full-length OGG1 operates on longer DNA or on nucleosomes. Here we report cryo-EM structures of human OGG1 bound to a 35-bp long DNA containing an 8-oxoG within an unmethylated Cp-8-oxoG dinucleotide as well as to a nucleosome with an 8-oxoG at super-helical location (SHL)-5. The 8-oxoG in the linear DNA is flipped out by OGG1, consistent with previous crystallographic findings with a 15-bp DNA. OGG1 preferentially binds near dsDNA ends at the nucleosomal entry/exit sites. Such preference may underlie the enzyme's function in DNA double-strand break repair. Unexpectedly, we find that OGG1 bends the nucleosomal entry DNA, flips an undamaged guanine, and binds to internal nucleosomal DNA sites such as SHL-5 and SHL+6. We suggest that the DNA base search mechanism by OGG1 may be chromatin context-dependent and that OGG1 may partner with chromatin remodelers to excise 8-oxoG at the nucleosomal internal sites.

Multiple Localization Analysis of the Major QTL-sfw 2.2 for Controlling Single Fruit Weight Traits in Melon Based on SLAF Sequencing.

Cucumis melo is an annual dicotyledonous trailing herb. It is fruity, cool, and refreshing to eat and is widely loved by consumers worldwide. The single fruit weight is an important factor affecting the yield, and thus the income and economic benefits, of melon crops. In this study, to identify the main QTLs (quantitative trait locus) controlling the single fruit weight of melon and thereby identify candidate genes controlling this trait, specific-locus amplified fragment sequencing (SLAF) analysis was performed on the offspring of female 1244 plants crossed with male MS-5 plants. A total of 115 individual plants in the melon F2 population were analyzed to construct a genetic linkage map with a total map distance of 1383.88 cM by the group in the early stages of the project, which was divided into 12 linkage groups with a total of 10,596 SLAF markers spaced at an average genetic distance of 0.13 cM. A total of six QTLs controlling single fruit weight (sfw loci) were detected. Seven pairs of markers with polymorphisms were obtained by screening candidate intervals from the SLAF data. The primary QTL sfw2.2 was further studied in 300 F2:3 family lines grown in 2020 and 2021, respectively, a positioning sfw2.2 between the markers CY Indel 11 and CY Indel 16, between 18,568,142 and 18,704,724 on chromosome 2. This interval contained 136.58 kb and included three genes with functional annotations, MELO3C029673, MELO3C029669, and MELO3C029674. Gene expression information for different fruit development stages was obtained from 1244 and MS-5 fruits on the 15d, 25d, and 35d after pollination, and qRT-PCR (quantitative reverse transcription-PCR) indicated that the expression of the MELO3C029669 gene significantly differed between the parents during the three periods. The gene sequences between the parents of MELO3C029669 were analyzed and compared, a base mutation was found to occur in the intronic interval between the parents of the gene, from A-G. Phylogenetic evolutionary tree analysis revealed that the candidate gene MELO3C029669 is most closely related to Pisum sativum Fimbrin-5 variant 2 and most distantly related to Cucumis melo var. makuwa. Therefore, it was hypothesized that MELO3C029669 is the primary major locus controlling single fruit weight in melon. These results not only provide a theoretical basis for further studies to find genes with functions in melon single fruit weight but also lay the foundation for accelerating breakthroughs and innovations in melon breeding.

SIRT7 remodels the cytoskeleton via RAC1 to enhance host resistance to Mycobacterium tuberculosis.

Phagocytosis of Mycobacterium tuberculosis (Mtb) followed by its integration into the matured lysosome is critical in the host defense against tuberculosis. How Mtb escapes this immune attack remains elusive. In this study, we unveiled a novel regulatory mechanism by which SIRT7 regulates cytoskeletal remodeling by modulating RAC1 activation. We discovered that SIRT7 expression was significantly reduced in CD14+ monocytes of TB patients. Mtb infection diminished SIRT7 expression by macrophages at both the mRNA and protein levels. SIRT7 deficiency impaired actin cytoskeleton-dependent macrophage phagocytosis, LC3II expression, and bactericidal activity. In a murine tuberculosis model, SIRT7 deficiency detrimentally impacted host resistance to Mtb, while Sirt7 overexpression significantly increased the host defense against Mtb, as determined by bacterial burden and inflammatory-histopathological damage in the lung. Mechanistically, we demonstrated that SIRT7 limits Mtb infection by directly interacting with and activating RAC1, through which cytoskeletal remodeling is modulated. Therefore, we concluded that SIRT7, in its role regulating cytoskeletal remodeling through RAC1, is critical for host responses during Mtb infection and proposes a potential target for tuberculosis treatment.IMPORTANCETuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a significant global health issue. Critical to macrophages' defense against Mtb is phagocytosis, governed by the actin cytoskeleton. Previous research has revealed that Mtb manipulates and disrupts the host's actin network, though the specific mechanisms have been elusive. Our study identifies a pivotal role for SIRT7 in this context: Mtb infection leads to reduced SIRT7 expression, which, in turn, diminishes RAC1 activation and consequently impairs actin-dependent phagocytosis. The significance of our research is that SIRT7 directly engages with and activates Rac Family Small GTPase 1 (RAC1), thus promoting effective phagocytosis and the elimination of Mtb. This insight into the dynamic between host and pathogen in TB not only broadens our understanding but also opens new avenues for therapeutic development.

Metal Effect on the Proton Conduction of Three Isostructural Metal-Organic Frameworks and Pseudo-Capacitance Behavior of the Cobalt Analogue.

Three isostructural transition metal-organic frameworks, [M(bta)0.5(bpt)(H2O)2]·2H2O (M = Co (1), Ni (2), Zn (3), H4bta = 1,2,4,5-benzenetetracarboxylic acid, bpt = 4-amino-3,5-bis(4-pyridyl)-1,2,4-triazole), were successfully constructed using different metal cations. These frameworks exhibit a three-dimensional network structure with multiple coordinated and lattice water molecules within the framework, contributing to high stability and a rich hydrogen-bond network. Proton conduction studies revealed that, at 333 K and 98% relative humidity, the proton conductivities (σ) of MOFs 1-3 reached 1.42 × 10-2, 1.02 × 10-2, and 6.82 × 10-3 S cm-1, respectively. Compared to the proton conductivity of the initial ligands, the σ values of the complexes increased by 2 orders of magnitude, with the activation energies decreasing from 0.36 to 0.18 eV for 1, 0.09 eV for 2, and 0.12 eV for 3. An in-depth analysis of the correlation between different metal centers and proton conduction performance indicated that the varying coordination abilities of the metal cations and the water absorption capacities of the frameworks might account for the differences in conductivity. Additionally, the potential of 1 as a supercapacitor electrode material was assessed. 1 exhibited a specific capacitance of 61.13 F g-1 at a current density of 0.5 A g-1, with a capacitance retention of 82.4% after 5000 cycles, making it a promising candidate for energy storage applications.

Enhance the Antimycobacterial Activity of Streptomycin with Ebselen as an Antibiotic Adjuvant Through Disrupting Redox Homeostasis.

Purpose: Tuberculosis (TB) remains a major health threat worldwide, and the spread of drug-resistant (DR) TB impedes the reduction of the global disease burden. Ebselen (EbSe) targets bacterial thioredoxin reductase (bTrxR) and causes an imbalance in the redox status of bacteria. Previous work has shown that the synergistic action of bTrxR and sensitization to common antibiotics by EbSe is a promising strategy for the treatment of DR pathogens. Thus, we aimed to evaluate whether EbSe could enhance anti-TB drugs against Mycobacterium marinum (M. marinum) which is genetically related to Mycobacterium tuberculosis (Mtb) and resistant to many antituberculosis drugs. Methods: Minimum inhibitory concentrations (MIC) of isoniazid (INH), rifampicin (RFP), and streptomycin (SM) against M. marinum were determined by microdilution. The Bliss Independence Model was used to determine the adjuvant effects of EbSe over the anti-TB drugs. Thioredoxin reductase activity was measured using the DTNB assay, and its effects on bacterial redox homeostasis were verified by the elevation of intracellular ROS levels and intracellular GSH levels. The adjuvant efficacy of EbSe as an anti-TB drug was further evaluated in a mouse model of M. marinum infection. Cytotoxicity was observed in the macrophage cells Raw264.7 and mice model. Results: The results reveal that EbSe acts as an antibiotic adjuvant over SM on M. marinum. EbSe + SM disrupted the intracellular redox microenvironment of M. marinum by inhibiting bTrxR activity, which could rescue mice from the high bacterial load, and accelerated recovery from tail injury with low mammalian toxicity. Conclusion: The above studies suggest that EbSe significantly enhanced the anti-Mtb effect of SM, and its synergistic combination showed low mammalian toxicity in vitro and in vivo. Further efforts are required to study the underlying mechanisms of EbSe as an antibiotic adjuvant in combination with anti-TB drug MS.

Long-term outcomes of subthalamic nucleus deep brain stimulation for Parkinson's disease in Singapore.

Introduction: Subthalamic nucleus deep brain stimulation (STN-DBS) is a proven treatment modality for Parkinson's disease (PD), reducing dyskinesia and time spent in the "OFF" state. This study evaluates the long-term outcomes of STN-DBS in PD patients up to 10 years post-surgery in Singapore. Method: We conducted a retrospective review of Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores, activities of daily living (ADLs), disease milestones, dopaminergic drug prescriptions, and adverse events in patients before and after STN-DBS surgery. Results: A total of 94 PD patients who underwent bilateral STN-DBS were included. STN-DBS reduced time in the "OFF" state by 36.9% at 1 year (P=0.034) and 40.9% at 5 years (P=0.006). Time with dyskinesia did not significantly change. Levodopa equivalent daily dose was reduced by 35.1% by 5 years (P<0.001). MDS-UPDRS-II and III scores increased from 5 years post-DBS by 40.5% and 35.4%, respectively. Independence in ADLs decreased, though not significantly. The prevalence of frequent falls increased at 5 years. Surgery- and device-related adverse events were uncommon and generally mild. Conclusion: STN-DBS provides sustained relief from motor complications and reduced medication requirements in PD patients in Singapore. This study highlights STN-DBS as an effective treatment option, significantly enhancing the quality of life for those with PD.

Evaluation of the effect of fluid management on intracranial pressure in patients undergoing laparoscopic gynaecological surgery based on the ratio of the optic nerve sheath diameter to the eyeball transverse diameter as measured by ultrasound: a randomised controlled trial.

BACKGROUND: During gynecological laparoscopic surgery, pneumoperitoneum and the Trendelenburg position (TP) can lead to increased intracranial pressure (ICP). However, it remains unclear whether perioperative fluid therapy impacts ICP. The purpose of this research was to evaluate the impact of restrictive fluid (RF) therapy versus conventional fluid (CF) therapy on ICP in gynecological laparoscopic surgery patients by measuring the ratio of the optic nerve sheath diameter (ONSD) to the eyeball transverse diameter (ETD) using ultrasound. METHODS: Sixty-four patients who were scheduled for laparoscopic gynecological surgery were randomly assigned to the CF group or the RF group. The main outcomes were differences in the ONSD/ETD ratios between the groups at predetermined time points. The secondary outcomes were intraoperative circulatory parameters (including mean arterial pressure, heart rate, and urine volume changes) and postoperative recovery indicators (including extubation time, length of post-anaesthesia care unit stay, postoperative complications, and length of hospital stay). RESULTS: There were no statistically significant differences in the ONSD/ETD ratio and the ONSD over time between the two groups (all p > 0.05). From T2 to T4, the ONSD/ETD ratio and the ONSD in both groups were higher than T1 (all p < 0.001). From T1 to T2, the ONSD/ETD ratio in both groups increased by 14.3%. However, the extubation time in the RF group was shorter than in the CF group [median difference (95% CI) -11(-21 to -2) min, p = 0.027]. There were no differences in the other secondary outcomes. CONCLUSION: In patients undergoing laparoscopic gynecological surgery, RF did not significantly lower the ONSD/ETD ratio but did shorten the tracheal extubation time, when compared to CF. TRIAL REGISTRATION: ChiCTR2300079284. Registered on December 29, 2023.

Batteries Within Diabetes Devices: A Narrative Review on Recycling, Environmental, and Sustainability Perspective.

The adoption of diabetes technology for the management of type 1 and insulin-treated type 2 diabetes has greatly increased. The annual volume of discarded continuous glucose monitoring (CGM) devices, considering only Dexcom and Freestyle Libre brands, totals more than 153 million units and Omnipod® contributes an additional estimated 43.8 million units.Although these technologies are clinically effective, their environmental impact is unknown. Batteries are a pivotal, yet often overlooked, component in diabetes technologies and can exert a detrimental impact on the environment.In this commentary article, we explore the environmental impact of batteries used in diabetes devices. Furthermore, we highlight various strategies, including recycling of used batteries and alternative design approaches, that may reduce the environmental burden, as they become the ubiquitous standard of care for people with diabetes.

Comparative Genomics Screens Identify a Novel Small Secretory Peptide, SlSolP12, which Activates Both Local and Systemic Immune Response in Tomatoes and Exhibits Broad-Spectrum Activity.

Small secreted peptides (SSPs) are essential for defense mechanisms in plant-microbe interactions, acting as danger-associated molecular patterns (DAMPs). Despite the first discovery of SSPs over three decades ago, only a limited number of SSP families, particularly within Solanaceae plants, have been identified due to inefficient approaches. This study employed comparative genomics screens with Solanaceae proteomes (tomato, tobacco, and pepper) to discover a novel SSP family, SolP. Bioinformatics analysis suggests that SolP may serve as an endogenous signal initiating the plant PTI response. Interestingly, SolP family members from tomato, tobacco, and pepper share an identical sequence (VTSNALALVNRFAD), named SlSolP12 (also referred to as NtSolP15 or CaSolP1). Biochemical and phenotypic analyses revealed that synthetic SlSolP12 peptide triggers multiple defense responses: ROS burst, MAPK activation, callose deposition, stomatal closure, and expression of immune defense genes. Furthermore, SlSolP12 enhances systemic resistance against Botrytis cinerea infection in tomato plants and interferes with classical peptides, flg22 and Systemin, which modulate the immune response. Remarkably, SolP12 activates ROS in diverse plant species, such as Arabidopsis thaliana, soybean, and rice, showing a broad spectrum of biological activities. This study provides valuable approaches for identifying endogenous SSPs and highlights SlSolP12 as a novel DAMP that could serve as a useful target for crop protection.

Cell Penetrating Peptide Enhances the Aphidicidal Activity of Spider Venom-Derived Neurotoxin.

HxTx-Hv1h, a neurotoxic peptide derived from spider venom, has been developed for use in commercial biopesticide formulations. Cell Penetrating Peptides (CPPs) are short peptides that facilitate the translocation of various biomolecules across cellular membranes. Here, we evaluated the aphidicidal efficacy of a conjugated peptide, HxTx-Hv1h/CPP-1838, created by fusing HxTx-Hv1h with CPP-1838. Additionally, we aimed to establish a robust recombinant expression system for HxTx-Hv1h/CPP-1838. We successfully achieved the secretory production of HxTx-Hv1h, its fusion with Galanthus nivalis agglutinin (GNA) forming HxTx-Hv1h/GNA and HxTx-Hv1h/CPP-1838 in yeast. Purified HxTx-Hv1h exhibited contact toxicity against Megoura crassicauda, with a 48 h median lethal concentration (LC50) of 860.5 µg/mL. Fusion with GNA or CPP-1838 significantly enhanced its aphidicidal potency, reducing the LC50 to 683.5 µg/mL and 465.2 µg/mL, respectively. The aphidicidal efficacy was further improved with the addition of surfactant, decreasing the LC50 of HxTx-Hv1h/CPP-1838 to 66.7 µg/mL-over four times lower compared to HxTx-Hv1h alone. Furthermore, we engineered HxTx-Hv1h/CPP-1838 multi-copy expression vectors utilizing the BglBrick assembly method and achieved high-level recombinant production in laboratory-scale fermentation. This study is the first to document a CPP fusion strategy that enhances the transdermal aphidicidal activity of a natural toxin like HxTx-Hv1h and opens up the possibility of exploring the recombinant production of HxTx-Hv1h/CPP-1838 for potential applications.

Integrating pathogen- and host-derived blood biomarkers for enhanced tuberculosis diagnosis: a comprehensive review.

This review explores the evolving landscape of blood biomarkers in the diagnosis of tuberculosis (TB), focusing on biomarkers derived both from the pathogen and the host. These biomarkers provide critical insights that can improve diagnostic accuracy and timeliness, essential for effective TB management. The document highlights recent advancements in molecular techniques that have enhanced the detection and characterization of specific biomarkers. It also discusses the integration of these biomarkers into clinical practice, emphasizing their potential to revolutionize TB diagnostics by enabling more precise detection and monitoring of the disease progression. Challenges such as variability in biomarker expression and the need for standardized validation processes are addressed to ensure reliability across different populations and settings. The review calls for further research to refine these biomarkers and fully harness their potential in the fight against TB, suggesting a multidisciplinary approach to overcome existing barriers and optimize diagnostic strategies. This comprehensive analysis underscores the significance of blood biomarkers as invaluable tools in the global effort to control and eliminate TB.

[Action mechanism of Huotu Jiji Pellets in the treatment of erectile dysfunction: An exploration based on network pharmacology and molecular docking].

OBJECTIVE: To explore the potential action mechanism of Huotu Jiji Pellets (HJP) in the treatment of erectile dysfunction (ED) based on network pharmacology and molecular docking. METHODS: We identified the main effective compounds and active molecular targets of HJP from the database of Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Integrative Pharmacology-Based Research Platform of Traditional Chinese Medicine (TCMIP) and the therapeutic target genes of ED from the databases of Genecards. Then we obtained the common targets of HJP and ED using the Venny software, constructed a protein-protein interaction (PPI) network of HJP acting on ED, and screened out the core targets with the Cytoscape software. Lastly we performed GO functional enrichment and KEGG pathway enrichment analyses of the core targets followed by molecular docking of HJP and the core targets using Chem3D and AutoDock Tools and QuickVina-W software. RESULTS: A total of 64 effective compounds, 822 drug-related targets, 1 783 disease-related targets and 320 common targets were obtained in this study. PPI network analysis showed that the core targets of HJP for ED included ESR1, HSP90AA1, SRC, and STAT3. GO functional enrichment analysis indicated the involvement of the core targets in such biological processes as response to xenobiotic stimulus, positive regulation of kinase activity, and positive regulation of MAPK cascade. KEGG pathway enrichment analysis suggested that PI3K-Akt, apoptosis, MAPK, HIF-1, VEGF, autophagy and other signaling pathways may be related to the mechanism of HJP acting on ED. Molecular docking prediction exhibited a good docking activity of the key active molecules of HJP with the core targets. CONCLUSION: This study showed that HJP acted on ED through multi-components, multi-targets and multi-pathways, which has provided some evidence and reference for the clinical treatment and subsequent studies of the disease.

Platelet-rich plasma ameliorates cartilage degradation in rat models of osteoarthritis via the OPG/RANKL/RANK system.

INTRODUCTION: Osteoarthritis (OA) is one of the most common degenerative joint diseases in the elderly, which is featured by the degradation of articular cartilage. Recently, platelet-rich plasma (PRP) injection into the affected joint has become one biological therapy for OA treatment. The OPG/RANKL/RANK signalling has been reported to mediate OA progression. Our study aimed to confirm whether PRP injection retards OA development through the regulation of the OPG/RANKL/RANK system. MATERIAL AND METHODS: The OA rat models were induced by medial menisci resection combined with anterior cruciate ligament transection. Four weeks after surgery, OA-induced rats received intra-articular injection with 50 µL PRP once a week for 6 weeks. Rats were euthanised one week after the 6th injection. Rat knee joints were subjected to histopathological examination by haematoxylin-eosin (H&E) and safranin O staining. Osteoprotegerin (OPG), receptor activator of nuclear factor kappaB (RANK), and RANK ligand (RANKL) in the articular cartilage of rats were tested through immunofluorescence staining and western blotting. Serum interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) levels were measured by enzyme-linked immunosorbent assay (ELISA). Matrix metalloproteinase-13 (MMP-13), aggrecan, collagen Ⅱ, IL-1ß, IL-6, tumour necrosis factor-alpha (TNF-α), and nuclear factor kappa-B (NF-κB) mRNA and protein expression in rat articular cartilage were examined by real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. RESULTS: Intra-articular injections of PRP significantly improved the structural integrity of the articular cartilage and enhanced the synthesis of glycosaminoglycans. PRP reduced MMP-13 protein level but increased aggrecan and collagen Ⅱ protein levels in articular cartilage of OA rats. OA-induced increase in serum IL-1ß, IL-6, and TNF-α concentrations as well as increased MMP-13, and decreased collagen II mRNA levels were reversed by the administration of PRP. OA increased IL-1ß, TNF-α, and NF-κB mRNA expression in rat articular cartilage whereas PRP administration ameliorated these changes. Moreover, in the articular tissue of OA-induced rats the increased OPG protein level was further elevated by PRP injections whereas the protein level of RANK did not change. The increase in the protein level of RANKL in OA-induced articular tissue was offset by PRP administration. PRP elevated OPG mRNA expression and the OPG/RANKL mRNA ratio, but reduced RANKL mRNA expression and the RANKL/RANK mRNA ratio in the articular tissue of OA-induced rats. CONCLUSIONS: PRP mitigates cartilage degradation and inflammation in experimental knee OA by regulating the OPG/RANKL/RANK signalling system.

Cord blood vitamin A and vitamin D levels in relation to physical growth in exclusively breastfed infants aged 0-6 months.

Background: Vitamins A and D are essential for the health of pregnant women and infants. Nevertheless, the relationship between umbilical cord blood vitamins A and D levels and the physical growth of exclusively breastfed infants remains uncertain. Objective: This cohort study aims to examine the relationship between cord blood vitamins A and D levels and the physical growth of exclusively breastfed infants aged 0-6 months. Methods: 140 singleton mother-infant pairs were recruited in total. Questionnaires were used to collect maternal and infant information, and liquid chromatography was utilized to quantify the levels of vitamins A and D in the umbilical cord blood. Anthropometric measurements were conducted at birth, at 3 and 6 months of age, and the weight-for-age z-score (WAZ), length-for-age z-score (LAZ), head circumference-for-age z-score (HAZ), and BMI-for-age z-score (BMIZ) were calculated. Univariate and multivariate linear regression models were used for the analysis. Results: The average concentration of vitamins A and D in cord blood was 0.58 ± 0.20 µmol/L and 34.07 ± 13.35 nmol/L, both below the normal range for children. After adjusting for confounding factors, vitamin A levels in cord blood positively correlated with HAZ growth in infants aged 3-6 months (ß= 0.75, P < 0.01) while vitamin D levels negatively correlated with LAZ growth (ß= -0.01, P = 0.01) and positively correlated with BMIZ growth (ß= 0.02, P < 0.01). Conclusion: Higher Vitamin A levels at birth promote HAZ growth in infants aged 3-6 months while higher vitamin D levels at birth promote BMIZ growth in infants aged 3-6 months. Clinical trial registration: https://register.clinicaltrials.gov, identifier NCT04017286.

Quintom cosmology and modified gravity after DESI 2024.

We reconstruct the cosmological background evolution under the scenario of dynamical dark energy through the Gaussian process approach, using the latest Dark Energy Spectroscopic Instrument (DESI) baryon acoustic oscillations (BAO) combined with other observations. Our results reveal that the reconstructed dark-energy equation-of-state (EoS) parameter w(z) exhibits the so-called quintom-B behavior, crossing -1 from phantom to quintessence regime as the universe expands. We investigate under what situation this type of evolution could be achieved from the perspectives of field theories and modified gravity. In particular, we reconstruct the corresponding actions for f(R),f(T), and f(Q) gravity, respectively. We explicitly show that, certain modified gravity can exhibit the quintom dynamics and fit the recent DESI data efficiently, and for all cases the quadratic deviation from the ΛCDM scenario is mildly favored.

Feasibility study of ADCs targeting TROP-2, HER2, and CD46 in Ductal Adenocarcinoma and Intraductal Carcinoma of the prostate.

BACKGROUND: Ductal Adenocarcinoma (DAC) and Intraductal Carcinoma of the Prostate (IDC-P) respond poorly to all the currently available conventional therapies. Given their accurate and efficient elimination of cancer cells, Antibody-Drug Conjugates (ADCs) have become one of the most promising anticancer treatments. However, no ADCs have so far been approved for Prostate Cancer (PCa) treatment. This study investigated TROP-2, HER2, and CD46 expression in DAC/IDC-P samples, indirectly analyzing their preliminary feasibility as therapeutic targets for future treatment of the two conditions. PATIENTS AND METHODS: We conducted a retrospective study involving 184 participants (87 DAC/IDC-P patients and 97 Prostatic Acinar Adenocarcinoma (PAC) patients with a Gleason score ≥ 8) without prior treatment between August 2017 and August 2022. Immunohistochemical staining was employed to detect the differential protein expressions of TROP-2, HER2, and CD46 in DAC/IDC-P, PAC, and normal prostate tissues. RESULTS: Compared to pure PAC tissues, TROP-2 expression was significantly higher in DAC/IDC-P and DAC/IDC-P-adjacent PAC tissues (H-score 68.8 vs. 43.8, p < 0.001, and 59.8 vs. 43.8, p = 0.022, respectively). No significant differences in HER2 expression were observed across different cancer tissues. Compared to both DAC/IDC-P-adjacent PAC and pure PAC tissues, CD46 expression was significantly higher in DAC/IDC-P tissues (42.3 vs. 28.6, p = 0.041, and 42.3 vs. 24.3, p = 0.0035, respectively). CONCLUSIONS: Herein, TROP-2 and CD46 expression was higher in DAC/IDC-P tissues than in pure PAC and normal prostate tissues. This finding implies that ADCs targeting the two proteins hold significant promise as potential future treatments for DAC/IDC-P.