Adrenal pheochromocytoma impacts three main pathways: cysteine-methionine, pyrimidine, and tyrosine metabolism. / è‚¾ä¸Šè ºå—œé“¬ç»†èƒžç˜¤å½±å“ä¸‰æ¡ä¸»è¦ä»£è°¢é€šè·¯ï¼šåŠèƒ±æ°¨é ¸-è›‹æ°¨é ¸ä»£è°¢ã€å˜§å•¶ä»£è°¢å’Œé ªæ°¨é ¸ä»£è°¢é€šè·¯.

Pheochromocytomas and paragangliomas (PPGLs) cause symptoms by altering the circulation levels of catecholamines and peptide hormones. Currently, the diagnosis of PPGLs relies on diagnostic imaging and the detection of catecholamines. In this study, we used ultra-performance liquid chromatography (UPLC)/quadrupole time-of-flight mass spectrometry (Q-TOF MS) analysis to identify and measure the perioperative differential metabolites in the plasma of adrenal pheochromocytoma patients. We identified differentially expressed genes by comparing the transcriptomic data of pheochromocytoma with the normal adrenal medulla. Through conducting two steps of metabolomics analysis, we identified 111 differential metabolites between the healthy group and the patient group, among which 53 metabolites were validated. By integrating the information of differential metabolites and differentially expressed genes, we inferred that the cysteine-methionine, pyrimidine, and tyrosine metabolism pathways were the three main metabolic pathways altered by the neoplasm. The analysis of transcription levels revealed that the tyrosine and cysteine-methionine metabolism pathways were downregulated in pheochromocytoma, whereas the pyrimidine pathway showed no significant difference. Finally, we developed an optimized diagnostic model of two metabolites, L-dihydroorotic acid and vanylglycol. Our results for these metabolites suggest that they may serve as potential clinical biomarkers and can be used to supplement and improve the diagnosis of pheochromocytoma.

Adrenal pheochromocytoma impacts three main pathways: cysteine-methionine, pyrimidine, and tyrosine metabolism. / è‚¾ä¸Šè ºå—œé“¬ç»†èƒžç˜¤å½±å“ä¸‰æ¡ä¸»è¦ä»£è°¢é€šè·¯ï¼šåŠèƒ±æ°¨é ¸-è›‹æ°¨é ¸ä»£è°¢ã€å˜§å•¶ä»£è°¢å’Œé ªæ°¨é ¸ä»£è°¢é€šè·¯.

Pheochromocytomas and paragangliomas (PPGLs) cause symptoms by altering the circulation levels of catecholamines and peptide hormones. Currently, the diagnosis of PPGLs relies on diagnostic imaging and the detection of catecholamines. In this study, we used ultra-performance liquid chromatography (UPLC)/quadrupole time-of-flight mass spectrometry (Q-TOF MS) analysis to identify and measure the perioperative differential metabolites in the plasma of adrenal pheochromocytoma patients. We identified differentially expressed genes by comparing the transcriptomic data of pheochromocytoma with the normal adrenal medulla. Through conducting two steps of metabolomics analysis, we identified 111 differential metabolites between the healthy group and the patient group, among which 53 metabolites were validated. By integrating the information of differential metabolites and differentially expressed genes, we inferred that the cysteine-methionine, pyrimidine, and tyrosine metabolism pathways were the three main metabolic pathways altered by the neoplasm. The analysis of transcription levels revealed that the tyrosine and cysteine-methionine metabolism pathways were downregulated in pheochromocytoma, whereas the pyrimidine pathway showed no significant difference. Finally, we developed an optimized diagnostic model of two metabolites, L-dihydroorotic acid and vanylglycol. Our results for these metabolites suggest that they may serve as potential clinical biomarkers and can be used to supplement and improve the diagnosis of pheochromocytoma.

Circular RNAs in Breast Cancer: An Update.

Breast cancer (BC), characterized by high heterogeneity, is the most commonly reported malignancy among females across the globe. Every year, many BC patients die owing to delayed diagnosis and treatment. Increasing researches have indicated that aberrantly expressed circular RNAs (circRNAs) are implicated in the tumorigenesis and progression of various tumors, including BC. Hence, this article provides a summary of the biogenesis and functions of circRNAs, as well as an examination of how circRNAs regulate the progression of BC. Moreover, circRNAs have aroused incremental attention as potential diagnostic and prognostic biomarkers for BC. Exosomes enriched with circRNAs can be secreted into the tumor microenvironment to mediate intercellular communication, affecting the progression of BC. Detecting the expression levels of exosomal circRNAs may provide reference for BC diagnosis and prognosis prediction. Illuminating insights into the earlier diagnosis and better treatment regimens of BC will be potentially available following elucidation of deeper regulatory mechanisms of circRNAs in this malignancy.

NADase CD38 is a key determinant of ovarian aging.

The ovary ages earlier than most other tissues, yet the underlying mechanisms remain elusive. Here a comprehensive analysis of transcriptomic landscapes in different organs in young and middle-aged mice revealed that the ovaries showed earlier expression of age-associated genes, identifying increased NADase CD38 expression and decreased NAD+ levels in the ovary of middle-aged mice. Bulk and single-cell RNA sequencing revealed that CD38 deletion mitigated ovarian aging, preserving fertility and follicle reserve in aged mice by countering age-related gene expression changes and intercellular communication alterations. Mechanistically, the earlier onset of inflammation induced higher expression levels of CD38 and decreased NAD+ levels in the ovary, thereby accelerating ovarian aging. Consistently, pharmacological inhibition of CD38 enhanced fertility in middle-aged mice. Our findings revealed the mechanisms underlying the earlier aging of the ovary relative to other organs, providing a potential therapeutic target for ameliorating age-related female infertility.

Melatonin Potentiates Sensitivity to 5-Fluorouracil in Gastric Cancer Cells by Upregulating Autophagy and Downregulating Myosin Light-Chain Kinase.

5-Fluorouracil is an effective chemotherapeutic drug for gastric cancer. However, the acquisition of chemotherapeutic resistance remains a challenge in treatment. Melatonin can enhance the therapeutic effect of 5-fluorouracil; however, the underlying mechanisms are not well understood. We investigated the effects of combinations of melatonin and 5-fluorouracil on the proliferation, migration and invasion of gastric cancer cells. Melatonin significantly potentiated the 5-fluorouracil-mediated inhibition of proliferation, migration and invasion in gastric cancer cells, which potentiates sensitivity to 5-FU by promoting the activation of Beclin-1-dependent autophagy and targeting the myosin light-chain kinase (MLCK) signaling pathway. Previous studies have shown that autophagy might be associated with the MLCK signaling pathway. The autophagy inhibitor, 3-methyladenine, effectively rescued the migratory and invasive capabilities of gastric cancer cells, while also reducing expression level of MLCK and the phosphorylation level of MLC. This indicates that autophagy is involved in tumor metastasis, which may be related to inhibition of the MLCK signaling pathway. Our findings indicate that melatonin can improve the effectiveness of 5-fluorouracil in gastric cancer and could be used as a supplemental agent in the treatment of gastric cancer with 5-fluorouracil.

Exosome-derived miR-372-5p promotes stemness and metastatic ability of CRC cells by inducing macrophage polarization.

Colorectal cancer (CRC) is the most common malignancy in the digestive system, and tumor metastasis is the main cause of death in clinical patients with CRC. It has been shown that exosomes promote phenotypic changes in macrophages and tumor metastasis in the CRC tumor microenvironment. In this study, we used miRNA-seq technology to screen out the highly expressed miR-372-5p among the miRNAs differentially expressed in plasma exosomes of clinical CRC patients. It was found that miR-372-5p highly expressed in HCT116 exosomes could be phagocytosed by macrophages and promote their polarization into M2 macrophages by regulating the PTEN/AKT pathway. Meanwhile, co-culture of CRC cells with conditioned medium (CM) of macrophages enhanced the EMT, stemness and metastasis of CRC cells. Mechanistically, CRC cells exosome-derived miR-372-5p induced polarized M2 macrophages to secrete chemokine C-X-C-Motif Ligand 12 (CXCL12), which activated the WNT/ß-catenin pathway to promote the EMT, stemness and metastatic ability of CRC cells. In summary, this study elucidated the molecular mechanism of exosomal miR-372-5p promoting metastasis and stemness in CRC, which may provide new therapeutic targets for CRC metastasis and prognosis assessment.

Colorectal cancer tumor cell-derived exosomal miR-203a-3p promotes CRC metastasis by targeting PTEN-induced macrophage polarization.

(1) Background: Tumor-associated macrophages (TAMs) are important immunocytes associated with liver metastasis of colorectal cancer (CRLM). However, the molecular processes underpinning the interaction between the TME and the tumour-derived exosomal miRNAs in CRLM are not being fully understood; (2) Methods: Transmission electron microscopy was utilized to confirm the existence of exosomes after differential ultracentrifugation. To determine the roles of exosomal miR-203a-3p, an in vivo and in vitro investigation was conducted. The mechanism by which exosomal miR-203a-3p governs the interaction between CRC cells and M2 macrophages was investigated using a dual-luciferase reporter assay, western blot, and other techniques; (3) Results: Overexpression of miR-203a-3p was associated with poor prognosis and liver metastasis in CRC patients. Exosomal miR-203a-3p was upregulated in the plasma of CRC patients and highly metastatic CRC cells HCT116, and it could be transported to macrophages via exosomes. Exosomal miR-203a-3p induced M2 polarization of macrophages by controlling PTEN and activating the PI3K/Akt signaling pathway. M2-polarized macrophages secreted the CXCL12, which increased cancer metastasis and resulted in pre-metastatic niches in CRLM by CXCL12/CXCR4/NF-κB signaling pathway. Co-culture of macrophages with miR-203a-3p-transfected or exosome-treated cells increased the ability of HCT116 cells to metastasize both in vitro and in vivo; (4) Conclusions: Exosomes produced by highly metastatic CRC cells and rich in miR-203a-3p may target PTEN and alter the TME, promoting liver metastasis in CRC patients. These findings offer fresh understanding of the liver metastatic process in CRC.

The Multimorbidity and Lifestyle Correlates in Chinese Population Residing in Macau: Findings from a Community-Based Needs Assessment Study.

Multimorbidity has become one of the most pressing public health concerns worldwide. The objectives of this study were to understand the prevalence of multimorbidity and its relationship with lifestyle factors among Chinese adults in Macau, and to investigate the combined contribution of common lifestyle factors in predicting multimorbidity. Data were collected through face-to-face interviews using a self-reported questionnaire on common chronic diseases, lifestyle factors and sociodemographics. BMI, physical activity, drinking status, smoking status and sleep quality were assessed, and a composite lifestyle score (0 to 9 points) was calculated, and the higher the score, the healthier the lifestyle. A total of 1443 participants were included in the analysis, of whom 55.2% were female, 51.8% were middle aged or elderly and 30.5% completed tertiary education or higher. The prevalence of multimorbidity was 10.3%. The combination of hypertension and hyperlipidaemia was the most common (22.2%) multimorbidity among the participants with multimorbidity. After the adjustment of the covariates, it was found that the participants who were overweight (OR: 1.95, 95% CI: 1.18-3.20, p = 0.009) or obese (OR: 3.76, 95% CI: 2.38-5.96, p < 0.001), former drinkers (OR: 2.43, 95% CI: 1.26-4.69, p = 0.008), and those who reported poor sleep quality (OR: 2.25, 95% CI: 1.49-3.40, p < 0.001) had a high risk of developing multimorbidity. A one-unit increase in the lifestyle score was associated with a 0.33-times reduction in the risk of developing multimorbidity (OR: 0.67; 95% CI: 0.59-0.77, p < 0.001). A combination of lifestyle factors can influence a variety of multimorbidity among the Chinese adults in Macau. Thus, comprehensively assessing the combined contribution of several lifestyle factors in predicting multimorbidity is important.

Collapsin response mediator protein 5-associated optic neuropathy: clinical characteristics, radiologic clues, and outcomes.

Objective: Collapsin response mediator protein 5-associated optic neuropathy (CRMP5-ON) is a rare entity of autoimmune optic neuropathy. This study aimed to review the neuro-ophthalmic findings and outcomes in a series of patients with CRMP5-ON to further characterize its clinical phenotype, radiologic clues, and outcomes. Methods: This was a retrospective case series and a single-center medical chart review of all patients with CRPM5-seropositive ON at the Department of Neurology, Beijing Tongren Hospital, from December 1, 2020, to March 31, 2023. The main outcome measures were neuro-ophthalmic manifestations, radiologic characteristics, and clinical outcomes of CRMP5-ON; coexisting neural autoantibody, paraneoplastic associations, and the impact of immunosuppressant therapy. Results: Five patients were identified. Four (80%) were female, and the average age at onset was 59.4 years (range 53-69 years), with an average follow-up of 15.3 months (range 1.4-28.7 months). The average best-corrected visual acuity (BCVA) at nadir was 20/120 (range 20/20 to count fingers). Seven of ten affected eyes (70%) showed diffuse defects of the central field. Painless bilateral involvement and optic disk edema occurred in 100% of patients, combined with vitritis, uveitis, or retinitis in four (80%). Four patients (80%) had MRI abnormalities along the optic nerve (one patient with optic nerve enhancement and three patients had optic nerve sheath enhancement or peribulbar fat enhancement). Three patients (60%) had optic neuropathy with other neurologic symptoms. Four patients (80%) had confirmed cancer (two were small-cell lung carcinoma, one was papillary thyroid carcinoma and another was thymoma and invasive pulmonary adenocarcinoma). All cancers were identified after the presentation of the optic neuropathy. The intervention included IVIG, IVMP, surgery and chemotherapy. The average BCVA at the last follow-up was 20/50 (range 20/20 to count fingers). Three patients had surgery during the initial hospitalization, and were stable during the follow-up. Among two patients who received IVMP, both had improvement after treatment, although one patient had worsening non-ocular neurologic symptoms during the steroid taper. Conclusion: CRMP5-ON presented with optic disc edema, often bilateral involved and combined with vitreitis, retinitis, or uveitis. CRMP5-ON can present with MRI optic nerve or perineural optic nerve enhancement, especially in the optic nerve sheath. CRMP5-ON is closely related to paraneoplastic neurologic syndrome. Cancer screening and intervention are crucial to prognosis.

Shared diagnostic genes and potential mechanism between PCOS and recurrent implantation failure revealed by integrated transcriptomic analysis and machine learning.

Polycystic ovary syndrome (PCOS) is a complex endocrine metabolic disorder that affects 5-10% of women of reproductive age. The endometrium of women with PCOS has altered immune cells resulting in chronic low-grade inflammation, which attribute to recurrent implantation failure (RIF). In this study, we obtained three PCOS and RIF datasets respectively from the Gene Expression Omnibus (GEO) database. By analyzing differentially expressed genes (DEGs) and module genes using weighted gene co-expression networks (WGCNA), functional enrichment analysis, and three machine learning algorithms, we identified twelve diseases shared genes, and two diagnostic genes, including GLIPR1 and MAMLD1. PCOS and RIF validation datasets were assessed using the receiver operating characteristic (ROC) curve, and ideal area under the curve (AUC) values were obtained for each disease. Besides, we collected granulosa cells from healthy and PCOS infertile women, and endometrial tissues of healthy and RIF patients. RT-PCR was used to validate the reliability of GLIPR1 and MAMLD1. Furthermore, we performed gene set enrichment analysis (GSEA) and immune infiltration to explore the underlying mechanism of PCOS and RIF cooccurrence. Through the functional enrichment of twelve shared genes and two diagnostic genes, we found that both PCOS and RIF patients had disturbances in metabolites related to the TCA cycle, which eventually led to the massive activation of immune cells.

Layered Double Hydroxide-Loaded miR-30a for the Treatment of Breast Cancer In Vitro and In Vivo.

MicroRNAs (miRNAs) play an essential role in cancer therapy, but the disadvantages of its poor inherent stability, rapid clearance, and low delivery efficiency affect the therapeutic efficiency. Loading miRNAs by nanoformulations can improve their bioavailability and enhance therapeutic efficiency, which is an effective miRNA delivery strategy. In this study, we synthesized layered double hydroxides (LDH), which are widely used as carriers of drugs or genes due to the characteristics of good biocompatibility, high loading capacity, and pH sensitivity. We loaded the suppressor oncogene miR-30a on LDH nanomaterials (LDH@miR-30a) and determined the mass ratio of miRNA binding to LDH by agarose gel electrophoresis. LDH@miR-30a was able to escape the lysosomal pathway and was successfully phagocytosed by breast cancer SKBR3 cells and remained detectable in the cells after 24 h of co-incubation. In vitro experiments showed that LDH@miR-30a-treated SKBR3 cells showed decreased proliferation and cell cycle arrest in the G0/G1 phase and LDH@miR-30a was able to regulate the epithelial-mesenchymal transition (EMT) process and inhibit cell migration and invasion by targeting SNAI1. Meanwhile, in vivo experiments showed that nude mice treated with LDH@miR-30a showed a significant reduction in their solid tumors and no significant impairment of vital organs was observed. In conclusion, LDH@miR-30a is an effective drug delivery system for the treatment of breast cancer.

Glycolysis-based drug delivery nanosystems for therapeutic use in tumors and applications.

Tumor cells are able to use glycolysis to produce energy under hypoxic conditions, and even under aerobic conditions, they rely mainly on glycolysis for energy production, the Warburg effect. Conventional tumor therapeutic drugs are unidirectional, lacking in targeting and have limited therapeutic effect. The development of a large number of nanocarriers and targeted glycolysis for the treatment of tumors has been extensively investigated in order to improve the therapeutic efficacy. This paper reviews the research progress of nanocarriers based on targeting key glycolytic enzymes and related transporters, and combines nanocarrier systems with other therapeutic approaches to provide a new strategy for targeted glycolytic treatment of tumors, providing a theoretical reference for achieving efficient targeted treatment of tumors.

Effect of BMI on the value of serum progesterone to predict clinical pregnancy outcome in IVF/ICSI cycles: a retrospective cohort study.

Background: Numerous research have investigated the predictor role of progesterone (P) level on the human Chorionic Gonadotropin (hCG) trigger day of assisted reproductive technology (ART) outcomes. However, the relationship of progesterone levels on hCG day to clinical pregnancy outcomes in IVF/ICSI cycles for patients with different BMI groups is still elusive. This study aimed to investigate the effects of progesterone elevation on triggering day on clinical pregnancy rate (CPR) of IVF/ICSI cycles in patients with different female BMI. Methods: We conducted a retrospective cohort study included 6982 normal-weight parents (18.5Kg/m2≤BMI<25Kg/m2) and 2628 overweight/obese patients (BMI≥25Kg/m2) who underwent fresh day 3 cleavage embryo transfer (ET) in IVF/ICSI cycles utilizing GnRH agonist to control ovarian stimulation. Results: The interaction between BMI and P level on triggering day on CPRs was significant (p<0.001). The average level of serum P was reduced with the increase in maternal BMI. Serum P adversely affected CPR in distinct BMI groups. In the normal weight group, CPRs were decreasedas serum P concentrations gradually increased (p<0.001 for overall trend). The CPRs (lower than 65.8%) of progesterone level > 1.00 ng/ml on triggering day were significantly lower than that (72.4%) of progesterone level <0.5 ng/ml. In the overweight/obese group, CPRs showed a decrease statistically with progesterone levels of ≥2.00 ng/ml compared to progesterone levels of <0.5 ng/ml (51.0% VS. 64.9%, p=0.016). After adjusting for confounders, progesterone elevation (PE) negatively correlated with CPRs only in the normal weight group (OR: 0.755 [0.677-0.841], p<0.001), not in the overweight/obese group (p=0.063). Conclusion: Women with higher BMI exhibited a lower progesterone level on triggering day. Additionally, PE on hCG day is related to decreased CPRs in GnRH agonist IVF/ICSI cycles with cleavage embryo transfers regardless of women's BMI level (normal weight VS. overweight/obesity).

Decreased NOTCH1 signaling activated autophagy in the mid-secretory endometrium of patients with recurrent implantation failure†.

Recurrent implantation failure severely impairs fertility in females of childbearing age, which poses a great challenge to assisted reproductive technology, and its etiology is still unclear. Several studies have demonstrated that endometrial autophagy takes an important part in human endometrial receptivity, but its role in recurrent implantation failure remains largely unknown. Here, we collected mid-secretory endometrial tissue from recurrent implantation failure patients and fertile controls during menstruation and early pregnancy. Immunohistochemistry, western blotting, and quantitative real-time PCR were performed to compare the expression of microtubule-associated protein 1 light chain 3B, sequestosome 1, NOTCH1 signaling pathway members, and endometrial receptivity markers between recurrent implantation failure and control groups. In addition, to assess endometrial autophagy, transmission electron microscopy was used to observe autophagosomes. By RNA interference, we further investigated the effects of NOTCH1 on autophagy in Ishikawa cells. We found that endometrial autophagy was upregulated in the mid-secretory and decidual phases than in the early-proliferative phase. Compared to the control group, more autophagosomes were observed in the mid-secretory endometrium of recurrent implantation failure patients, which was accompanied by the downregulation of NOTCH1 signaling pathway members and endometrial receptivity markers. Moreover, knockdown of NOTCH1 impaired the receptivity of Ishikawa cells via protein kinase B/mammalian target of rapamycin pathway-mediated autophagy activation. Our data suggested that abnormally elevated autophagy and decreased NOTCH1 signaling pathway activity were observed in the mid-secretory endometrium of patients with recurrent implantation failure, perhaps due to decreased NOTCH1 pathway-mediated autophagy activation in endometrial cells impairing receptivity.

The reference value of anti-Müllerian hormone to diagnose polycystic ovary syndrome is inversely associated with BMI: a retrospective study.

BACKGROUND: This study aimed to evaluate the cut-off value of anti-Müllerian hormone (AMH) combined with body mass index (BMI) in the diagnosis of polycystic ovary syndrome (PCOS) and polycystic ovary morphology (PCOM). METHODS: This retrospective study included 15,970 patients: 3775 women with PCOS, 2879 women with PCOM, and 9316 patients as controls. Multivariate logistic regression analysis was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for AMH. We randomly divided the patients into two data sets. In dataset 1, a receiver operating characteristic (ROC) curve was generated to analyze the accuracy of basic AMH levels in diagnosing PCOS and PCOM. The optimal cut-off value was calculated in dataset 1 and validated in dataset 2, expressed as sensitivity and specificity. RESULTS: In the PCOS group, obese patients had the lowest AMH levels, while underweight patients had the highest AMH level (P < 0.001). After adjusting for age, the ratio of luteinizing hormone (LH) and follicle stimulating hormone (FSH), serum testosterone level, and BMI, AMH was an independent predictor of PCOS and PCOM. In the group with BMI < 18.5 kg/m2, the optimistic AMH cut-off value was 5.145 ng/mL with a sensitivity of 84.3% and specificity of 89.1%, whereas in the BMI ≥ 28 kg/m2 group, the optimistic AMH cut-off value was 3.165 ng/mL with a sensitivity of 88.7% and specificity of 74.6%. For the BMI range categories of 18.5-24, 24.0-28 kg/m2, the optimistic AMH cut-off values were 4.345 ng/mL and 4.115 ng/mL, respectively. The tendency that the group with lower weight corresponded to higher AMH cut-off values was also applicable to PCOM. In the same BMI category, patients with PCOM had a lower AMH diagnosis threshold than those with PCOS (< 18.5 kg/m2, 5.145 vs. 4.3 ng/mL; 18.5-24 kg/m2, 4.345 vs. 3.635 ng/mL; 24.0-28 kg/m2, 4.115 vs. 3.73 ng/mL; ≥ 28 kg /m2, 3.165 vs. 3.155 ng/mL). These cut-off values had a good diagnostic efficacy in the validation dataset. Based on different phenotypes and severity of ovulation disorders, the distribution of AMH in PCOS were also significantly different (P < 0.001). CONCLUSIONS: AMH is a potential diagnostic indicator of PCOS and is adversely associated with BMI. The AMH cut-off value for diagnosing PCOS was significantly higher than that for PCOM.

Exosomal lncRNA NEAT1 induces paclitaxel resistance in breast cancer cells and promotes cell migration by targeting miR-133b.

The lncRNA nuclear paraspeckle assembly transcript 1 (lncRNA NEAT1) has been associated with the development, metastasis and drug resistance of breast cancer (BC). However, the mechanisms underlying NEAT1-induced paclitaxel resistance in the microenvironment of BC remain unclear. In this study, NEAT1 expression was found to be high in paclitaxel-resistant BC cells (SKBR3/PR cells) and exosomes derived from these cells. NEAT1 promoted the migration of BC cells and their resistance to paclitaxel, whereas its downregulation reduced the drug resistance. In addition, downregulation of NEAT1 decreased the migration and proliferation of BC cells by inhibiting the expression of CXCL12 by reducing the adsorption of miR-133b. Furthermore, inhibition of miR-133b reversed the interference of NEAT1 and CXCL12 in paclitaxel resistance, migration and proliferation of BC cells. Knockdown of NEAT1 in a xenograft-bearing mouse model remarkably inhibited cancer progression and improved the response to paclitaxel. Altogether, this study revealed that SKBR3/PR cell-derived exosomal lncRNA NEAT1 can induce paclitaxel resistance and cell migration and growth in the tumour microenvironment of BC and may serve as a new target for the clinical treatment of BC.

miR-142-3p improves paclitaxel sensitivity in resistant breast cancer by inhibiting autophagy through the GNB2-AKT-mTOR Pathway.

Breast cancer has overtaken lung cancer as the most prevalent cancer worldwide. The development of advanced drug resistance inhibits the efficacy of paclitaxel(PTX)as a first-line chemotherapeutic agent for breast cancer. Autophagy and microRNAs (miRNAs) play a key role in chemoresistance. This study investigated the miR-142-3p effect on PTX resistance by regulating autophagy. A PTX-resistant breast cancer cell line was constructed, and miR-142-3p and G protein beta polypeptide 2 (GNB2) were filtered out using RNA sequencing and protein microarray analysis. The study revealed that miR-142-3p expression was lower in drug-resistant cells compared parental cells. Higher miR-142-3p expression inhibited the viability, migration, and autophagic flux of drug-resistant cells, while promoting apoptosis and sensitivity to PTX treatment. Mechanistically, miR-142-3p was found to amend PTX resistance by targeting GNB2, further revealing that the knockdown of GNB2 expression could activate the AKT-mTOR pathway. This study suggests that GNB2 is an essential target for miR-142-3p to restrain autophagy, providing a new reference value for improving breast cancer PTX treatment.

The Effect of Sperm DNA Fragmentation on In Vitro Fertilization Outcomes for Women With Polycystic Ovary Syndrome.

Background: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disease in reproductive women associated with poor pregnancy outcomes. In modern society, people pay more attention to the female factor, but it is uncertain whether sperm quality is another factor affecting pregnancy outcomes of patients with PCOS. Method: The effect of sperm DNA fragmentation (SDF) on oocyte fertilization, embryonic development, and pregnancy outcomes for patients with PCOS who underwent in vitro fertilization (IVF) treatment was studied. A total of 141 PCOS patients and 332 control patients undergoing IVF treatment were recruited from January 2017 to December 2019. All female patients were designated into two groups according to the Rotterdam criteria. Each group was divided into two sets, DNA fragmentation index (DFI) ≤15% and DFI > 15%, on the basis of sperm DFI. Result: There were no differences in basic clinical characteristics between couples with a sperm DFI ≤ 15% or DFI > 15%. For control patients, no differences were observed in IVF outcomes. However, for PCOS patients, although there were no differences in the fertilization (60.4% vs. 59.9%, p = 0.831), high-quality embryo (68.5% vs. 67.9% p = 0.832), clinical pregnancy (78.4% vs. 66.7%, p = 0.148), and abortion (12.5% vs. 11.5%, p = 1.000) rates, a significantly lower high-quality blastocyst formation rate (26.3% vs. 16.3%, p = 0.023) was observed for couples with a sperm DFI > 15% compared with a sperm DFI ≤ 15%. Conclusion: For PCOS patients undergoing IVF, oocytes fertilized using sperm with higher DFI led to a lower high-quality blastocyst formation rate but had no influence on fertilization, high-quality embryo, clinical pregnancy, and miscarriage rates.

Resveratrol-Loaded TPGS-Resveratrol-Solid Lipid Nanoparticles for Multidrug-Resistant Therapy of Breast Cancer: In Vivo and In Vitro Study.

Multidrug resistance (MDR) is a serious problem during cancer therapy. The purpose of the present study was to formulate D-α-Tocopheryl polyethylene glycol 1000 succinate-resveratrol-solid lipid nanoparticles (TPGS-Res-SLNs) to improve its therapeutic efficacy against breast cancer. In this study, the solvent injection method was used to prepare the TPGS-Res-SLNs. It was found that the TPGS-Res-SLNs exhibited zeta potential and drug-loading of -25.6 ± 1.3 mV and 32.4 ± 2.6%, respectively. Therefore, it was evident that the TPGS-Res-SLNs can increase cellular uptake of chemotherapeutic drugs, induce mitochondrial dysfunction, and augment tumor treatment efficiency by inducing apoptosis. Moreover, it was found that SKBR3/PR cells treated with TPGS-Res-SLNs exhibited significant inhibition of cell migration and invasion, as compared with free resveratrol. In addition, results from in vivo SKBR3/PR xenograft tumor models revealed that TPGS-Res-SLNs has better efficacy in promoting apoptosis of tumor cells owing to high therapeutic outcomes on tumors when compared with the efficacy of free resveratrol. In conclusion, the findings of the present study indicate significant potential for use of TPGS-Res-SLNs as an efficient drug delivery vehicle to overcome drug resistance in breast cancer therapy.

NAD+ deficiency and mitochondrial dysfunction in granulosa cells of women with polycystic ovary syndrome‡.

Polycystic ovary syndrome (PCOS) is a prevalent heterogeneous endocrine disorder characterized by ovulation dysfunction, androgen excess, ovarian polycystic changes, insulin resistance, and infertility. Although underlying mechanisms for PCOS are still unknown, inflammation and mitochondrial dysfunction in granulosa cells (GCs) of PCOS patients have been reported. Here, we found that Nicotinamide Adenine Dinucleotide (NAD+) levels in GCs of PCOS patients was significantly decreased when compared with controls. Also, we found that higher expression of inflammation factors, increased reactive oxygen species (ROS) accumulation, lower adenosine triphosphate (ATP) generation, and decreased mitochondrial membrane potential, as well as abnormal mitochondrial dynamics in GCs of PCOS patients. In addition, the NAD+ levels were decreased after activation of inflammation in human granulosa-like tumor cell line (KGN) treated by Lipopolysaccharide (LPS). However, supplementation of nicotinamide riboside (NR), a NAD+ precursor, could largely restore the NAD+ content, reduce ROS levels and improve mitochondrial function demonstrated by increased mitochondrial membrane potential and ATP generation in LPS-treated KGN cells. Our data suggested that inflammation decreased NAD+ levels in GCs of PCOS patients, while supplementation of NR could restore NAD+ levels and alleviated mitochondrial dysfunction in GCs of PCOS patients.