Landscape and progress of global peptide drugs in obstetrics and gynaecology.

Peptides have gained popularity in the global market during recent years and have been placed between small molecule drugs and biologics. However, little is known about the comprehensive landscape of peptide drugs in obstetrics and gynaecology. Herein, we analysed new peptide drug-related clinical trials in obstetrics and gynaecology registered on ClinicalTrials.gov. The number and percentage were used for statistical analysis, and a time trend analysis was conducted by calculating the annual growth rate. We aimed to provide the first overview of the changing landscape and status of global peptide drugs in this prospective field, including exploring drug targets, the cutting-edge oncotherapy of peptide vaccines and peptide-drug conjugates, and unsolved challenges with oral administration.

Advancements in lead therapeutic phytochemicals polycystic ovary syndrome: A review.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases in women of reproductive age and features complex pathological symptoms and mechanisms. Existing medical treatments have, to some extent, alleviated the deterioration of PCOS. However, these strategies only temporarily control symptoms, with a few side effects and no preventive effect. Phytochemicals extracted from medicinal herbs and plants are vital for discovering novel drugs. In recent years, many kinds of research have proven that phytochemicals isolated from traditional Chinese medicine (TCM) and medicinal plants show significant potential in preventing, alleviating, and treating PCOS. Nevertheless, compared to the abundance of experimental literature and minimal specific-topic reviews related to PCOS, there is a lack of systematic reviews to summarize these advancements in this promising field. Under this background, we systematically document the progress of bioactive phytochemicals from TCM and medicinal plants in treating PCOS, including flavonoids, polyphenols, and alkaloids. According to the literature, these valuable phytochemicals demonstrated therapeutic effects on PCOS supported by in vivo and in vitro experiments, mainly depending on anti-inflammatory, antioxidation, improvement of hormone disorder and insulin resistance (IR), and alleviation of hyperinsulinemia. Based on the current progress, future research directions should emphasize 1) exploring bioactive phytochemicals that potentially mediate bone metabolism for the treatment of PCOS; 2) improving unsatisfactory bioavailability by using advanced drug delivery systems such as nanoparticles and antibody-conjugated drugs, as well as a chemical modification; 3) conducting in-depth research on the pathogenesis of PCOS to potentially impact the gut microbiota and its metabolites in the evolution of PCOS; 4) revealing the pharmacological effects of these bioactive phytochemicals on PCOS at the genetic level; and 5) exploring the hypothetical and unprecedented functions in regulating PCOS by serving as proteolysis-targeting chimeras and molecular glues compared with traditional small molecule drugs. In brief, this review aims to provide detailed mechanisms of these bioactive phytochemicals and hopefully practical and reliable insight into clinical applications concerning PCOS.

Salidroside Decreases Atherosclerosis Plaque Formation via Inhibiting Endothelial Cell Pyroptosis.

Pyroptosis, a new pro-inflammatory programmed cell death, is linked to atherosclerosis (AS). Our previous studies suggested that salidroside (SAL) can alleviate AS and exert anti-oxidative and anti-inflammatory properties. However, the effect of SAL on atherosclerosis-related pyroptosis has not been studied. Here, we investigated the effect of SAL on pyroptosis to explain the underlying mechanisms of SAL on atherosclerosis-related inflammation. We established an atherosclerosis mouse model via western diet (HFD) to explore the protective effect of SAL. According to our results, administration of SAL for 12 weeks markedly reduced the atherosclerotic plaque in aorta. Meanwhile, SAL also alleviated the pyroptosis, as evidenced by inhibiting caspase-1 activation, interleukin-1ß (IL-1ß) release, and TUNEL-positive staining, and decreasing the expression of Gasdermin D (GSDMD). Furthermore, SAL also decreased the activation of caspase-1 and inhibited the release of IL-1ß induced by lipopolysaccharide (LPS) and adenosine triphosphate (ATP) in human umbilical vein endothelial cell (HUVECs). Our data indicate that SAL inhibit NLRP3-related pyroptosis, which might be the underlying mechanism of SAL anti-inflammatory in atherosclerosis.

NLRP3/IL1ß inflammasome associated with the aging bladder triggers bladder dysfunction in female rats.

Bladder dysfunction is associated with fibrosis­-mediated aging, but the corresponding mechanism remains to be elucidated. Activation of the NACHT, LRR and PYD domains­containing protein 3 (NLRP3) inflammasome is related to chronic diseases associated with aging, including organ fibrosis. The present study aimed to explore the role of NLRP3/interleukin 1ß in aging­associated bladder dysfunction. Female Sprague­Dawley rats were divided into the following two groups (n=10 rats/group): 2­month­old group (young group) and 24­month­old group (old group). Urodynamics were performed to assess the bladder function of the rats. The histological alterations were identified using Masson's trichrome staining. The protein expression of the NLRP3 inflammasome and NAD­dependent protein deacetylase sirtuin­3, mitochondrial (SIRT3) were detected by western blot analysis, and immunohistochemistry was used to examine a senescence marker (p21) and the NLRP3 inflammasome in the bladder. The localization of the key molecule Caspase1 was determined using immunofluorescence. The voiding time was longer in the old group compared with the young group. The expression levels of SIRT3 were reduced in the bladders of the old group, while those of the NLRP3 inflammasome and the senescence marker were significantly higher in the bladders of the old group compared with the young group. Increased collagen deposition leads to chronic bladder fibrosis with increased NLRP3. In the histological examination, the bladders of the old group displayed increased collagen deposition, urothelial thinning and detrusor shrinkage compared with the young group. Tissue fibrosis and urothelial alterations are the principal causes of bladder dysfunction during aging. Downregulated SIRT3 and upregulated expression of the NLRP3 inflammasome are involved in the degradation of aging bladders. Inflamm­aging is a novel mechanism underlying bladder dysfunction.

Salidroside attenuates endothelial cellular senescence via decreasing the expression of inflammatory cytokines and increasing the expression of SIRT3.

OBJECTIVE: Endothelial cellular senescence is an important contributor to the endothelial dysfunction and atherosclerosis. Our previous studies suggested that salidroside (SAL) can alleviate atherosclerosis and protect endothelial cells against oxidative stress induced damage. However, the effect and mechanism of SAL on endothelial cellular senescence is still unclear. Here, we investigated the underlying mechanisms of SAL on preventing endothelial cellular premature senescence. METHODS AND RESULTS: We established a hyperhomocysteinemia (HHcy)mouse model via high methionine diet (HMD) to explore the protective effect of SAL. According to our results, the HMD elevated the concentration of serum homocysteine. HHcy induced the collagen deposition and the up-regulation of senescence markers, i.e. p16INK4A and p21CIP1, in intima-medial of aorta. In addition, SAL also inhibited the expression of CD68 and intercellular adhesion molecule 1 (ICAM1) in aorta. In senescent human umbilical vein endothelial cells (HUVECs) induced by H2O2, SAL treatment alleviated the expression of p16INK4A and p21CIP1 and reduced the activity of senescence-associated (SA)-ß-gal. CONCLUSION: our data suggested that SAL decreased the expression of inflammatory cytokines and up-regulated the expression of SIRT3, which might be the underlying mechanism of SAL on preventing endothelial cells from premature senescence.

Salidroside improves endothelial function and alleviates atherosclerosis by activating a mitochondria-related AMPK/PI3K/Akt/eNOS pathway.

Salidroside (SAL) is a phenylpropanoid glycoside isolated from the medicinal plant Rhodiola rosea. A recent study has reported that SAL can efficiently decrease atherosclerotic plaque formation in low-density lipoprotein receptor-deficient mice. This study was to investigate the molecular mechanism of antiatherogenic effects of SAL. Given the importance of endothelial nitric oxide synthase (eNOS) in atherosclerosis, we sought to elucidate whether SAL could stimulate eNOS activation and also to explore its upstream signaling pathway. Six-week old apoE(-/-) male mice were fed a high-fat diet for 8weeks and then were administered with SAL for another 8weeks. SAL significantly improved endothelial function associated with increasing eNOS activation, thus reduced the atherosclerotic lesion area. SAL increased eNOS-Ser1177 phosphorylation and decreased eNOS-Thr495 phosphorylation, indicative of eNOS activation in endothelium. The aortic sinus lesions in SAL treated mice displayed reduced inflammation. SAL significantly activated AMP-activated protein kinase (AMPK). Both AMPK inhibitor and AMPK small interfering RNA (siRNA) abolished SAL-induced Akt-Ser473 and eNOS-Ser1177 phosphorylation. In contrast, LY294002, the PI3k/Akt pathway inhibitor, abolished SAL-induced phosphorylation and expression of eNOS. High performance liquid chromatography (HPLC) analysis revealed that SAL decreased cellular ATP content and increased the cellular AMP/ATP ratio, which was associated with the activation of AMPK. SAL was found to decrease the mitochondrial membrane potential (ΔΨm), which is a likely consequence of reduced ATP production. The action of SAL to reduce atherosclerotic lesion formation may at least be attributed to its effect on improving endothelial function by promoting nitric oxide (NO) production, which was associated with mitochondrial depolarization and subsequent activation of the AMPK/PI3K/Akt/eNOS pathway. Taken together, our data described the effects of SAL on mitochondria, which played critical roles in improving endothelial function in atherosclerosis.