Preparation of near-infrared photoacoustic imaging and photothermal treatment agent for cancer using a modifiable acid-triggered molecular platform.

Ratiometric near-infrared fluorescent pH probes with various pKa values were innovatively designed and synthesized based on cyanine with a diamine moiety. The photochemical properties of these probes were thoroughly evaluated. Among the series, IR-PHA exhibited an optimal pKa value of approximately 6.40, closely matching the pH of cancerous tissues. This feature is particularly valuable for real-time pH monitoring in both living cells and living mice. Moreover, when administered intravenously to tumor-bearing mice, IR-PHA demonstrated rapid and significant enhancement of near-infrared fluorescence and photoacoustic signals within the tumor region. This outcome underscores the probe's exceptional capability for dual-modal cancer imaging utilizing near-infrared fluorescence (NIRF) and photoacoustic (PA) modalities. Concurrently, the application of a continuous-wave near-infrared laser efficiently ablated cancer cells in vivo, attributed to the photothermal effect induced by IR-PHA. The results strongly indicate that IR-PHA is well-suited for NIRF/PA dual-modality imaging and photothermal therapy of tumors. This makes it a promising candidate for theranostic applications involving small molecules.

N6-methyladenosine modification of KLF2 may contribute to endothelial-to-mesenchymal transition in pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a progressive disease characterized by pulmonary vascular remodeling. Increasing evidence indicates that endothelial-to-mesenchymal transition (EndMT) in pulmonary artery endothelial cells (PAECs) is a pivotal trigger initiating this remodeling. However, the regulatory mechanisms underlying EndMT in PH are still not fully understood. METHODS: Cytokine-induced hPAECs were assessed using RNA methylation quantification, qRT-PCR, and western blotting to determine the involvement of N6-methyladenosine (m6A) methylation in EndMT. Lentivirus-mediated silencing, overexpression, tube formation, and wound healing assays were utilized to investigate the function of METTL3 in EndMT. Endothelial-specific gene knockout, hemodynamic measurement, and immunostaining were performed to explore the roles of METTL3 in pulmonary vascular remodeling and PH. RNA-seq, RNA Immunoprecipitation-based qPCR, mRNA stability assay, m6A mutation, and dual-luciferase assays were employed to elucidate the mechanisms of RNA methylation in EndMT. RESULTS: The global levels of m6A and METTL3 expression were found to decrease in TNF-α- and TGF-ß1-induced EndMT in human PAECs (hPAECs). METTL3 inhibition led to reduced endothelial markers (CD31 and VE-cadherin) and increased mesenchymal markers (SM22 and N-cadherin) as well as EndMT-related transcription factors (Snail, Zeb1, Zeb2, and Slug). The endothelial-specific knockout of Mettl3 promoted EndMT and exacerbated pulmonary vascular remodeling and hypoxia-induced PH (HPH) in mice. Mechanistically, METTL3-mediated m6A modification of kruppel-like factor 2 (KLF2) plays a crucial role in the EndMT process. KLF2 overexpression increased CD31 and VE-cadherin levels while decreasing SM22, N-cadherin, and EndMT-related transcription factors, thereby mitigating EndMT in PH. Mutations in the m6A site of KLF2 mRNA compromise KLF2 expression, subsequently diminishing its protective effect against EndMT. Furthermore, KLF2 modulates SM22 expression through direct binding to its promoter. CONCLUSIONS: Our findings unveil a novel METTL3/KLF2 pathway critical for protecting hPAECs against EndMT, highlighting a promising avenue for therapeutic investigation in PH.

A real-world pharmacovigilance study of FDA Adverse Event Reporting System (FAERS) events for Bruton's tyrosine kinase inhibitors (BTKis) single and its combination therapy.

BACKGROUND: Bruton's tyrosine kinase inhibitors (BTKis) are targeted treatments for B-cell tumors but have significant side effects. This study assesses and contrasts the side effects of BTKis alone and its four combination therapies. RESEARCH DESIGN AND METHODS: The reporting odds ratio (ROR) was used to analyze the data on three BTKis monotherapies and combinations of ibrutinib with rituximab, obinutuzumab, venetoclax, and lenalidomide in the FDA Adverse Event Reporting System (FAERS) database up to December 2022. RESULTS: We analyzed the top 20 PTs for each treatment regimen. In monotherapies, atrial fibrillation (ROR (95% CI): 9.88 (9.47-10.32)) in zanubrutinib and rash (6.97 (5.42-8.98)) in acalabrutinib had higher associations. In combinations, infection (6.86 (6.11-7.70)), atrial fibrillation (27.96 (22.61-34.58)) and myelosuppression (10.09 (8.89-11.46)) were vital signals when ibrutinib was combined with obinutuzumab, and pyrexia (4.22 (2.57-6.93)) had a high signal value when combined with lenalidomide. Hemorrhage had a lower signal value when combined with venetoclax compared to ibrutinib alone (2.50 (2.18-2.87) vs 3.60 (3.52-3.68)). CONCLUSIONS: The ibrutinib-obinutuzumab combo has the highest risk of infection, atrial fibrillation, and myelosuppression, and the ibrutinib-lenalidomide combo has the highest risk of pyrexia. However, the ibrutinib-venetoclax combo has a lower risk of hemorrhage than monotherapy.

A rare case of daratumumab-associated encephalopathy in multiple myeloma.

Aim: Daratumumab, a CD38 monoclonal antibody, has been widely used in patients with multiple myeloma. Although a variety of adverse events have been reported, consciousness impairment has not been reported yet. We report a case of encephalopathy associated with daratumumab. Case presentation: A 57-year-old male, diagnosed with relapsed multiple myeloma, was treated with daratumumab. He developed a loss of consciousness after the first administration. Cerebral spinal fluid and magnetic resonance imaging of the brain suggested encephalopathy. Conclusion: It is recommended to be aware of rare but life threatening side effects of daratumumab. We present a case of rare encephalopathy characterized by consciousness disorder associated with daratumumab, which was successfully resolved on prompt institution of steroids, although the mechanism was unknown.

Daratumumab is a drug. It is used to treat multiple myeloma. Many patients use this drug. It has many side effects. But consciousness disorder is rare. A 57-year-old male was diagnosed with multiple myeloma. He was treated with daratumumab. He became unconscious after this treatment. Steroids helped his recovery.

Mn-Co-Ce/biochar based particles electrodes for removal of COD from coking wastewater by 3D/HEFL system: Characteristics, optimization, and mechanism.

In this work, the Mn, Co, Ce co-doped corn cob biochar (MCCBC) as catalytic particle electrodes in a three-dimensional heterogeneous electro-Fenton-like (3D-HEFL) system for the efficient degradation of coking wastewater was investigated. Various characterization methods such as SEM, EDS, XRD, XPS and electrochemical analysis were employed for the prepared materials. The results showed that the MCCBC particle electrodes had excellent electrochemical degradation performances of COD in coking wastewater, and the COD removal and degradation rates of the 3D/HEFL system were 85.35% and 0.0563 min-1 respectively. RSM optimized conditions revealed higher COD removal rate at 89.23% after 31.6 min of electrolysis. The efficient degradability and wide adaptability of the 3D/HEFL system were due to its beneficial coupling mechanism, including the synergistic effect between the system factors (3D and HEFL) as well as the synergistic interactions between the ROS (dominated by •OH and supplemented by O2•-) in the system. Moreover, the COD removal rate of MCCBC could still remain at 81.41% after 5 cycles with a lower ion leaching and a specific energy consumption of 11.28 kWh kg-1 COD. The superior performance of MCCBC, as catalytic particle electrodes showed a great potential for engineering applications for the advanced treatment of coking wastewater.

46, XX disorder of sexual development associated with mixed germ cell tumor of the prostate: a rare case report.

BACKGROUND: Extragonadal germ cell tumors originating from the prostate are exceptionally rare. To the best of our knowledge, there have been no reported cases of mixed germ cell tumors in individuals with 46 XX disorder of sex development. In this study, we conducted a comprehensive analysis using whole genome sequencing to investigate the clinicopathological and molecular genetic characteristics of a submitted case, with the objective of elucidating its underlying pathogenesis. CASE PRESENTATION: A 40-year-old male patient was diagnosed with a combination of 46, XX disorder of sex development and a primary prostate mixed germ cell tumor with yolk sac tumor and teratoma components. Whole-genome sequencing revealed that the tumor cells had a high somatic mutational load. Analysis of genomic structural variations and copy number variants confirmed the patient's karyotype as 46, XX (SRY +). Additionally, the patient exhibited short stature, small bilateral testes, slightly enlarged breasts, elevated serum alpha-fetoprotein concentrations, elevated follicle-stimulating hormone and luteinizing hormone levels, and low testosterone levels. DISCUSSION: A case of 46, XX disorder of sex development, along with a primary prostatic mixed germ cell tumor, was diagnosed. This diagnosis has contributed to advancing our understanding of the genetic and phenotypic profile of the disease and may provide some insights for its treatment.

Chinese Healthy Eating Index (CHEI) and risk of diabetes in Chinese adults: a prospective cohort study.

PURPOSE: The Chinese Healthy Eating Index (CHEI) is a valid instrument to assess the diet quality of the Chinese population, but evidence regarding the relationship between CHEI and the risk of diabetes remains limited. We aimed to investigate the prospective association of CHEI with diabetes among Chinese adults. METHODS: 1563 adults free of diabetes at baseline and with at least two survey data from 1997 to 2018 were included. Dietary information was collected by three consecutive 24-h recalls combined with household food inventory, and long-term diet quality was evaluated by the CHEI. Diabetes was defined as self-reported physician-diagnosed diabetes and/or fasting blood glucose ≥ 7.0 mmol/L, and/or HbA1c ≥ 6.5%. Cox proportional hazard models and restricted cubic spline analysis were used to estimate the associations between CHEI and diabetes. RESULTS: During a median follow-up of 12.0 years, 192 (10.3%) participants developed new-onset diabetes. Generally, a five-point higher CHEI score was significantly associated with a 17% lower risk of diabetes (HR, 0.83; 95%CI 0.71-0.97). In stratified analysis, inverse associations between CHEI and diabetes were more vigorous in females (HR, 0.68; 95%CI 0.54-0.85) than in males (P for interaction = 0.01). In addition, there was an L-shaped association between CHEI and diabetes risk in the whole population (P for non-linearity = 0.026), while no significant non-linear association was observed in females or males, respectively. CONCLUSION: Our results suggested that a long-term higher-quality diet evaluated by CHEI was significantly associated with lower risks of diabetes, and the favorable associations were more pronounced among females.

Inducing tumor ferroptosis via a pH-responsive NIR-II photothermal agent initiating lysosomal dysfunction.

Ferroptosis is a unique programmed cell death process that was discovered a few years ago and plays an important role in tumor biology and treatment. However, it still remains a challenge to modulate tumor ferroptosis by spatiotemporally controlled cell-intrinsic Fenton chemistry. Herein, a pH activated photothermal sensitizer IR-PE has been designed and synthesized on the basis of cyanine bearing a diamine moiety, which is capable of triggering the lysosomal dysfunction-mediated Fenton pathway under the irradiation of near-infrared light to evoke ferroptosis, thereby improving antitumor efficacy and mitigating systemic side effects.

Exploring the mechanism of action of Qian Lie Xing Fang during the treatment of benign prostatic hyperplasia via network pharmacology and molecular dynamics simulation analyses.

This study aimed to explore the historical research progress on benign prostatic hyperplasia from the perspective of traditional Chinese medicine theory and the treatment of benign prostatic hyperplasia (BPH) with Qian Lie Xing Fang (QLXF) via the warming and tonifying of kidney yang, promotion of blood circulation, and clearing of meridians. First, network pharmacology analysis was used to screen and identify possible pathways for BPH treatment with QLXF. Subsequently, molecular docking analysis helped explore the mechanism of action by which the components of QLXF affected androgen receptor (AR) and type 5 phosphodiesterase inhibitor (PDE-5) levels. Targets for treatment with QLXF were identified from the online Mendelian inheritance in man and DisGeNET databases. BPH-related genes were identified using GeneCards and online Mendelian inheritance in man databases, and their intersection was used to construct a protein-protein interaction network analysis graph. Subsequently, gene ontology and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were performed. The semiflexible docking of the ingredients of QLXF acting on the 2 targets was performed via molecular docking and molecular dynamics simulation, to elucidate the mechanism of action by which the active ingredients affect AR and PDE-5 levels further. This enabled us to explore the pattern of interactions between small active ingredient molecules, the target protein, and the stability after binding at the microscopic level. Gene ontology enrichment analysis showed that QLXF affected several processes, such as DNA transcription factor binding, kinase binding, protein homodimerization activity, protein structure domain-specific binding, and protein-coupled amine receptor activity in BPH patients. KEGG results showed that chemical carcinogenic reactive oxidative species and the JAK-STAT, Pl3k-Akt, FoxO, NF-κB, and other pathways were significantly enriched. Conducting molecular docking studies to investigate the interaction of active components from QLXF with AR and PDE-5, it was found that MOL002260 may possess the potential to inhibit PDE-5 activity, while MOL010578 may exhibit the capability to inhibit AR activity. QLXF is closely associated with various biological processes and KEGG signaling pathways related to BPH. The active ingredients of QLXF were investigated for their interactions with AR and PDE-5, with a primary focus on the small molecules MOL002260 and MOL010578.

Eltrombopag plus cyclosporine in refractory immune thrombocytopenia: a single-center study.

Background: With the development of thrombopoietin receptor agonists, the prognosis of immune thrombocytopenia (ITP) in patients in whom there was a poor response to first-line treatment has greatly improved. However, there are still some patients who are refractory to eltrombopag. Objectives: To explore the efficacy and safety of eltrombopag combined with low-dose cyclosporine in the management of patients with refractory ITP. Methods: A total of 21 participants with ITP who failed to respond to multiple lines of therapy (including a daily dose of 75 mg of eltrombopag for at least 30 days) treated at The First Affiliated Hospital of Zhejiang Chinese Medical University between January 2018 and August 2022 were included. All enrolled patients subsequently received 50 mg of eltrombopag daily and low-dose cyclosporine (3 mg/kg/d, with an initial target concentration of 75-120 ng/mL). The efficacy and safety of the combined therapies were evaluated. Results: A total of 76.2% (16/21) of the patients responded to the combination of cyclosporine and eltrombopag, with a median time to response of 14.5 (range, 5-37) days. A complete response (platelet count ≥ 100 × 109/L) was observed in 81.3% (13/16) of the patients, among whom 1 patient experienced relapse due to self-reduction in eltrombopag. During a median follow-up of 180 days, there were no relapses, and 70% (7/10) of the patients successfully stopped or decreased concomitant ITP medications. One patient had both a catheter-related deep vein thrombosis and a venous cerebral thrombotic event later; no other severe drug-related adverse events were observed. Conclusion: Combining low-dose cyclosporine with eltrombopag may be an effective alternative for multirefractory ITP that is nonresponsive to eltrombopag alone.

Effect of recombinant human growth hormone plus vitamin D on development and lipid metabolism in children with growth hormone deficiency.

The combination of rhGH and vitamin D has been suggested as a potential therapeutic approach for children with GHD. This retrospective study aimed to investigate the impact of recombinant human growth hormone plus vitamin D on development and lipid metabolism in children with growth hormone deficiency. A total of 198 children treated in our hospital from December 2011 to December 2021 were recruited. The study assessed development-related indices, lipid metabolism indices, growth factor indices, thyroid indices, and adverse reactions. After treatment, the development-related indices of children in both groups improved (P < 0.05), but the experimental group showed significantly better HtSDS and annual height growth rate (P < 0.05). Moreover, the experimental group had lower levels of TG, T-CHO, and LDL-C versus the observation group (P < 0.05), while no significant difference was observed in HDL-C levels between the two groups before and after treatment (P > 0.05). Moreover, patients receiving recombinant human growth hormone plus vitamin D had significantly higher IGF-1 and IGFBP-3 levels than those receiving recombinant human growth hormone alone (P < 0.05). The T3, T4, and TSH levels of children in both groups increased after treatment (P < 0.05). The incidence of adverse events did not significantly differ between the two groups (P > 0.05). In conclusion, our findings suggest that recombinant human growth hormone plus vitamin D effectively improves the development and lipid metabolism of children with growth hormone deficiency. Additionally, it increases growth factor levels without compromising thyroid function or increasing the risk of adverse drug reactions.

A mitochondria-targeting self-assembled carrier-free lonidamine nanodrug for redox-activated drug release to enhance cancer chemotherapy.

Mitochondria play a vital role in maintaining cellular homeostasis. In recent years, studies have found that mitochondria have an important role in the occurrence and development of tumors, and targeting mitochondria has become a new strategy for tumor treatment. Lonidamine (LND), as a hexokinase inhibitor, can block the energy supply and destroy mitochondria. However, poor water solubility and low mitochondrial selectivity limit its clinical application. To overcome these obstacles, we report redox-activated self-assembled carrier-free nanoparticles (Cy-TK-LND NPs) based on a small molecule prodrug, in which photosensitizer IR780 (Cy) which targets mitochondria is conjugated to LND via a sensitive thioketal (TK) linker. Intracellular oxidative stress induced by laser radiation leads to the responsive cleavage of Cy-TK-LND NPs, facilitating the release of free LND into mitochondria. Subsequently, LND damages mitochondria, triggering the apoptosis pathway. The results show the effective killing effect of Cy-TK-LND NPs on cancer cells in vitro and in vivo. The IC50 value of irradiated Cy-TK-LND NPs is 5-fold lower than that of free LND. Moreover, tumor tissue section staining results demonstrate that irradiated Cy-TK-LND NPs induce necrosis and apoptosis of tumor cells, upregulate cytochrome C and pro-apoptotic Bax, and downregulate anti-apoptotic Bcl-2. Generally, Cy-TK-LND NPs exhibit efficient mitochondria-targeted delivery to improve the medicinal availability of LND. Accordingly, such a carrier-free prodrug-based nanomedicine holds promise as an effective cancer chemotherapy strategy.

Clinical Reasoning: A 60-Year-Old Man With Asymmetric Weakness and Persistent Fever.

Peripheral neuropathies, especially those with atypical features, remain a diagnostic challenge. In this case, a 60-year-old patient presented with acute-onset weakness starting in the right hand then sequentially involving the left leg, left hand, and right leg over 5 days. The asymmetric weakness was accompanied by persistent fever and elevated inflammatory markers. Subsequent development of rashes combined with careful review of the history led us to the final diagnosis and targeted treatment. This case highlights clinical pattern recognition with the help of electrophysiologic studies in peripheral neuropathies, which provide shortcuts to narrow the differential diagnosis. We also illustrate the important pitfalls from history taking to ancillary testing in diagnosing the rare but treatable cause of peripheral neuropathy (eFigure 1, links.lww.com/WNL/C541).

Pathogenicity Analysis of a Novel Variant in GTPBP3 Causing Mitochondrial Disease and Systematic Literature Review.

Defect of GTPBP3, the human mitochondrial tRNA-modifying enzyme, can lead to Combined Oxidative Phosphorylation Deficiency 23 (COXPD23). Up to now, about 20 different variants of the GTPBP3 gene have been reported; however, genotype-phenotype analysis has rarely been described. Here, we reported a 9-year-old boy with COXPD23 who presented with hyperlactatemia, hypertrophic cardiomyopathy, seizures, feeding difficulties, intellectual disability and motor developmental delay, and abnormal visual development. Biallelic pathogenic variants of the GTPBP3 gene were identified in this boy, one novel variant c.1102dupC (p. Arg368Profs*22) inherited from the mother and the other known variant c.689A>C (p. Gln230Pro) inherited from father. We curated 18 COXPD23 patients with GTPBP3 variants to investigate the genotype-phenotype correlation. We found that hyperlactatemia and cardiomyopathy were critical clinical features in COXPD23 and the average onset age was 1.7 years (3 months of age for the homozygote). Clinical classification of COXPD23 for the two types, severe and mild, was well described in this study. We observed arrhythmia and congestive heart failure frequently in the severe type with early childhood mortality, while developmental delay was mainly observed in the mild type. The proportion of homozygous variants (71.4%) significantly differed from that of compound heterozygous variants (18.1%) in the severe type. Compared with the variants in gnomAD, the proportion of LOFVs in GTPBP3 was higher in COXPD23 patients (48.6% versus 8.9%, p < 0.0001 ****), and 31% of them were frameshift variants, showing the LOF mechanism of GTPBP3. Additionally, the variants in patients were significantly enriched in the TrmE-type G domain, indicating that the G domain was crucial for GTPBP3 protein function. The TrmE-type G domain contained several significant motifs involved in the binding of guanine nucleotides and Mg2+, the hydrolysis of GTP, and the regulation of the functional status of GTPases. In conclusion, we reported a mild COXPD23 case with typical GTPBP3-related symptoms, including seizures and abnormal visual development seldom observed previously. Our study provides novel insight into understanding the clinical diagnosis and genetic counseling of patients with COXPD23 by exploring the genetic pathogenesis and genotype-phenotype correlation of COXPD23.

Case report: Large-size intramuscular nodular fasciitis, a challenging histopathologic diagnosis confirmed by molecular detection of USP6 gene rearrangement: Case report and literature review.

The intramuscular subtype of nodular fasciitis (NF) is rare with lesions normally not more than 2 cm in size and characterized by pseudosarcomatous morphology. We report a case of a 27-year-old man with a large-size intramuscular NF. The patient came for treatment complaining of an increasingly enlarged mass in the left upper arm for 4 months. Magnetic resonance imaging (MRI) confirmed the presence of a well-defined tumor measuring 5 cm within the outer edge of the middle humerus. Microscopically, the neoplasm was rich in fibroblasts and myofibroblasts in an interlaced pattern with high mitotic index and evident multinuclear giant cells. Erythrocyte extravasation was easily seen in the stroma. The tumor border was infiltrative. Immunohistochemically, the tumor cells were positive for smooth muscle actin (SMA) and negative for cytokeratin, desmin, H-Caldesmon, CD34, S100, ALK, and ß-catenin. Fibrosarcoma was highly suspected by histopathological and immunohistochemical examination. Molecular detection demonstrated evidence of ubiquitin-specific peptidase 6 (USP6) gene rearrangement in this tumor. Based on the findings, the tumor was diagnosed as intramuscular NF. At 56 months after the initial surgery, the patient had recovered with no evidence of recurrence or metastasis. Large-size intramuscular NF is very rare and easily overdiagnosed as malignant tumor due to its obvious pseudosarcomatoid pathological features. USP6 gene rearrangement detection can effectively avoid this major misdiagnosis.

Generation of an induced pluripotent stem cell line FDHPIi001-A derived from a female patient with WDR45-related neurodegeneration disease carrying non-canonical splice site c.344 + 5G > T.

The WDR45 encodes a beta-propeller scaffold protein which leads to ß-propeller protein-associated neurodegeneration (BPAN) with iron accumulation in the brain. Using episomal reprogramming approach, we generated an iPSC line from peripheral blood mononuclear cells (PBMCs) from a 9-year-old girl with a non-canonical splice site c.344 + 5G > T in the WDR45 gene. The iPSC line had been fully examined about pluripotency marker, karyotype, and three germ layer differentiation.

Exploring inhibitory components of Hedyotis diffusa on androgen receptor through molecular docking and molecular dynamics simulations.

To explore the effective ingredients and mechanisms of action in Hedyotis diffusa (HD) that have inhibitory effects on androgen receptors (AR) using molecular docking and molecular dynamics simulations (MDS). The effective ingredients of HD were collected through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database and literatures. All components were docked with AR using Libdock. The receptor ligand interaction between the optimal ligand and AR were analyzed. Two simulation systems, namely I and II, containing AR and testosterone propionates (TP) were constructed, which System II contained the optimal ligand. The duration of the MDS was set to 300 ns. The distance between TP and AR peripheral active sites, root mean square deviation of ligand and receptor, receptor radius of gyration, distance between ligand center and binding site center, and ligand receptor binding energy were analyzed. 37 components of HD were collected, and the optimal ligand was MOL001656. MOL001656 forms hydrogen bonds with residues LEU48, PHE108, GLN55, LEU45, and ASN49 of AR. MDS have found that binding of TP to AR active sites can be observed in System I. The root mean square deviation of AR and MOL001656 both tended to stabilize in System II, with no significant fluctuations in the radius of gyration of AR and no significant fluctuations in the distance between ligand and binding cavity, indicating that the receptor ligand structure is relatively stable and their binding is relatively stable. The binding energy between AR and MOL001656 was -29.33 ±â€…3.84 kcal/mol. HD contains multiple effective ingredients that may have inhibitory AR activity. MOL001656 can occupy binding sites, thereby may exerting AR inhibitory effects.

Study on the mechanism of Jin Gui Shen Qi Pill in the treatment of erectile dysfunction based on bioinformatics analysis.

Erectile dysfunction (ED) is a male disease, which is easy to cause disharmony in sexual life. However, at present, there are few drugs with small side effects in clinic. Jin Gui Shen Qi Pill (JGSQP) is a traditional Chinese medicine compound with obvious clinical effect in treating ED. Therefore, it is imperative to explore clinical drugs based on inhibiting the pathological characteristics of ED. First, the active ingredients and action targets in JGSQP were screened by applying Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and SWISS Target Prediction. Further, a systematic pharmacological analysis platform for traditional Chinese medicine, and the ED targets were screened by applying Gene Cards and Online Mendelian Inheritance in Man databases to construct drug active ingredient-target-disease mapping, followed by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) network analysis. Finally, Molecular docking and molecular dynamics simulations were used to screen the active ingredients of JGSQP acting on PDE-5, and analyze the ligand-receptor interaction relationship and binding free energy. The results showed that there were 212 potential targets of JGSQP for ED disease, and GO analysis revealed that the main pathways were positive regulation of DNA-binding transcription factor activity, regulation of vascular diameter, and negative regulation of vascular diameter, etc. KEGG analysis revealed that the main pathways were HIF-1 signaling pathway, prolactin signaling pathway, fluid shear stress, and atherosclerosis, etc. PPI network analysis revealed that the core targets TGFB1 and EGFR have important roles. Molecular docking and molecular dynamics simulations showed that the main components acting on PDE-5 were MOL000546, MOL011169, MOL000279, MOL000273 and Sildenafil. MOL000546 was able to bind stably to PDE-5. The multi-component, multi-target, and multi-pathway action characteristics of JGSQP were confirmed by network pharmacology, which predicted the possible mechanism of action of JGSQP in the treatment of ED and provided a theoretical reference for further experimental validation.

[Genetic analysis and pathological features of one 46,XX testicular disorder of sex development cases with prostate germ cell tumor].

OBJECTIVE: To analyze the clinical and genetic characteristics of a 46,XX case of testicular disease with prostate germ cell tumor and explore its pathogenesis. METHODS: The clinical features and pathological examination of the patient were reviewed, and the genetic basis was analyzed by chromosome karyotyping analysis and fluorescence in situ hybridization. RESULTS: The patient had slightly short stature, small testicles and large breast. Serum alpha fetoprotein was significantly increased, along with increased follicle stimulating hormone, luteinizing hormone and prolactine, and lower level of testosterone. The karyotype was 46,XX. Fluorescence in situ hybridization has identified the presence of SRY gene at the end of short arm of one X chromosome. The pathological diagnosis was primary germ cell tumor of prostate, mainly of yolk sac tumor type. CONCLUSION: A rare case of 46,XX testicular disorder of sex development combined with germ cell tumor of the prostate was diagnosed, which has enriched the phenotype spectrum of the disease and provided clues for the treatment of the disease.

Circular RNA circESPL1 knockdown alleviates lipopolysaccharide (LPS)-induced lung cell injury via sponging miR-326 to regulate MAPK14.

BACKGROUND: Infantile pneumonia (IP) is a common inflammatory disease, which brings a heavy burden to young children's health. Previous studies suggested that circular RNA (circRNA) hsa_circ_0026579 (also called circESPL1) was significantly upregulated in pneumonia patients, which was associated with the disease severity. This subject aimed to explore the functional effects and potential regulatory mechanism of circESPL1 on lipopolysaccharide (LPS)-induced lung cell injury. METHODS: WI-38 and MRC-5 cells were stimulated by LPS to mimic the inflammatory injury model. CircESPL1, microRNA-326 (miR-326), and Mitogen-Activated Protein Kinase 14 (MAPK14)levels were measured using real-time quantitative polymerase chain reaction (RT-qPCR). Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and flow cytometry assays were performed to assess cell proliferation and apoptosis. Western blot analysis of B-cell lymphoma-2 (Bcl-2), Bcl-2 related X protein (Bax), C-caspase 3, and MAPK14 protein levels. Tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), and IL-1ß levels were examined using an Enzyme-linked immunosorbent assay (ELISA). Using Starbase analysis, the binding between miR-326 and circESPL1 or MAPK14 was predicted, followed by confirmation using a dual-luciferase reporter and RNA Immunoprecipitation (RIP) assays. RESULTS: Increased circESPL1 and MAPK14, and reduced miR-326 were observed in serum samples from preeclampsia sufferers and LPS-treated lung cells (P < 0.05). Furthermore, circESPL1 deficiency overturned LPS-mediated cell proliferation, apoptosis, and inflammatory response in vitro (P < 0.05). In terms of molecular mechanisms, circESPL1 worked as a sponge of miR-326, and miR-326 absence reversed the protective role of circESPL1 silencing on LPS-triggered lung cell injury (P < 0.05). Also, miR-326 directly targeted MAPK14, and MAPK14 overexpression abolished miR-326-mediated impacts under LPS treatment (P < 0.05). CONCLUSION: CircESPL1 knockdown might attenuate LPS-caused lung cell injury by regulating the miR-326/ MAPK14 axis, providing useful insight for exploring a novel therapeutic approach for IP.