Hepatocyte nuclear factor 1B deletion, but not intragenic mutation, might be more susceptible to hypomagnesemia.

AIMS: HNF1B syndrome is caused by defects in the hepatocyte nuclear factor 1B (HNF1B) gene, which leads to maturity-onset diabetes of the young type 5 and congenital organ malformations. This study aimed to identify a gene defect in a patient presenting with diabetes and severe diarrhea, while also analyzing the prevalence of hypomagnesemia and its correlation with the HNF1B genotype. MATERIALS AND METHODS: Whole exome sequencing was used to identify responsible point mutations and small indels in the proband and their family members. Multiplex ligation-dependent probe amplification was carried out to identify HNF1B deletions. Furthermore, an analysis of published data on 539 cumulative HNF1B cases, from 29 literature sources, was carried out to determine the correlation between the HNF1B genotype and the phenotype of serum magnesium status. RESULTS: Using multiplex ligation-dependent probe amplification, we identified a de novo heterozygous HNF1B deletion in the patient, who showed dorsal pancreas agenesis and multiple kidney cysts, as detected by magnetic resonance imaging. Magnesium supplementation effectively alleviated the symptoms of diarrhea. Hypomagnesemia was highly prevalent in 192 out of 354 (54.2%) patients with HNF1B syndrome. Compared with patients with intragenic mutations, those with HNF1B deletions were more likely to suffer from hypomagnesemia, with an odds ratio of 3.1 (95% confidence interval 1.8-5.4). CONCLUSIONS: Hypomagnesemia is highly prevalent in individuals with HNF1B syndrome, and those with HNF1B deletion are more susceptible to developing hypomagnesemia compared with those with intragenic mutations. The genotype-phenotype associations in HNF1B syndrome have significant implications for endocrinologists in terms of genotype detection, treatment decisions and prognosis assessment.

Exploring the potential mechanism of Heng-Gu-Gu-Shang-Yu-He-Ji therapy for osteoporosis based on network pharmacology and transcriptomics.

ETHNOPHARMACOLOGICAL RELEVANCE: Heng-Gu-Gu-Shang-Yu-He-Ji (Osteoking, OK) is a well-known formula for fracture therapy. In clinic, OK is effective in treating fractures while alleviating osteoporosis (OP) symptoms. However, active components of OK and the associated molecular mechanisms remain not fully elucidated. AIM OF THE STUDY: This study aims to systematically evaluate the anti-osteoporosis efficacy of OK and for the first time combine network pharmacology with high-throughput whole gene transcriptome sequencing to study its underlying mechanism. MATERIALS AND METHODS: In this study, the osteoporosis model was established by the castration of both ovaries. The level of serum bone turnover factor was detected by enzyme-linked immunosorbent assay. Micro-CT and HE staining were used to observe the changes of bone histopathology, and nano-indentation technique was used to detect the biomechanical properties of rat bone. The main active Chemical components of OK were identified using UPLC-DAD. Efficacy verification and mechanism exploration were conducted by network pharmacology, molecular docking, whole gene transcriptomics and in vivo experiments. RESULTS: In our study, OK significantly improved bone microarchitecture and bone biomechanical parameters in OVX rats, reduced osteoclast indexes such as C-telopeptide of type I collage (CTX-I) and increased Osteoprotegerin (OPG)/Receptor activator of NF-κB ligand (RANKL) levels. Mechanistically, PI3K/AKT pathway was a common pathway for genome enrichment analysis (KEGG) of both network pharmacology and RNA-seq studies. G protein-ß-like protein (GßL), Ribosomal-protein S6 kinase homolog 2 (S6K2), and Phosphoinositide 3-kinase (PI3K) appeared differentially expression in the PI3K-AKT signaling pathway. These results were also confirmed by qRT-PCR and immunohistochemistry. CONCLUSIONS: OK may be used to treat osteoporosis, at least partly by activating PI3K/AKT/mTORC1 signaling pathway.

Integrated Network Pharmacology, Molecular Docking and Animal Experiment to Explore the Efficacy and Potential Mechanism of Baiyu Decoction Against Ulcerative Colitis by Enema.

Background: Baiyu Decoction (BYD), a clinical prescription of traditional Chinese medicine, has been proven to be valuable for treating ulcerative colitis (UC) by enema. However, the mechanism of BYD against UC remains unclear. Purpose: A combination of bioinformatics methods including network pharmacology and molecular docking and animal experiments were utilized to investigate the potential mechanism of BYD in the treatment of UC. Materials and Methods: Firstly, the representative compounds of each herb in BYD were detected by liquid chromatography-mass spectrometry. Subsequently, we predicted the core targets and potential pathways of BYD for treating UC through network pharmacology. And rat colitis model was established with dextran sodium sulfate. UC rats were subjected to BYD enema administration, during which we recorded body weight changes, disease activity index, and colon length to assess the effectiveness of BYD. Besides, quantitative real-time PCR, western blotting, ELISA and immunofluorescence were used to detect intestinal inflammatory factors, intestinal barrier biomarkers and TOLL-like receptor pathway in rats. Finally, the core components and targets of BYD were subjected to molecular docking so as to further validate the results of network pharmacology. Results: A total of 41 active compositions and 203 targets related to BYD-UC were subjected to screening. The results of bioinformatics analysis showed that quercetin and kaempferol may be the main compounds. Additionally, AKT1, IL-6, TP53, TNF and IL-1ß were regarded as potential therapeutic targets. KEGG results explained that TOLL-like receptor pathway might play a pivotal role in BYD protecting against UC. In addition, animal experiments and molecular docking validated the network pharmacology results. BYD enema treatment can reduce body weight loss, lower disease activity index score, reverse colon shortening, relieve intestinal inflammation, protect intestinal barrier, and inhibit TOLL-like receptor pathway in UC rats. Besides, molecular docking suggested that quercetin and kaempferol docked well with TLR4, AKT1, IL-6, TP53. Conclusion: Utilizing network pharmacology, animal studies, and molecular docking, enema therapy with BYD was confirmed to have anti-UC efficacy by alleviating intestinal inflammation, protecting the intestinal barrier, and inhibiting the TOLL-like receptor pathway. Researchers should focus not only on oral medications but also on the rectal administration of medications in furtherance of the cure of ulcerative colitis.

Cortical Reorganization After Optical Alignment in Strabismic Patients Outside of Critical Period.

Purpose: To measure visual crowding, an essential bottleneck on object recognition and reliable psychophysical index of cortex organization, in older children and adults with horizontal concomitant strabismus before and after strabismus surgery. Methods: Using real-time eye tracking to ensure gaze-contingent display, we examined the peripheral visual crowding effects in older children and adults with horizontal concomitant strabismus but without amblyopia before and after strabismus surgery. Patients were asked to discriminate the orientation of the central tumbling E target letter with flankers arranged along the radial or tangential axis in the nasal or temporal hemifield at different eccentricities (5° or 10°). The critical spacing value, which is the minimum space between the target and the flankers required for correct discrimination, was obtained for comparisons before and after strabismus surgery. Results: Twelve individuals with exotropia (6 males, 21.75 ± 7.29 years, mean ± SD) and 15 individuals with esotropia (6 males, 24.13 ± 5.96 years) participated in this study. We found that strabismic individuals showed significantly larger critical spacing with nasotemporal asymmetry along the radial axis that related to the strabismus pattern, with exotropes exhibiting stronger temporal field crowding and esotropes exhibiting stronger nasal field crowding before surgical alignment. After surgery, the critical spacing was reduced and rebalanced between the nasal and temporal hemifields. Furthermore, the postoperative recovery of stereopsis was associated with the extent of nasotemporal balance of critical spacing. Conclusions: We find that optical realignment (i.e., strabismus surgery) can normalize the enlarged visual crowding effects, a reliable psychophysical index of cortical organization, in the peripheral visual field of older children and adults with strabismus and rebalance the nasotemporal asymmetry of crowding, promoting the recovery of postoperative stereopsis. Our results indicated a potential of experience-dependent cortical organization after axial alignment even for individuals who are out of the critical period of visual development, illuminating the capacity and limitations of optics on sensory plasticity and emphasizing the importance of ocular correction for clinical practice.

MicroRNA-338-3p helps regulate ovarian function by affecting granulosa cell function and early follicular development.

BACKGROUND: Follicular development in mammalian ovaries is a complex and dynamic process, and the interactions and regulatory-feedback loop between the follicular microenvironment, granulosa cells (GCs), and oocytes can affect follicular development and normal ovary functions. Abnormalities in any part of the process may cause abnormal follicular development, resulting in infertility. Hence, exploring the pathogenesis of abnormal follicular development is extremely important for diagnosing and treating infertile women. METHODS: RNA sequencing was performed with ovarian cortical tissues established in vitro. In situ-hybridization assays were performed to study microRNA-338-3p (miR-338-3p) expressed in GCs and oocytes. In vitro culture models were established with GCs and neonatal mouse ovaries to study the biological effects of miR-338-3p. We also performed in vivo experiments by injecting adeno-associated virus vectors that drive miR-338-3p overexpression into the mouse ovarian bursae. RESULTS: Sequencing analysis showed that miR-338-3p was expressed at significantly higher levels in ovarian cortical tissues derived from patients with ovarian insufficiency than in cortical tissues derived from patients with normal ovarian function; miR-338-3p was also significantly highly expressed in the GCs of patients with diminished ovarian reserve (P < 0.05). In situ-hybridization assays revealed that miR-338-3p was expressed in the cytoplasm of GCs and oocytes. Using in vitro culture models of granulosa cells, we found that miR-338-3p overexpression significantly suppressed the proliferation and oestradiol-production capacity of GCs (P < 0.05). In vitro culture models of neonatal mouse ovaries indicated that miR-338-3p overexpression suppressed the early follicular development in mouse ovaries. Further analysis revealed that miR-338-3p might be involved in transforming growth factor ß-dependent regulation of granulosa cell proliferation and, thus, early follicular development. Injecting miR-338-3p-overexpression vectors into the mouse ovarian bursae showed that miR-338-3p down-regulated the oocyte mitochondrial membrane potential in mice and disrupted mouse oestrous cycles. CONCLUSION: miR-338-3p can affect early follicular development and normal ovary functions by interfering with the proliferation and oestradiol production of GCs. We systematically elucidated the regulatory effect of miR-338-3p on follicular development and the underlying mechanism, which can inspire new studies on the diagnosis and treatment of diseases associated with follicular development abnormalities.

Association between antihypertensive drugs and hepatocellular carcinoma: A trans-ancestry and drug-target Mendelian randomization study.

BACKGROUND AND AIMS: Antihypertensive drugs were recently reported to have an oncogenic role in common cancer, however, whether these drugs would affect the risk of hepatocellular carcinoma (HCC) remains unclear. METHODS: A drug-target Mendelian randomization method was adopted to examine the long-term effect of 12 antihypertensive drugs classes on the risk of HCC in Europeans and East Asians. To proxy antihypertensive drugs, we leveraged genetic variants located near or within drug target genes that were associated with systolic blood pressure (SBP). Genetically proxied drugs associated with reduced risk of coronary artery disease were included in primary analysis. Genetic summary statistics of SBP and HCC were derived from publicly available large-scale genome-wide association studies in Europeans and East Asians respectively. Expression quantitative trait loci (eQTLs) of drugs target genes were used to proxy drugs in a sensitivity analysis. RESULTS: Genetically proxied thiazides and related diuretics were associated with decreased risk of HCC in both Europeans (OR [95% CI]: 0.79 [0.73, 0.86] per 1 mmHg reduction in SBP; p < 0.001) and East Asians (0.60 [0.45, 0.82]; p = 0.001). Genetically proxied beta-adrenoceptor blockers (BBs) were strongly associated with increased risk of HCC in Europeans (1.46 [1.12, 1.91]; p = 0.004). These findings were replicated in deCODE genetics study and remained consistent when using eQTLs to proxy antihypertensive drugs. CONCLUSIONS: Our findings suggested that thiazides diuretics may lower the risk of HCC in both Europeans and East Asians, while BBs may increase the risk of HCC specifically in Europeans. Further studies are warranted to explore the potential of repurposing or retargeting antihypertensive drugs for HCC prevention.

A systematic review and meta-analysis comparing the diagnostic capability of automated breast ultrasound and contrast-enhanced ultrasound in breast cancer.

Objective: To compare the diagnostic performance of automated breast ultrasound (ABUS) and contrast-enhanced ultrasound (CEUS) in breast cancer. Methods: Published studies were collected by systematically searching the databases PubMed, Embase, Cochrane Library and Web of Science. The sensitivities, specificities, likelihood ratios and diagnostic odds ratio (DOR) were confirmed. The symmetric receiver operator characteristic curve (SROC) was used to assess the threshold of ABUS and CEUS. Fagan's nomogram was drawn. Meta-regression and subgroup analyses were applied to search for sources of heterogeneity among the included studies. Results: A total of 16 studies were included, comprising 4115 participants. The combined sensitivity of ABUS was 0.88 [95% CI (0.73-0.95)], specificity was 0.93 [95% CI (0.82-0.97)], area under the SROC curve (AUC) was 0.96 [95% CI (0.94-0.96)] and DOR was 89. The combined sensitivity of CEUS was 0.88 [95% CI (0.84-0.91)], specificity was 0.76 [95% CI (0.66-0.84)], AUC was 0.89 [95% CI (0.86-0.92)] and DOR was 24. The Deeks' funnel plot showed no existing publication bias. The prospective design, partial verification bias and blinding contributed to the heterogeneity in specificity, while no sources contributed to the heterogeneity in sensitivity. The post-test probability of ABUS in BC was 75%, and the post-test probability of CEUS in breast cancer was 48%. Conclusion: Compared with CEUS, ABUS showed higher specificity and DOR for detecting breast cancer. ABUS is expected to further improve the accuracy of BC diagnosis.

Clinical value of lymphocyte count in autoimmune diabetic nephropathy. / æ·‹å·´ç»†èƒžè®¡æ•°åœ¨è‡ªèº«å ç–«æ€§ç³–å°¿ç— è‚¾ç— ä¸­çš„ä¸´åºŠä»·å€¼ï¼ˆè‹±æ–‡ï¼‰.

OBJECTIVES: In recent years, the prevalence of diabetic nephropathy (DN) has increased significantly. An increasing number of studies have shown that lymphocyte-associated inflammatory responses play a role in DN. This study aims to investigate the relationship between lymphocytes and DN in patients with autoimmune diabetes. METHODS: The clinical data of 226 patients with Type 1 diabetes (T1D) and 79 patients with latent autoimmune diabetes in adults (LADA) were retrospectively studied and stratified according to the urinary albumin to creatinine ratio (ACR). Risk factors associated with DN were analyzed using correlation analysis and logistic regression. RESULTS: In T1D and LADA patients, systolic blood pressure (SBP), uric acid duration, and diabetes duration in patients with normoalbuminuria were lower or shorter than those in patients with macroalbuminuria (P<0.05). The lymphocyte count of T1D patients was significantly higher than that in LADA patients (P<0.05), while the neutrophil to lymphocyte ratio (NLR) of T1D patients was significantly lower than that in LADA patients (P<0.05). The lymphocyte count in the T1D patients with normoalbuminuria was lower than that those with macroalbuminuria (P<0.05). The NLR was lower in the T1D patients with macroalbuminuria than those with microalbuminuria and normoproteinuria (all P<0.01). Based on logistic regression analysis, lymphocytes were independently associated with DN in T1D after adjusting for various known risk factors such as course of disease, age, gender, dyslipidemia, hypertension, and smoking status. Analysis of the receiver operating characteristic curve of subjects predicting lymphocytes in normoalbuminuria showed that the area under the curve was 0.601 (95% CI 0.510 to 0.693, P=0.039), and when the cutoff value of lymphocytes was 2.332, the sensitivity was 37.0%, and the specificity was 82.5%. CONCLUSIONS: Lymphocyte counts in autoimmune diabetic patients are closely associated with DN, suggesting that lymphocyte-mediated inflammation may be involved in the pathogenesis of DN in autoimmune diabetic patients. This study provides a possible perspective for using lymphocytes as a potential biomarker for the early identification of individuals at risk for DN and potential therapeutic targets for DN.

Rdh54 stabilizes Rad51 at displacement loop intermediates to regulate genetic exchange between chromosomes.

Homologous recombination (HR) is a double-strand break DNA repair pathway that preserves chromosome structure. To repair damaged DNA, HR uses an intact donor DNA sequence located elsewhere in the genome. After the double-strand break is repaired, DNA sequence information can be transferred between donor and recipient DNA molecules through different mechanisms, including DNA crossovers that form between homologous chromosomes. Regulation of DNA sequence transfer is an important step in effectively completing HR and maintaining genome integrity. For example, mitotic exchange of information between homologous chromosomes can result in loss-of-heterozygosity (LOH), and in higher eukaryotes, the development of cancer. The DNA motor protein Rdh54 is a highly conserved DNA translocase that functions during HR. Several existing phenotypes in rdh54Δ strains suggest that Rdh54 may regulate effective exchange of DNA during HR. In our current study, we used a combination of biochemical and genetic techniques to dissect the role of Rdh54 on the exchange of genetic information during DNA repair. Our data indicate that RDH54 regulates DNA strand exchange by stabilizing Rad51 at an early HR intermediate called the displacement loop (D-loop). Rdh54 acts in opposition to Rad51 removal by the DNA motor protein Rad54. Furthermore, we find that expression of a catalytically inactivate allele of Rdh54, rdh54K318R, favors non-crossover outcomes. From these results, we propose a model for how Rdh54 may kinetically regulate strand exchange during homologous recombination.

A novel genomic instability-derived lncRNA signature to predict prognosis and immune characteristics of pancreatic ductal adenocarcinoma.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignant tumor of the digestive system. Its grim prognosis is mainly attributed to the lack of means for early diagnosis and poor response to treatments. Genomic instability is shown to be an important cancer feature and prognostic factor, and its pattern and extent may be associated with poor treatment outcomes in PDAC. Recently, it has been reported that long non-coding RNAs (lncRNAs) play a key role in maintaining genomic instability. However, the identification and clinical significance of genomic instability-related lncRNAs in PDAC have not been fully elucidated. Methods: Genomic instability-derived lncRNA signature (GILncSig) was constructed based on the results of multiple regression analysis combined with genomic instability-associated lncRNAs and its predictive power was verified by the Kaplan-Meier method. And real-time quantitative polymerase chain reaction (qRT-PCR) was used for simple validation in human cancers and their adjacent non-cancerous tissues. In addition, the correlation between GILncSig and tumor microenvironment (TME) and epithelial-mesenchymal transition (EMT) was investigated by Pearson correlation analysis. Results: The computational framework identified 206 lncRNAs associated with genomic instability in PDAC and was subsequently used to construct a genome instability-derived five lncRNA-based gene signature. Afterwards, we successfully validated its prognostic capacity in The Cancer Genome Atlas (TCGA) cohort. In addition, via careful examination of the transcriptome expression profile of PDAC patients, we discovered that GILncSig is associated with EMT and an adaptive immunity deficient immune profile within TME. Conclusions: Our study established a genomic instability-associated lncRNAs-derived model (GILncSig) for prognosis prediction in patients with PDAC, and revealed the potential functional regulatory role of GILncSig.

Baicalin Ameliorates DSS-Induced Colitis by Protecting Goblet Cells through Activating NLRP6 Inflammasomes.

Objective: Baicalin is an active compound found in many natural herbs and has been used to treat intestinal disorders such as diarrhea and colon cancer. In this study, we used a dextran sodium sulfate (DSS)-induced colitis mouse model to investigate baicalin's mechanisms in the treatment of colitis. Methods: 3% DSS was administered through the drinking supply for 7 days to induce colitis followed by the administration of 5-aminosalicylic acid and baicalin at three different doses (25, 50, and 100 mg/kg, W/W) for an additional 7 days. Body weight, stool consistency, and colon length were recorded. Colon tissue was stained with hematoxylin and eosin (H&E) to be used for histopathological scoring. Cytokine levels of the colon tissue and serum were evaluated using real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. mRNA expression and protein levels of tight junctions (TJs) were detected with qRT-PCR and Western blotting. Goblet cells and the mucosal layer of the colon were visualized by Alcian Blue/periodic acid-Schiff (AB/PAS) staining. Mucin 2 (MUC2) was evaluated in both mRNA expression and protein levels. Nod-like receptor pyrin domain-containing protein 6 (NLRP6) inflammasomes were detected by immunohistochemistry and Western blotting. Results: Treatment with baicalin significantly relieved colitis as evidenced by reversing both weight loss and colon length shortening. In addition, baicalin inhibited inflammation by reducing proinflammatory cytokines and protected the intestinal barrier by upregulating tight junction proteins. Moreover, goblet cell count and intestinal mucosa thickness were both significantly increased after baicalin treatment. Giving baicalin could upregulate the expression of NLRP6 and interleukin (IL-18) both in mRNA and protein. Conclusion: Baicalin ameliorates DSS-induced colitis by protecting goblet cells through activating NLRP6 inflammasomes.

On-Site Synthesis and Characterizations of Atomically-Thin Nickel Tellurides with Versatile Stoichiometric Phases through Self-Intercalation.

Self-intercalation of native metal atoms in two-dimensional (2D) transition metal dichalcogenides has received rapidly increasing interest, due to the generation of intriguing structures and exotic physical properties, however, only reported in limited materials systems. An emerging type-II Dirac semimetal, NiTe2, has inspired great attention at the 2D thickness region, but has been rarely achieved so far. Herein, we report the direct synthesis of mono- to few-layer Ni-tellurides including 1T-NiTe2 and Ni-rich stoichiometric phases on graphene/SiC(0001) substrates under ultra-high-vacuum conditions. Differing from previous chemical vapor deposition growth accompanied with transmission electron microscopy imaging, this work combines precisely tailored synthesis with on-site atomic-scale scanning tunneling microscopy observations, offering us visual information about the phase modulations of Ni-tellurides from 1T-phase NiTe2 to self-intercalated Ni3Te4 and Ni5Te6. The synthesis of Ni self-intercalated NixTey compounds is explained to be mediated by the high metal chemical potential under Ni-rich conditions, according to density functional theory calculations. More intriguingly, the emergence of superconductivity in bilayer NiTe2 intercalated with 50% Ni is also predicted, arising from the enhanced electron-phonon coupling strength after the self-intercalation. This work provides insight into the direct synthesis and stoichiometric phase modulation of 2D layered materials, enriching the family of self-intercalated materials and propelling their property explorations.

Baicalin improves the functions of granulosa cells and the ovary in aged mice through the mTOR signaling pathway.

BACKGROUND: The mammalian follicle is the basic functional unit of the ovary, and its normal development is required to obtaining oocytes capable of fertilization. As women get older or decline in ovarian function due to certain pathological factors, the growth and development of follicles becomes abnormal, which ultimately leads to infertility and other related female diseases. Kuntai capsules are currently used in clinical practice to improve ovarian function, and they contain the natural compound Baicalin, which is a natural compound with important biological activities. At present, the role and mechanism of Baicalin in the development of ovarian follicles is unclear. METHODS: Human primary granulosa cells collected from follicular fluid, and then cultured and treated with Baicalin or its normal control, assessed for viability, subjected to RT-PCR, western blotting, flow cytometry, and hormone analyses. The estrus cycle and oocytes of CD-1 mice were studied after Baicalin administration and compared with controls. Ovaries were collected from the mice and subjected to hematoxylin-eosin staining and immunohistochemistry analysis. RESULTS: We showed that Baicalin had a dose-dependent effect on granulosa cells cultured in vitro. A low concentration of Baicalin (for example, 10 µM) helped to maintain the viability of granulosa cells; however, at a concentration exceeding 50 µM, it exerted a toxic effect. A low concentration significantly improved the viability of granulosa cells and inhibited cell apoptosis, which may be related to the resultant upregulation of Bcl-2 expression and downregulation of Bax and Caspase 3. By constructing a hydrogen peroxide-induced cell oxidative stress damage model, we found that Baicalin reversed the cell damage caused by hydrogen peroxide. In addition, Baicalin increased the secretion of estradiol and progesterone by upregulating P450arom and stAR. The results of the in vivo experiment showed that the intragastric administration of Baicalin to aged mice improved the estrous cycle and oocyte quality. Furthermore, we observed that Baicalin enhanced the viability of granulosa cells through the mTOR pathway, which in turn improve ovarian function. CONCLUSION: These results indicate that Baicalin could improve the viability of ovarian granulosa cells and the secretion of steroid hormones and thus could help to improve degenerating ovarian function and delay ovarian aging.

Theaflavin 3, 3'-Digallate Delays Ovarian Aging by Improving Oocyte Quality and Regulating Granulosa Cell Function.

Ovarian aging refers to the gradual decline of ovarian function with increasing physiological age, manifested as decreased ovarian reserve, elevated aging-related markers, and reduced oocyte quality. With a declining female fertility and a growing aging population, it is urgent to delay ovarian aging to maintain fertility and improve the life quality of women. Theaflavin 3, 3'-digallate (TF3) is a naturally bioactive polyphenol compound extracted from black tea, and its antioxidant properties play an important role in maintaining human health and delaying aging; however, the effects of TF3 on female reproduction and ovarian function are not yet clear. Here, we show that TF3 can preserve primordial follicle pool, partially restore the estrous cycle, and increase the offspring number of aged mice. Meanwhile, TF3 gavage increased the number of oocytes retrieved, decreased the level of reactive oxygen species, increased the level of glutathione, and decreased the abnormal rate of oocyte spindle after ovulation induction. Moreover, TF3 inhibited human granulosa cell apoptosis and improved their antioxidative stress ability. High-throughput sequencing and small-molecule-targeted pharmacological prediction show that TF3 affects multiple pathways and gene expression levels, mainly involved in reproductive and developmental processes. It may also affect cellular function by targeting mTOR to regulate the autophagic pathway, thereby delaying the process of ovarian aging. This study shows that TF3 can be used as a potential dietary supplement to protect ovary function from aging and thereby improving the life quality of advanced-age women.

A Facile Low-Dose Photosensitizer-Incorporated Dissolving Microneedles-Based Composite System for Eliciting Antitumor Immunity and the Abscopal Effect.

Nanomedicine-based photodynamic therapy (PDT) for melanoma treatment has attracted great attention. However, the complex design of polymer nanoparticles and high doses of photosensitizers used in intravenous injections (for sufficient accumulation of drugs in tumor lesions) pose a huge challenge to the commercialization and further clinical application. Herein, we fabricated the carrier-free nanoassemblies of a chlorin e6 (L-Ce6 NAs)-integrated fast-dissolving microneedles patch (L-Ce6 MNs) enriching only about 3 µg of Ce6 in the needle tips via a facile fabrication method. The L-Ce6 MNs had sufficient mechanical strength to penetrate the skin and facilitated the transportation of L-Ce6 NAs to a depth of 200-500 µm under the skin, thereby achieving efficient and accurate drug delivery to tumor lesions. In a xenograft mouse melanoma model, the L-Ce6 MNs-based PDT with low dose of Ce6 (0.12 mg/kg) exerted efficient ablation of the primary lesions in situ through reactive oxygen species (ROS) generation. More importantly, a significant abscopal effect was also elicited by activating immunogenic cell death (ICD) and releasing danger-associated molecular patterns (DAMPs), which in turn promoted dendritic cells (DCs) maturation and the subsequent antigen presentation, thereby facilitating the T-cell-mediated immune response without synergetic immunotherapies. Collectively, our findings indicate the facile, controllable, and fast-dissolving microneedles patch with a low dose of photosensitizers presented great therapeutic potential for enhanced photoimmunotherapy.

Combination of Nanomaterials in Cell-Based Drug Delivery Systems for Cancer Treatment.

Cell-based drug delivery systems have shown tremendous advantages in cancer treatment due to their distinctive properties. For instance, delivery of therapeutics using tumor-tropic cells like neutrophils, lymphocytes and mesenchymal stem cells can achieve specific tumor targeting due to the "Trojan Horse" effect. Other circulatory cells like erythrocytes and platelets can greatly improve the circulation time of nanoparticles due to their innate long circulation property. Adipocytes, especially cancer-associated adipocytes, play key roles in tumor development and metabolism, therefore, adipocytes are regarded as promising bio-derived nanoplatforms for anticancer targeted drug delivery. Nanomaterials are important participants in cell-based drug delivery because of their unique physicochemical characteristics. Therefore, the integration of various nanomaterials with different cell types will endow the constructed delivery systems with many attractive properties due to the merits of both. In this review, a number of strategies based on nanomaterial-involved cell-mediated drug delivery systems for cancer treatment will be summarized. This review discusses how nanomaterials can be a benefit to cell-based therapies and how cell-derived carriers overcome the limitations of nanomaterials, which highlights recent advancements and specific biomedical applications based on nanomaterial-mediated, cell-based drug delivery systems.

Relationship between Acute Mastitis and Constitution of Traditional Chinese Medicine in Chinese Breastfeeding Mothers.

OBJECTIVE: The purpose of this study was to explore the relationship between acute mastitis and the constitution of traditional Chinese medicine (TCM) and the potential risk factors of acute mastitis in Chinese breastfeeding mothers. METHOD: A retrospective study on infant feeding practices was conducted in the Breast Surgery Department of Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine between February 2017 and March 2018. A total of 184 women with acute mastitis and 201 women without mastitis of childbearing age were included in this study. All participants filled a baseline questionnaire on demographic characteristics, previous deliveries, and mastitis history and other possible risk factors; data were collected by face-to-face interview. Logistic regression analysis was conducted to ascertain pertinent risk factors affecting the incidence of acute mastitis. The biased constitution of TCM of participants was identified through questionnaires surveyed with the TCM constitution table (ZYYXH/T157-2009). The relationship between acute mastitis and the constitution of TCM was assessed. RESULTS: The protective factors included regular nipple cleansing and cesarean section. The risk factors were nipple infection, Primipara, improper diet, emotional stimuli, postpartum colostrum overdue for more than 72 h, breastfeeding more than 7 times each day, and late primiparity age. Forty-five percent of acute mastitis occurred within 8 weeks after postpartum, and the most common biased constitution of TCM at this period was Qi-Deficiency Constitution (QDC) and Qi-Stagnation Constitution (QSC). Another peak was 25-48 weeks after delivery, accounting for 18%, and the most common biased constitution of TCM was QSC and QDC. More participants were or were prone to be classified as Balanced Constitution (BC) in the control group than the case group (88.5% vs 29.6%), while QDC was the most common constitution of TCM in the case group. The logistic regression analysis further proved that BC was the protective factor of acute mastitis while QDC was a risk factor. CONCLUSIONS: The protective factors of acute mastitis were regular nipple cleansing and cesarean section. The risk factor was nipple infection. Among all the constitutions of TCM, BC was a protective factor, while QDC was a risk factor. For all breastfeeding mothers with various constitutions of TCM, regular nipple cleansing and breast vacuuming, a healthy lifestyle, and a positive mental state can keep mastitis away.

Exploring the Molecular Mechanism of Astragali Radix-Curcumae Rhizoma against Gastric Intraepithelial Neoplasia by Network Pharmacology and Molecular Docking.

BACKGROUND: Astragali Radix-Curcumae Rhizoma (ARCR), a classic drug pair, has been widely used for the treatment of gastric intraepithelial neoplasia (GIN) in China. However, the underlying mechanisms of this drug pair are still unknown. Thus, elucidating the molecular mechanism of ARCR for treating GIN is imperative. METHODS: The active components and targets of ARCR were determined from the TCMSP database, and the differentially expressed genes related to GIN were identified from the GSE130823 dataset. The protein-protein interaction (PPI) network and ARCR-active component-target-pathway network were constructed by STRING 11.0 and Cytoscape 3.7.2, respectively. In addition, a receiver operating characteristic curve (ROC) was conducted to verify the key targets, and enrichment analyses were performed using R software. Molecular docking was carried out to test the binding capacity between core active components and key targets. RESULTS: 31 active components were obtained from ARCR, among which 22 were hit by the 51 targets associated with GIN. Gene Ontology (GO) functional enrichment analysis showed that biological process (BP), molecular function (MF), and cellular component (CC) were most significantly enriched in response to a drug, catecholamine binding, and apical part of the cell, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated ARCR against GIN through regulation of neuroactive ligand-receptor interaction, nitrogen metabolism, calcium signaling pathway, chemical carcinogenesis-receptor activation, drug metabolism, gap junction, and cancers. In the PPI network, 15 potential targets were identified, of which nine key targets were proven to have higher diagnostic values in ROC. Molecular docking revealed a good binding affinity of active components (quercetin, bisdemethoxycurcumin, and kaempferol) with the corresponding targets (CYP3A4, CYP1A1, HMOX1, DRD2, DPP4, ADRA2A, ADRA2C, NR1I2, and LGALS4). CONCLUSION: This study revealed the active components and molecular mechanism by which ARCR treatment is effective against GIN through regulating multipathway, such as neuroactive ligand-receptor interaction, nitrogen metabolism, and calcium signaling pathway.