Peptidomic analysis of follicular fluid in patients with polycystic ovarian syndrome.

Objective: The aim of this study was to analyze and compare the differential expression of peptides within the follicular fluid of polycystic ovary syndrome (PCOS) patients versus normal women by using peptidomics techniques. The underlying mechanisms involved in PCOS pathogenesis will be explored, together with screening and identification of potential functional peptides via bioinformatics analysis. Materials and methods: A total of 12 patients who underwent in vitro fertilization and embryo transfer (IVF-ET) at the Reproductive Medicine Center of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from 1 September 2022 to 1 November 2022 were included in this study. The follicular fluid of PCOS patients (n = 6) and normal women (n = 6) were collected. The presence and concentration differences of various peptides were detected by the LC-MS/MS method. GO and KEGG analysis were performed on the precursor proteins of the differentially-expressed peptides, and protein network interaction analysis was carried out to identify functionally-relevant peptides among the various peptides. Results: A variety of peptides within the follicular fluid of PCOS versus normal patients were detected by peptidomics techniques. Altogether, 843 upregulated peptides and 236 downregulated peptides were detected (absolute fold change ≥2 and p < 0.05). Of these, 718 (718 = 488 + 230) peptides were only detected in the PCOS group, while 205 (205 = 174 + 31) were only detected in the control group. Gene Ontology enrichment and pathway analysis were performed to characterize peptides through their precursor proteins. We identified 18 peptides from 7 precursor proteins associated with PCOS, and 4 peptide sequences were located in the functional domains of their corresponding precursor proteins. Conclusion: In this study, differences in the follicular development of PCOS versus normal patients were revealed from the polypeptidomics of follicular development, which thus provided new insights for future studies on the pathological mechanisms of PCOS development.

Hyperthermia-triggered NO release based on Cu-doped polypyrrole for synergistic catalytic/gas cancer therapy.

Nitric oxide (NO) is a crucial gaseous medium for tumor growth and progression, but it may also cause mitochondrial disorder and DNA damage by drastically increasing its concentration in tumor. Due to its challenging administration and unpredictable release, NO based gas therapy is difficult to eliminate malignant tumor at low safe doses. To address these issues, herein, we develop a multifunctional nanocatalyst called Cu-doped polypyrrole (CuP) as an intelligent nanoplatform (CuP-B@P) to deliver the NO precursor BNN6 and specifically release NO in tumors. Under the aberrant metabolic environment of tumors, CuP-B@P catalyzes the conversion of antioxidant GSH into GSSG and excess H2O2 into ·OH through Cu+/Cu2+ cycle, which results in oxidative damage to tumor cells and the concomitant release of cargo BNN6. More importantly, after laser exposure, nanocatalyst CuP can absorb and convert photons into hyperthermia, which in turn, accelerates the aforesaid catalytic efficiency and pyrolyzes BNN6 into NO. Under the synergistic effect of hyperthermia, oxidative damage, and NO burst, almost complete tumor elimination is achieved in vivo with negligible toxicity to body. Such an ingenious combination of NO prodrug and nanocatalytic medicine provides a new insight into the development of NO based therapeutic strategies. STATEMENT OF SIGNIFICANCE: A hyperthermia-responsive NO delivery nanoplatform (CuP-B@P) based on Cu-doped polypyrrole was designed and fabricated, in which CuP catalyzed the conversion of H2O2 and GSH into ·OH and GSSG to induce intratumoral oxidative damage. After laser irradiation, hyperthermia ablation and responsive release of NO further coupled with oxidative damage to eliminate malignant tumors. This versatile nanoplatform provides new insights into the combined application of catalytic medicine and gas therapy.

Parameter study on characteristic pulse diagram of polycystic ovary syndrome based on logistic regression analysis.

This study aimed to explore the parameters of the independent predictive characteristic pulse diagram of polycystic ovary syndrome (PCOS) by analysing the pulse characteristics between healthy women and the PCOS group. A total of 278 women were recruited for this study. Pulse wave parameters were collected by the pulse spectrum analyser. The single-factor analysis of the pulse diagram parameters was used to identify significant indicators, and the logistic regression analysis was carried out on the above indicators with statistical differences to obtain independent predictors. According to the single-factor and multi-factor analyses, h1, h5, h3/h1, t, t1 and t5 were independent predictors of PCOS diagnosis. The results showed that PCOS patients had a faster heart rate, decreased left ventricular systolic function and decreased aortic compliance compared to healthy individuals. These findings suggested that the characteristic pulse parameters screened out are valuable for the diagnosis of PCOS.IMPACT STATEMENTWhat is already known on this subject? Polycystic ovary syndrome (PCOS) is a common gynecological reproductive endocrine and metabolic disease, which is significant for screening and early intervention in the disease. However, due to the lack of pulse's diagnostic evidence of PCOS, there is still an unknown area in the research on the correlation between PCOS and pulse diagram parameters.What do the results of this study add? This study fills the gap between the research on PCOS and pulse wave. The study also shows that the pulse characteristic parameters h1, h5, h3/h1, t, t1, and t5 are independent predictors of PCOS, suggesting that the patients have a higher heart rate, lower ventricular systolic function, and aortic compliance than healthy individuals.What are the implications of these findings for clinical practice and/or further research? Prominent risk factors for pulse parameters associated with the occurrence of PCOS facilitate early screening and diagnosis of the disease. The objectification of pulse diagnosis helps to establish a health management model, which can be used for the accurate assessment and treatment of PCOS by traditional Chinese medicine (TCM). It provides a clinical reference for the study of pulse diagnosis objectification.

Targeted Wolfram-Doped Polypyrrole for Photonic Hyperthermia-Synergized Radiotherapy.

Single ionizing radiation at a tolerable dose is ineffectual in eliminating malignancies but readily generates harmful effects on surrounding normal tissues. Herein, we intelligently fabricated novel wolfram-doped polypyrrole (WPPy) through a simple oxidative polymerization method with WCl6 as an oxidizing catalyst, which possessed good biocompatibility, high photothermal conversion, and intensive radiosensitivity capacities to concurrently serve as a photothermal reagent and a radiosensitizer for hyperthermia-synergized radiotherapy (RT) against a malignant tumor. In comparison with traditional polypyrrole without noble metal doping, the innovative introduction of WCl6 not only successfully launched the polymerization of a pyrrole monomer but also endowed WPPy with additional radiosensitization. More importantly, after further decoration with an active targeted component (SP94 polypeptide), the obtained WPPy@SP94 significantly increased tumor internalization and accumulation in vitro and in vivo and induced obvious DNA damage as well as robust ROS generation under X-ray irradiation, which meanwhile synergized with strong photonic hyperthermia to effectively inhibit tumor growth by single drug injection. Moreover, such biocompatible WPPy@SP94 showed negligible adverse effects on normal cells and tissues. WPPy@SP94 developed in this study not only expands the category of polypyrrole chemical syntheses but also sheds light on WPPy@SP94-based radiosensitizers for cancer RT.

Novel biodegradable two-dimensional vanadene augmented photoelectro-fenton process for cancer catalytic therapy.

Fenton reaction-based chemodynamic therapy is hardly a self-sufficient cancer treatment, due to its stringent reaction conditions, limited substrate concentration, and negative feedback from the tumor microenvironment. Herein, we synthesized a novel two-dimensional (2D) vanadium-based nanosheets (Vanadene, V NSs) with polyvalent surfaces (VIV/VV), a very narrow band gap of 0.8 eV, and high biodegradability by a liquid-phase exfoliation strategy. The polyvalent surface endowed its multiple capabilities to modulate TME through GSH consumption and O2 production via VV and to catalyze a Fenton-like reaction to produce ·OH under a mild condition via VIV. In addition, efficient energy conversions including near-infrared (NIR)-thermal conversion (photothermal therapy, PTT) and NIR-electron conversion (photodynamic therapy, PDT) were ensured by the narrow band gap, in which NIR-thermal conversion enhanced the Fenton-like reaction activity through accelerating ionization while NIR-electron conversion catalyzed the conversion of O2 to ·O2- for further breaking redox homeostasis. Moreover, V NSs-based nanocatalyst can be slowly degraded into non-toxic species, enabling it to be innocuously eliminated from the body after completing tumor eradication by single drug injection and single NIR irradiation. Therefore, this study provides new insights into a universal nanoplatform for NIR-enhanced combination cancer therapy, highlighting the utility of 2D V NSs in the field of biomedicine.

Polypyrrole Nanoenzymes as Tumor Microenvironment Modulators to Reprogram Macrophage and Potentiate Immunotherapy.

Nanozyme-based tumor catalytic therapy has attracted widespread attention in recent years, but its therapeutic outcome is drastically diminished by species of nanozyme, concentration of substrate, pH value, and reaction temperature, etc. Herein, a novel Cu-doped polypyrrole nanozyme (CuP) with trienzyme-like activities, including catalase (CAT), glutathione peroxidase (GPx), and peroxidase (POD), is first proposed by a straightforward one-step procedure, which can specifically promote O2 and ·OH elevation but glutathione (GSH) reduction in tumor microenvironment (TME), causing irreversible oxidative stress damage to tumor cells and reversing the redox balance. The PEGylated CuP nanozyme (CuPP) has been demonstrated to efficiently reverse immunosuppressive TME by overcoming tumor hypoxia and re-educating macrophage from pro-tumoral M2 to anti-tumoral M1 phenotype. More importantly, CuPP exhibits hyperthermia-enhanced enzyme-mimic catalytic and immunoregulatory activities, which results in intense immune responses and almost complete tumor inhibition by further combining with αPD-L1. This work opens intriguing perspectives not only in enzyme-catalytic nanomedicine but also in macrophage-based tumor immunotherapy.

Establishment of DNA Methylation Profile Associated with TCM Syndrome in Endometriosis.

Objectives: To screen the potential epigenetic biomarkers associated with endometriosis (EMS) and traditional Chinese medicine (TCM) syndrome EMS types. Methods: A cohort of 99 participants comprising 42 EMS patients with cold coagulation blood stasis (CCBS) syndrome, 35 EMS patients with Qi stagnation blood stasis (QSBS) syndrome, and 22 women of childbearing age without EMS were recruited. Reduced representation bisulfite sequencing (RRBS) was used to establish the differential DNA methylation profiles in human peripheral blood samples obtained from four non-EMS and four EMS patients with CCBS or QSBS syndrome, respectively. Differentially expressed genes (DEGs) were verified in 18 non-EMS, 38 CCBS-EMS, and 31 QSBS-EMS using pyrosequencing. Results: Methylation sites of 123942, 127229, and 115961 were found in peripheral blood DNA of non-EMS, CCBS-EMS, and QSBS-EMS patients, respectively. GO and KEGG analyses showed that the pathological process of EMS may be closely related to the nervous system development, cell junctions, GABA-gated chloride ion channel activity, nicotine addiction, Hippo signaling pathway, mRNA surveillance pathway, and Wnt signaling pathway. The methylation level at CpG site within HDAC6 gene in QSBS-EMS patients was significantly different from that in control women. Conclusions: The changes in DNA methylation in peripheral blood samples may be associated with EMS and TCM syndrome EMS types. The methylation level of HDAC6 gene may be used to distinguish QSBS-EMS patients from women without EMS.

Systematic Transcriptome and Regulatory Network Analyses Reveal the Hypoglycemic Mechanism of Dendrobium fimbriatum.

Type 2 diabetes (T2D) is a long-term metabolic disorder disease characterized by high blood sugar and relative lack of insulin. Previous studies have demonstrated that Dendrobium has potent glucose-lowing effects and may serve as add-ons or alternatives to classic medications for T2D prevention and treatment, but the underlying molecular mechanisms were still unclear. We performed biochemical and transcriptional profiling (RNA sequencing [RNA-seq] and microRNA sequencing [miRNA-seq]) analyses on the pancreas and liver of Dendrobium fimbriatum extract (DFE)-fed diabetic rats and control animals. Our sequencing and experimental data indicated that DFE significantly alleviated diabetes symptoms through inhibiting inflammation and preventing islet cell apoptosis in diabetic pancreas. Transcription factors in Stat/nuclear factor κB (NF-κB)/Irf families combined with miR-148a/375/9a served as key regulators in the inflammation and apoptosis pathways under DFE administration. Meanwhile, DFE improved the energy metabolism, lipid transport, and oxidoreductase activity in the liver, and thus decreased lipid accumulation and lipotoxicity-induced hepatocyte apoptosis. Our findings revealed that DFE may serve as a potential therapeutic agent to prevent T2D, and also showed the combination of transcriptome profiling and regulatory network analysis could act as an effective approach for investigating potential molecular mechanisms of traditional Chinese medicine on diseases.

Integrating Transcriptome and Experiments Reveals the Anti-diabetic Mechanism of Cyclocarya paliurus Formula.

Type 2 diabetes (T2D) is generally regarded as a metabolic disorder disease with various phenotypic expressions. Traditional Chinese medicine (TCM) has been widely used for preventing and treating diabetes. In our study, we demonstrated that Cyclocarya paliurus formula extractum (CPE), a compound of TCM, can ameliorate diabetes in diabetic rats. Transcriptome profiles were performed to elucidate the anti-diabetic mechanisms of CPE on pancreas and liver. Pancreatic transcriptome analysis showed CPE treatment significantly inhibited gene expressions related to inflammation and apoptosis pathways, among which the transcription factors (TFs) nuclear factor κB (NF-κB), STAT, and miR-9a/148/200 may serve as core regulators contributing to ameliorate diabetes. Biochemical studies also demonstrated CPE treatment decreased pro-inflammatory cytokines (tumor necrosis factor alpha [TNF-α], interleukin [IL]-1ß, and IL-6) and reduced ß cell apoptosis. In liver tissue, our transcriptome and biochemical experiments showed that CPE treatment reduced lipid accumulation and liver injury, and it promoted glycogen synthesis, which may be regulated by TFs Srebf1, Mlxipl, and miR-122/128/192. Taken together, our findings revealed CPE could be used as a potential therapeutic agent to prevent and treat diabetes. It is the first time to combine transcriptome and regulatory network analyses to study the mechanism of CPE in preventing diabetes, giving a demonstration of exploring the mechanism of TCM on complex diseases.

Evaluation of a crataegus-based multiherb formula for dyslipidemia: a randomized, double-blind, placebo-controlled clinical trial.

Background. We for the first time examined the effects of a multiherb formula containing Crataegus pinnatifida (1 g daily), Alisma orientalis, Stigma maydis, Ganoderma lucidum, Polygonum multiflorum, and Morus alba on plasma lipid and glucose levels in Chinese patients with dyslipidemia. Methods. In this randomized, double-blind, placebo-controlled study, 42 patients were randomized at a ratio of 1 : 1 to receive the herbal formula or placebo for 12 weeks and 40 patients completed the study. Lipid profiles, glucose, glycated haemoglobin (HbA1c), and laboratory safety parameters were performed before and after treatment. Results. The difference in the changes in low-density lipoprotein cholesterol (LDL-C) levels between placebo and active treatment (-9%) was significantly (P < 0.05) better with active treatment. HbA1c levels significantly decreased by -3.9% in the active treatment group, but the change was not significantly different from that with placebo (-1.1%) (P = 0.098). There were no apparent adverse effects or changes in laboratory safety parameters with either treatment. Conclusions. The multiherb formula had mild beneficial effects on plasma LDL-C after 12-weeks treatment in subjects with dyslipidemia without any noticeable adverse effects.