Different dosage forms of GnRHa with endocrine therapy in premenopausal hormone Receptor-Positive breast cancer.

BACKGROUND: Despite the wide use of a three-month gonadotropin-releasing hormone agonist (3M GnRHa) for ovarian function suppression (OFS) in premenopausal breast cancer patients, it remains unclear whether it is as effective and safe as a one-month GnRHa regimen (1M GnRHa) when combined with selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs), especially in younger patients. METHODS: This retrospective cohort study included 1109 premenopausal hormone receptor-positive (HR+) breast cancer patients treated with GnRHa plus SERM or AI. The estradiol (E2) inhibition rate within 1-24 months after treatment with 1M or 3M GnRHa in cohorts and different subgroups was analyzed. RESULTS: Following 1:1 propensity score matching, 950 patients with a mean age of 39 years and a median follow-up of 46 months were included. Both the 1M and 3M groups achieved >90% E2 inhibition within 24 months (94.53% vs 92.84%, 95% CI (-4.78%, 1.41%)), confirming the non-inferiority of 3M GnRHa. Both 1M and 3M GnRHa rapidly and consistently reduced E2 levels. 60 (6.3%) patients experienced incomplete ovarian function suppression (iOFS), with similar rates in the 1M and 3M groups (5.5% vs 7.2%). iOFS mainly occurred within the first 12 months, with age <40 years and no prior chemotherapy being the risk factors. Similar disease-free survival (DFS) and overall survival (OS) were found in the 1M and 3M groups, and in patients with complete and incomplete OFS (p > .05). CONCLUSIONS: The OFS with 3M GnRHa was not inferior to that with 1M GnRHa, regardless of age or combination with a SERM or an AI.

Effects of acupuncture on pregnancy outcomes in women undergoing in vitro fertilization: an updated systematic review and meta-analysis.

PURPOSE: To evaluate the effects of acupuncture on IVF-ET outcomes. METHODS: Digital databases, including Pubmed, Embase, the Cochrane Library, the Web of Science and ScienceDirect, were searched from their inception to July 2022. The MeSH terms we used included: acupuncture, in vitro fertilization, assisted reproductive technology and randomized controlled trial. The reference lists of relevant documents were also searched. The biases of included studies were assessed by the Cochrane Handbook 5.3. The major outcomes were clinical pregnancy rate (CPR) and live birth rate (LBR). The pregnancy outcomes reported in these trials were pooled and expressed as risk ratios (RR) with 95% confidence interval (CI) in the Review Manager 5.4 meta-analysis software. Heterogeneity of the therapeutic effect was evaluated with a forest plot analysis. Publication bias was assessed by a funnel plot analysis. RESULTS: Twenty-five trials (a total of 4757 participants) were included in this review. There were no significant publication biases for most of the comparisons among these studies. The pooled CPR (25 trials) of all the acupuncture groups (43.6%) was significantly higher than that of all the control groups (33.2%, P < 0.00001), and the pooled LBR (11 trials) of all the acupuncture groups (38.0%) was significantly higher than that of all the control groups (28.7%, P < 0.00001). Different acupuncture methods (manual acupuncture, electrical acupuncture and transcutaneous acupoint electrical stimulation), acupuncture time (before or during the time of controlled ovarian hyperstimulation and around the time of embryo transfer), and acupuncture courses (at least 4 sessions and less than 4 sessions) have respectively positive effects on IVF outcomes. CONCLUSION: Acupuncture can significantly improve CPR and LBR among women undergoing IVF. Placebo acupuncture can be a relatively ideal control measure.

Genome-Wide Identification and Expression Analysis of the Cucumber FKBP Gene Family in Response to Abiotic and Biotic Stresses.

The FKBP (FK506-binding protein) gene family is an important member of the PPlase protease family and plays a vital role during the processes of plant growth and development. However, no studies of the FKBP gene family have been reported in cucumber. In this study, 19 FKBP genes were identified in cucumber, which were located on chromosomes 1, 3, 4, 6, and 7. Phylogenetic analysis divided the cucumber FKBP genes into three subgroups. The FKBP genes in the same subgroup exhibited similar structures and conserved motifs. The cis-acting elements analysis revealed that the promoters of cucumber FKBP genes contained hormone-, stress-, and development-related cis-acting elements. Synteny analysis of the FKBP genes among cucumber, Arabidopsis, and rice showed that 12 kinds of syntenic relationships were detected between cucumber and Arabidopsis FKBP genes, and 3 kinds of syntenic relationships were observed between cucumber and rice FKBP genes. The tissue-specific expression analysis showed that some FKBP genes were expressed in all tissues, while others were only highly expressed in part of the 10 types of tissues. The expression profile analysis of cucumber FKBP genes under 13 types of stresses showed that the CsaV3_1G007080 gene was differentially expressed under abiotic stresses (high temperature, NaCl, silicon, and photoperiod) and biotic stresses (downy mildew, green mottle mosaic virus, Fusarium wilt, phytophthora capsica, angular leaf spot, and root-knot nematode), which indicated that the CsaV3_1G007080 gene plays an important role in the growth and development of cucumber. The interaction protein analysis showed that most of the proteins in the FKBP gene family interacted with each other. The results of this study will lay the foundation for further research on the molecular biological functions of the cucumber FKBP gene family.

LncRNA EILA promotes CDK4/6 inhibitor resistance in breast cancer by stabilizing cyclin E1 protein.

CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy are now standard first-line therapy for advanced HR+/HER2- breast cancer, but developing resistance is just a matter of time in these patients. Here, we report that a cyclin E1-interacting lncRNA (EILA) is up-regulated in CDK4/6i-resistant breast cancer cells and contributes to CDK4/6i resistance by stabilizing cyclin E1 protein. EILA overexpression correlates with accelerated cell cycle progression and poor prognosis in breast cancer. Silencing EILA reduces cyclin E1 protein and restores CDK4/6i sensitivity both in vitro and in vivo. Mechanistically, hairpin A of EILA binds to the carboxyl terminus of cyclin E1 protein and hinders its binding to FBXW7, thereby blocking its ubiquitination and degradation. EILA is transcriptionally regulated by CTCF/CDK8/TFII-I complexes and can be inhibited by CDK8 inhibitors. This study unveils the role of EILA in regulating cyclin E1 stability and CDK4/6i resistance, which may serve as a biomarker to predict therapy response and a potential therapeutic target to overcome resistance.

Literature review and prospect on oral cognition and disease diagnosis and treatment between Han and Tang dynasties.

Chinese medicine entered a significant period from foundation to maturity between Han and Tang dynasties when the Chinese traditional stomatology was a key stage. Sorting and analysis of existing literature and research outcomes have showed that current research on stomatology between Han and Tang dynasties focuses on oral physiology, pathology, diagnosis and treatment, and health care. It also involves stomatology history and explanation of termino-logies related to mouth and teeth recorded in medical books, use of simple methods, and thinking with citation and analysis of literature simply listed and reasoning preliminarily deducted. From the macro perspective, current research has not unveiled the whole picture of stomatology between the two dynasties and left a series of key issues unresolved. Thus, new methods should be developed and employed to carry out medical research on stomatology between Han and Tang dynasties given that is has a prosperous future.

Natural product P57 induces hypothermia through targeting pyridoxal kinase.

Induction of hypothermia during hibernation/torpor enables certain mammals to survive under extreme environmental conditions. However, pharmacological induction of hypothermia in most mammals remains a huge challenge. Here we show that a natural product P57 promptly induces hypothermia and decreases energy expenditure in mice. Mechanistically, P57 inhibits the kinase activity of pyridoxal kinase (PDXK), a key metabolic enzyme of vitamin B6 catalyzing phosphorylation of pyridoxal (PL), resulting in the accumulation of PL in hypothalamus to cause hypothermia. The hypothermia induced by P57 is significantly blunted in the mice with knockout of PDXK in the preoptic area (POA) of hypothalamus. We further found that P57 and PL have consistent effects on gene expression regulation in hypothalamus, and they may activate medial preoptic area (MPA) neurons in POA to induce hypothermia. Taken together, our findings demonstrate that P57 has a potential application in therapeutic hypothermia through regulation of vitamin B6 metabolism and PDXK serves as a previously unknown target of P57 in thermoregulation. In addition, P57 may serve as a chemical probe for exploring the neuron circuitry related to hypothermia state in mice.

Cuyun Recipe ameliorates pregnancy loss by regulating macrophage polarization and hypercoagulable state during the peri-implantation period in an ovarian hyperstimulation mouse model.

BACKGROUND: The Chinese herbal prescription Cuyun Recipe (CYR) has been widely used to treat clinical infertility and has shown good efficacy. Animal experiments have shown that CYR can promote implantation in mice, however, the exact mechanism underlying the implantation has not been elucidated. PURPOSE: To investigate the effect and mechanism of CYR on regulating macrophage polarization and hypercoagulability during the peri-implantation period in mice with ovarian hyperstimulation. METHODS: An ovarian hyperstimulation mouse model was developed, followed by treatment with CYR. Mice were sacrificed on day (D)4.5, D6, or D8 of gestation. The number of implantation sites, the pathological changes of the uterus and ovaries were assessed. The polarization of monocytes/macrophages in the spleen and endometrium, the expression and localization of cytokines were further detected. Furthermore, analyses of hypercoagulable state of the blood were also performed. RESULTS: Treatment with CYR increased the average number of implantation sites, promoted angiogenesis in endometrial, and regulated monocytes/macrophages and the cytokine levels. Moreover, CYR downregulated the overexpression of D-dimer and fgl2 after ovarian hyperstimulation. CONCLUSION: CYR facilitates embryo implantation by alleviating ovarian hyperstimulation, promoting endometrial decidualization and angiogenesis, regulating macrophage polarization, and reversing the hypercoagulable state of the blood.

SERPINA3-ANKRD11-HDAC3 pathway induced aromatase inhibitor resistance in breast cancer can be reversed by HDAC3 inhibition.

Endocrine resistance is a major challenge for breast cancer therapy. To identify the genes pivotal for endocrine-resistance progression, we screened five datasets and found 7 commonly dysregulated genes in endocrine-resistant breast cancer cells. Here we show that downregulation of serine protease inhibitor clade A member 3 (SERPINA3) which is a direct target gene of estrogen receptor α contributes to aromatase inhibitor resistance. Ankyrin repeat domain containing 11 (ANKRD11) works as a downstream effector of SERPINA3 in mediating endocrine-resistance. It induces aromatase inhibitor insensitivity by interacting with histone deacetylase 3 (HDAC3) and upregulating its activity. Our study suggests that aromatase inhibitor therapy downregulates SERPINA3 and leads to the ensuing upregulation of ANKRD11, which in turn promotes aromatase inhibitor resistance via binding to and activating HDAC3. HDAC3 inhibition may reverse the aromatase inhibitor resistance in ER-positive breast cancer with decreased SERPINA3 and increased ANKRD11 expression.

The role of Hippo pathway in ovarian development.

The follicle is the functional unit of the ovary, whereby ovarian development is largely dependent on the development of the follicles themselves. The activation, growth, and progression of follicles are modulated by a diverse range of factors, including reproductive endocrine system and multiple signaling pathways. The Hippo pathway exhibits a high degree of evolutionary conservation between both Drosophila and mammalian systems, and is recognized for its pivotal role in regulating cellular proliferation, control of organ size, and embryonic development. During the process of follicle development, the components of the Hippo pathway show temporal and spatial variations. Recent clinical studies have shown that ovarian fragmentation can activate follicles. The mechanism is that the mechanical signal of cutting triggers actin polymerization. This process leads to the disruption of the Hippo pathway and subsequently induces the upregulation of downstream CCN and apoptosis inhibitors, thereby promoting follicle development. Thus, the Hippo pathway plays a crucial role in both the activation and development of follicles. In this article, we focused on the development and atresia of follicles and the function of Hippo pathway in these processes. Additionally, the physiological effects of Hippo pathway in follicle activation are also explored.

Polyketides with potential bioactivities from the mangrove-derived fungus Talaromyces sp. WHUF0362.

Metabolites of microorganisms have long been considered as potential sources for drug discovery. In this study, five new depsidone derivatives, talaronins A-E (1-5) and three new xanthone derivatives, talaronins F-H (6-8), together with 16 known compounds (9-24), were isolated from the ethyl acetate extract of the mangrove-derived fungus Talaromyces species WHUF0362. The structures were elucidated by analysis of spectroscopic data and chemical methods including alkaline hydrolysis and Mosher's method. Compounds 1 and 2 each attached a dimethyl acetal group at the aromatic ring. A putative biogenetic relationship of the isolated metabolites was presented and suggested that the depsidones and the xanthones probably had the same biosynthetic precursors such as chrysophanol or rheochrysidin. The antimicrobial activity assay indicated that compounds 5, 9, 10, and 14 showed potent activity against Helicobacter pylori with minimum inhibitory concentration (MIC) values in the range of 2.42-36.04 µmol/L. While secalonic acid D (19) demonstrated significant antimicrobial activity against four strains of H. pylori with MIC values in the range of 0.20 to 1.57 µmol/L. Furthermore, secalonic acid D (19) exhibited cytotoxicity against cancer cell lines Bel-7402 and HCT-116 with IC50 values of 0.15 and 0.19 µmol/L, respectively. The structure-activity relationship of depsidone derivatives revealed that the presence of the lactone ring and the hydroxyl at C-10 was crucial to the antimicrobial activity against H. pylori. The depsidone derivatives are promising leads to inhibit H. pylori and provide an avenue for further development of novel antibiotics. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-023-00170-5.

Discovery of 2,5-disubstituted furan derivatives featuring a benzamide motif for overcoming P-glycoprotein mediated multidrug resistance in MCF-7/ADR cell.

P-glycoprotein (P-gp) is one of the drug efflux transporters that triggers multidrug resistance (MDR) in cells. Herein, by utilizing the strategies of active skeleton splicing and structural optimization on the lead compound 5 m, a total of 50 novel 2,5-disubstituted furan derivatives were designed, synthesized, and screened for P-gp inhibitory activity. The structure-activity relationship analysis enabled the identification of an important pharmacophore N-phenylbenzamide, which resulted in the discovery of a promising drug lead compound Ⅲ-8. Ⅲ-8 possesses broad-spectrum reversal activity and low toxicity in MCF-7/ADR cells. Western blot and Rh123 accumulation assay demonstrated that Ⅲ-8 displayed the reversal activity by inhibiting P-gp efflux. Molecular docking analysis indicated a potent affinity of Ⅲ-8 to P-gp by forming H-bond interactions with residues Asn 721 and Met 986. Ⅲ-8 was determined to be a highly effective and safe P-gp inhibitor in an MCF-7/ADR xenograft mouse model.

Clinical trials using dental stem cells: 2022 update.

For nearly 20 years, dental stem cells (DSCs) have been successfully isolated from mature/immature teeth and surrounding tissue, including dental pulp of permanent teeth and exfoliated deciduous teeth, periodontal ligaments, dental follicles, and gingival and apical papilla. They have several properties (such as self-renewal, multidirectional differentiation, and immunomodulation) and exhibit enormous potential for clinical applications. To date, many clinical articles and clinical trials using DSCs have reported the treatment of pulpitis, periapical lesions, periodontitis, cleft lip and palate, acute ischemic stroke, and so on, and DSC-based therapies obtained satisfactory effects in most clinical trials. In these studies, no adverse events were reported, which suggested the safety of DSC-based therapy. In this review, we outline the characteristics of DSCs and summarize clinical trials and their safety as DSC-based therapies. Meanwhile, we also present the current limitations and perspectives of DSC-based therapy (such as harvesting DSCs from inflamed tissue, applying DSC-conditioned medium/DSC-derived extracellular vesicles, and expanding-free strategies) to provide a theoretical basis for their clinical applications.

Phytochemistry and pharmacology of natural prenylated flavonoids.

Prenylated flavonoids are a special kind of flavonoid derivative possessing one or more prenyl groups in the parent nucleus of the flavonoid. The presence of the prenyl side chain enriched the structural diversity of flavonoids and increased their bioactivity and bioavailability. Prenylated flavonoids show a wide range of biological activities, such as anti-cancer, anti-inflammatory, neuroprotective, anti-diabetic, anti-obesity, cardioprotective effects, and anti-osteoclastogenic activities. In recent years, many compounds with significant activity have been discovered with the continuous excavation of the medicinal value of prenylated flavonoids, and have attracted the extensive attention of pharmacologists. This review summarizes recent progress on research into natural active prenylated flavonoids to promote new discoveries of their medicinal value.

HDAC7 inhibits cell proliferation via NudCD1/GGH axis in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. In the absence of effective molecular markers for TNBC, there is an urgent clinical need for promising therapeutic target for TNBC. Histone deacetylases (HDACs), key regulators for chromatin remodeling and gene expression, have been suggested to play critical roles in cancer development. However, little is known ~the functions and implications of HDACs in TNBC treatment in the future. By analyzing the expression and prognostic significance of HDAC family members in TNBC through TCGA and METABRIC databases, HDAC7 was found to be downregulated in TNBC samples and the survival of patients with lower expression of HDAC7 was shorter. Furthermore, HDAC7 was negatively associated with NudC domain containing 1 (NudCD1) and γ-glutamyl hydrolase (GGH). Loss of NudCD1 or GGH predicted improved overall survival time (OS) of patients with TNBC. In vitro experiments showed that silencing of HDAC7 enhanced TNBC cell proliferation, while overexpression HDAC7 inhibited TNBC cell proliferation. The results of functional experiments confirmed that HDAC7 negatively modulated GGH and NudCD1 expression. Furthermore, decrease of NudCD1 or GGH inhibited cell proliferation. Notably, the HDAC7-NudCD1/GGH axis was found to be associated with NK cell infiltration. Overall, the present study revealed a novel role of HDAC7-NudCD1/GGH axis in TNBC, which might provide a promising treatment strategy for patients with TNBC.

Cucurbitane-type triterpenoids from the fruits of Citrullus colocynthis.

A phytochemical investigation of the fruits of Citrullus colocynthis resulted in the isolation of 21 structurally diverse cucurbitane triterpenoids, including 9 previously undescribed ones, colocynins A-I (1-9). Their absolute configurations were elucidated by means of quantum chemical electronic circular dichroism (ECD) calculations, CD exciton chirality method, and single-crystal X-ray crystallography. Colocynins A-C (1-3) represent the first examples of nonanorcucurbitane-type triterpenoids. An anti-acetylcholinesterase activity assay showed that 6, 10, 13, 18, and 20 exhibited inhibitory activities, with IC50 values ranging from 5.0 to 21.7 µM. In addition, 18 and 21 showed significant cytotoxicity against PACA, A431, and HepG2 cells, with IC50 values ranging from 0.042 to 0.60 and 3.6-14.4 µM, respectively.

A comparative in vitro and in vivo study of porcine- and bovine-derived non-cross-linked collagen membranes.

The porcine-derived non-cross-linked collagen membrane Bio-gide® (BG) and the bovine-derived non-cross-linked collagen membrane Heal-all® (HA) were compared to better understand their in vitro biophysical characteristics and in vivo degradation patterns as a reference for clinical applications. It was showed that the porosity, specific surface area, pore volume and pore diameter of BG were larger than those of HA (64.5 ± 5.2% vs. 48.6 ± 6.1%; 18.6 ± 2.8 m2 /g vs. 2.3 ± 0.6 m2 /g; 0.114 ± 0.002 cm3 /g vs. 0.003 ± 0.001 cm3 /g; 24.4 ± 3.5 nm vs. 7.3 ± 1.7 nm, respectively); the average swelling ratio of BG was higher than that of HA (412.6 ± 41.2% vs. 270.0 ± 2.7%); the tensile strength of both dry and wet HA was higher than those of BG (18.26 ± 3.27 MPa vs. 4.02 ± 1.35 MPa; 2.24 ± 0.21 MPa vs. 0.16 ± 0.02 MPa, respectively); 73% of HA remained after 72 h in collagenase solution, whereas only 8.2% of BG remained. A subcutaneous rat implantation model revealed that, at 3, 7, 14, 28, and 56 days postmembrane implantation, there were more total inflammatory cells, especially more M1 and M2 polarized macrophages and higher M2/M1 ratio in BG than in HA; in addition, the fibrous capsule around BG was also thicker than that around HA. Moreover, concentrations of dozens of cytokines including interleukin-2(IL-2), IL-7, IL-10 and so forth. in BG were higher than those in HA. It is suggested that BG and HA might be suitable for different clinical applications according to their different characteristics.

Overexpressed Cyclin D1 and CDK4 proteins are responsible for the resistance to CDK4/6 inhibitor in breast cancer that can be reversed by PI3K/mTOR inhibitors.

CDK4/6 inhibitors are the standard treatment in advanced HR+/HER2- breast cancer patients. Nevertheless, the resistance to CDK4/6 inhibitors is inevitable and the strategies to overcome resistance are of great interest. Here, we show that the palbociclib-resistant breast cancer cells expressed significantly higher levels of Cyclin D1 and CDK4 proteins because of upregulated protein synthesis. Silencing Cyclin D1 or CDK4 led to cell cycle arrest while silencing Cyclin E1 or CDK2 restored the sensitivity to palbociclib. Furthermore, PI3K/mTOR pathway was hyper-activated in palbociclib-resistant cells, leading to more phosphorylated 4E-BP1 and higher levels of Cyclin D1 and CDK4 translation. Targeting PI3K/mTOR pathway with a specific PI3Kα inhibitor (BYL719) or an mTOR inhibitor (everolimus) reduced the protein levels of Cyclin D1 and CDK4, and restored the sensitivity to palbociclib. The tumor samples expressed significantly higher levels of Cyclin D1, CDK4, p-AKT and p-4E-BP1 after progression on palbociclib treatment. In conclusion, our findings suggest that overexpressed Cyclin D1 and CDK4 proteins lead to the resistance to CDK4/6 inhibitor and PI3K/mTOR inhibitors are able to restore the sensitivity to CDK4/6 inhibitors, which provides the biomarker and rationale for the combinational use of CDK4/6 inhibitors and PI3K/mTOR inhibitors after CDK4/6 inhibitor resistance in breast cancer.

Corrigendum: Bone marrow mesenchymal stem cells in premature ovarian failure: Mechanisms and prospects.

[This corrects the article DOI: 10.3389/fimmu.2022.997808.].

Bone marrow mesenchymal stem cells in premature ovarian failure: Mechanisms and prospects.

Premature ovarian failure (POF) is a common female reproductive disorder and characterized by menopause, increased gonadotropin levels and estrogen deficiency before the age of 40 years old. The etiologies and pathogenesis of POF are not fully clear. At present, hormone replacement therapy (HRT) is the main treatment options for POF. It helps to ameliorate perimenopausal symptoms and related health risks, but can't restore ovarian function and fertility fundamentally. With the development of regenerative medicine, bone marrow mesenchymal stem cells (BMSCs) have shown great potential for the recovery of ovarian function and fertility based on the advantages of abundant sources, high capacity for self-renewal and differentiation, low immunogenicity and less ethical considerations. This systematic review aims to summarize the possible therapeutic mechanisms of BMSCs for POF. A detailed search strategy of preclinical studies and clinical trials on BMSCs and POF was performed on PubMed, MEDLINE, Web of Science and Embase database. A total of 21 studies were included in this review. Although the standardization of BMSCs need more explorations, there is no doubt that BMSCs transplantation may represent a prospective therapy for POF. It is hope to provide a theoretical basis for further research and treatment for POF.

Two New Austocystin Analogs from the Marine-Derived Fungus Aspergillus sp. WHUF05236.

Two new austocystin analogs, austocystin P (1) and austocystin Q (2), along with fourteen known compounds (3-16) were isolated from the fermentation extract of Aspergillus sp. WHUF05236. The planar structures of 1 and 2 were elucidated through 1D, 2D NMR and MS analyses. Their absolute configurations were determined by the time-dependent density functional (TDDFT)-ECD calculation. Compounds 3, 11, and 12 exhibited antimicrobial activities against Helicobacter pylori with MIC values ranging from 20.00 to 43.47 µM. Compounds 3, 6, and 7 showed cytotoxicities against the human colon cancer cell lines Hct-116 with IC50 values of 101.79, 65.46, and 36.72 µM, respectively.