Prediction of Visual Outcome After Rhegmatogenous Retinal Detachment Surgery Using Artificial Intelligence Techniques.

Purpose: This study aimed to develop artificial intelligence models for predicting postoperative functional outcomes in patients with rhegmatogenous retinal detachment (RRD). Methods: A retrospective review and data extraction were conducted on 184 patients diagnosed with RRD who underwent pars plana vitrectomy (PPV) and gas tamponade. The primary outcome was the best-corrected visual acuity (BCVA) at three months after the surgery. Those with a BCVA of less than 6/18 Snellen acuity were classified into a vision impairment group. A deep learning model was developed using presurgical predictors, including ultra-widefield fundus images, structural optical coherence tomography (OCT) images of the macular region, age, gender, and preoperative BCVA. A fusion method was used to capture the interaction between different modalities during model construction. Results: Among the participants, 74 (40%) still had vision impairment after the treatment. There were significant differences in age, gender, presurgical BCVA, intraocular pressure, macular detachment, and extension of retinal detachment between the vision impairment and vision non-impairment groups. The multimodal fusion model achieved a mean area under the curve (AUC) of 0.91, with a mean accuracy of 0.86, sensitivity of 0.94, and specificity of 0.80. Heatmaps revealed that the macular involvement was the most active area, as observed in both the OCT and ultra-widefield images. Conclusions: This pilot study demonstrates that artificial intelligence techniques can achieve a high AUC for predicting functional outcomes after RRD surgery, even with a small sample size. Machine learning methods identified The macular region as the most active region. Translational Relevance: Multimodal fusion models have the potential to assist clinicians in predicting postoperative visual outcomes prior to undergoing PPV.

Taurine Alleviates Experimental Colitis by Enhancing Intestinal Barrier Function and Inhibiting Inflammatory Response through TLR4/NF-κB Signaling.

Taurine (Tau) is a semiessential amino acid in mammals with preventive and therapeutic effects on several intestinal disorders. However, the exact function of taurine in ulcerative colitis (UC) is still largely unclear. In this study, we used two taurine-deficient mouse models (CSAD-/- and TauT-/- mice) to explore the influence of taurine on the progression of UC in both dextran sulfate sodium (DSS)-induced colitis and LPS-stimulated Caco-2 cells. We found that cysteine sulfinic acid decarboxylase (CSAD) and taurine transporter (TauT) expressions and taurine levels were markedly reduced in colonic tissues of mice treated with DSS. The CSAD and TauT knockouts exacerbated DSS-induced clinical symptoms and pathological damage and aggravated the intestinal barrier dysfunction and the colonic mucosal inflammatory response. Conversely, taurine pretreatment enhanced the intestinal barrier functions by increasing goblet cells and upregulating tight junction protein expression. Importantly, taurine bound with TLR4 and inhibited the TLR4/NF-κB pathway, ultimately reducing proinflammatory factors (TNF-α and IL-6) and oxidative stress. Our findings highlight the essential role of taurine in maintaining the intestinal barrier integrity and inhibiting intestinal inflammation, indicating that taurine is a promising supplement for colitis treatment.

Exogenous CaCl2 reduces the oxidative cleavage of carotenoids in shredded carrots by targeting CAMTA4-mediated transcriptional repression of carotenoid degradation pathway.

Carotenoid oxidative cleavage is a significant factor contributing to the color changes of shredded carrots and treatment with calcium chloride (CaCl2, 1% w/v) has been observed to alleviate the whitening symptom and color loss. However, the specific mechanism by which CaCl2 treatment suppresses carotenoid degradation remains unclear. In this study, the effect of CaCl2 and EGTA (calcium ion chelating agent) treatment on carotenoid biosynthesis and degradation in shredded carrots and the mechanism involved was investigated. CaCl2 treatment promoted the expression and activity of carotenoid biosynthetic enzyme (phytoene synthase, PSY), but inhibited the increases of the degradative enzyme activity of carotenoid cleavage dioxygenase (CCD) and down-regulated the corresponding transcripts, thus delayed the degradation of total carotenoid and maintaining higher levels of major carotenoid compounds including ß-carotene, α-carotene, lycopene, and lutein in shredded carrots during storage. However, EGTA treatment promoted the gene expression and enzyme activity of CCD and increased the degradation of carotenoid compounds in shredded carrots during storage. Furthermore, the CaCl2 treatment induced DcCAMTA4, identified as a calcium decoder in shredded carrots, which, in turn, suppressed the expressions of DcCCD1 and DcCCD4 by interacting with their promoters. The transient overexpression of DcCAMTA4 in tobacco leaves led to reduced expression of NtCCD1 and NtCCD4, maintaining a higher content of carotenoids. Thus, CaCl2 alleviated the oxidative cleavage of carotenoids in shredded carrots through the DcCAMTA4-mediated carotenoid degradation pathway.

Exogenous chlorogenic acid inhibits quality deterioration in fresh-cut potato slices.

Fresh-cut potatoes are prone to surface browning and physiological degradation. Chlorogenic acid (CGA), a natural phenolic antioxidant, has demonstrated preservative properties in various postharvest products. However, the underlying mechanisms of its application on maintaining quality remain unclear. Therefore, the effect of exogenous CGA treatment on quality deterioration of potato slices and the mechanisms involved were investigated. Results revealed CGA treatment retarded the browning coloration, suppressed microbial growth and inhibited the declines in starch, and ascorbic acid contents in potato slices. Meanwhile, the treatment activated the phenylpropanoid pathway but decreased the activities of phenolic decomposition-related enzymes such as polyphenol oxidase (PPO) and tyrosinase and downregulated StPPO expression. Moreover, the treated slices exhibited reduced accumulation of reactive oxygen species and increased activity of antioxidant enzymes. Additionally, they displayed enhanced 2,2-diphenyl-1-picrylhydrazyl radicals scavenging capacity and higher ATP levels. Therefore, these findings indicated that CGA treatment was effective for quality maintenance and antioxidant capacity enhancement in fresh-cut potatoes, thereby providing potential strategies for the preservation and processing of fresh-cut produce.

Effect of aflibercept combined with triamcinolone acetonide on aqueous humor growth factor and inflammatory mediators in diabetic macular edema.

AIM: To investigate the efficacy of aflibercept combined with sub-tenon injection of triamcinolone acetonide (TA) in treating diabetic macular edema (DME) and to examine changes in growth factors and inflammatory mediator levels in aqueous humor after injection. METHODS: Totally 67 DME patients (67 eyes) and 30 cataract patients (32 eyes) were enrolled as the DME group and the control group, respectively. The DME group was divided into the aflibercept group (34 cases) and the aflibercept combined with TA group (combined group, 33 cases). The aqueous humor of both groups was collected during the study period. The aqueous levels of vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-1ß (IL-1ß) were detected using a microsphere suspension array technology (Luminex 200TM). Aqueous cytokines, best-corrected visual acuity (BCVA), central macular thickness (CMT), and complications before and after treatment were compared between the aflibercept group and combined group. RESULTS: The concentrations of VEGF, MCP-1, IL-6, and IL-8 in the aqueous humor were significantly higher in the DME group than those of the control group (all P<0.01). After 1mo of surgery, the concentrations of VEGF, MCP-1, IL-6, and IL-8 in the aqueous humor were significantly lower in the combined group than those of the aflibercept group (all P<0.01). The BCVA and CMT values of the two groups were statistically different after 1 and 2mo of treatment (P<0.01). However, the difference was not statistically significant after 3mo of treatment (P>0.05). CONCLUSION: The cytokines VEGF, MCP-1, IL-6, and IL-8 in the aqueous humor of DME patients are significantly increased. Aflibercept and aflibercept combined with TA have good efficacy in DME patients, can effectively reduce CMT, improve the patient's vision, and have high safety. Aflibercept combined with TA can quickly down-regulate the aqueous humor cytokines and help to relieve macular edema rapidly. However, the long-term efficacy is comparable to that of aflibercept alone.

Glutamate application maintains quality and antioxidant capacity of fresh-cut carrots by modulating GABA shunt, phenylpropanoid and ROS metabolism.

The effects of exogenous glutamate treatment on the quality attributes, γ-aminobutyric acid (GABA) shunt, phenylpropanoid pathway, and antioxidant capacity of fresh-cut carrots were investigated. Results showed that glutamate treatment suppressed the increases in lightness and whiteness values, inhibited the degradation of total carotenoids and maintained better flavor and taste in fresh-cut carrots. Moreover, glutamate treatment rapidly promoted the activities of glutamate decarboxylase and GABA transaminase, thus improving the GABA content. It also significantly enhanced the activities of phenylalanine ammonia-lyase, cinnamate-4-hydroxylase, and 4-coumarate coenzyme A ligase and promoted the accumulation of total phenolics as well as the main individual phenolic compounds, including chlorogenic and caffeic acid. In addition, glutamate application activated the reactive oxygen system-related enzyme including peroxidase, superoxide dismutase, ascorbate peroxidase, and catalase activities to maintain higher antioxidant capacity in fresh-cut carrots. These results demonstrated that exogenous glutamate treatment maintained better nutritional quality and alleviated color deterioration by accelerating the accumulation of GABA and phenolics and enhancing the antioxidant capacity in fresh-cut carrots.

CK1α deficiency impairs mouse uterine adenogenesis by inducing epithelial cell apoptosis through GSK3ß pathway and inhibiting Foxa2 expression through p53 pathway†.

Uterine glands and their secretions are crucial for conceptus survival and implantation in rodents and humans. In mice, the development of uterine gland known as adenogenesis occurs after birth, whereas the adenogenesis in humans initiates from fetal life and completed at puberty. Uterine adenogenesis involves dynamic epithelial cell proliferation, differentiation, and apoptosis. However, it is largely unexplored about the mechanisms governing adenogenesis. CK1α plays important roles in regulating cell division, differentiation, and death, but it is unknown whether CK1α affects adenogenesis. In the current study, uterus-specific CK1α knockout female mice (Csnk1a1d/d) were infertile resulted from lack of uterine glands. Subsequent analysis revealed that CK1α deletion induced massive apoptosis in uterine epithelium by activating GSK3ß, which was confirmed by injections of GSK3ß inhibitor SB216763 to Csnk1a1d/d females, and the co-treatment of SB216763 and CK1 inhibitor d4476 on cultured epithelial cells. Another important finding was that our results revealed CK1α deficiency activated p53, which then blocked the expression of Foxa2, an important factor for glandular epithelium development and function. This was confirmed by that Foxa2 expression level was elevated in p53 inhibitor pifithrin-α injected Csnk1a1d/d mouse uterus and in vitro dual-luciferase reporter assay between p53 and Foxa2. Collectively, these studies reveal that CK1α is a novel factor regulating uterine adenogenesis by inhibiting epithelial cell apoptosis through GSK3ß pathway and regulating Foxa2 expression through p53 pathway. Uncovering the mechanisms of uterine adenogenesis is expected to improve pregnancy success in humans and other mammals.

PGF2alpha Inhibits 20alpha-HSD Expression by Suppressing CK1alpha-induced ERK and SP1 Activation in the Corpus Luteum of Pregnant Mice.

Prostaglandin F2α (PGF2α) is a luteolytic hormone that promotes parturition in mammals at the end of pregnancy by reducing progesterone secretion from the corpus luteum (CL). In rodents and primates, PGF2α rapidly converts progesterone to 20α-hydroxyprogesterone (20α-OHP) by promoting 20α-hydroxysteroid dehydrogenase (20α-HSD) expression. However, the specific mechanism of 20α-HSD regulation by PGF2α remains unclear. Casein Kinase 1α (CK1α) is a CK1 family member that regulates a variety of physiological functions, including reproductive development. Here, we investigated the effects of CK1α on pregnancy in female mice. Our experiments showed that CK1α is expressed in mouse CL, and its inhibition enhanced progesterone metabolism, decreased progesterone levels, and affected mouse embryo implantation. Further, CK1α mediated the effect of PGF2α on 20α-HSD in mouse luteal cells in vitro. Our results are the first to show that CK1α affects the 20α-HSD mRNA level by affecting the ERK signalling pathway to regulate the expression of the transcription factor SP1. These findings improve our understanding of PGF2α regulation of 20α-HSD.

H. pylori-induced NF-κB-PIEZO1-YAP1-CTGF axis drives gastric cancer progression and cancer-associated fibroblast-mediated tumour microenvironment remodelling.

BACKGROUND: Gastric cancer (GC) is one of the most common tumours in East Asia countries and is associated with Helicobacter pylori infection. H. pylori utilizes virulence factors, CagA and VacA, to up-regulate pro-inflammatory cytokines and activate NF-κB signaling. Meanwhile, the PIEZO1 upregulation and cancer-associated fibroblast (CAF) enrichment were found in GC progression. However, the mechanisms of PIEZO1 upregulation and its involvement in GC progression have not been fully elucidated. METHODS: The CAF enrichment and clinical significance were investigated in animal models and primary samples. The expression of NF-κB and PIEZO1 in GC was confirmed by immunohistochemistry staining, and expression correlation was analysed in multiple GC datasets. GSEA and Western blot analysis revealed the YAP1-CTGF axis regulation by PIEZO1. The stimulatory effects of CTGF on CAFs were validated by the co-culture system and animal studies. Patient-derived organoid and peritoneal dissemination models were employed to confirm the role of the PIEZO1-YAP1-CTGF cascade in GC. RESULTS: Both CAF signature and PIEZO1 were positively correlated with H. pylori infection. PIEZO1, a mechanosensor, was confirmed as a direct downstream of NF-κB to promote the transformation from intestinal metaplasia to GC. Mechanistic studies revealed that PIEZO1 transduced the oncogenic signal from NF-κB into YAP1 signaling, a well-documented oncogenic pathway in GC progression. PIEZO1 expression was positively correlated with the YAP1 signature (CTGF, CYR61, and c-Myc, etc.) in primary samples. The secreted CTGF by cancer cells stimulated the CAF infiltration to form a stiffened collagen-enrichment microenvironment, thus activating PIEZO1 to form a positive feedback loop. Both PIEZO1 depletion by shRNA and CTGF inhibition by Procyanidin C1 enhanced the efficacy of 5-FU in suppressing the GC cell peritoneal metastasis. CONCLUSION: This study elucidates a novel driving PIEZO1-YAP1-CTGF force, which opens a novel therapeutic avenue to block the transformation from precancerous lesions to GC. H. pylori-NF-κB activates the PIEZO1-YAP1-CTGF axis to remodel the GC microenvironment by promoting CAF infiltration. Targeting PIEZO1-YAP1-CTGF plus chemotherapy might serve as a potential therapeutic option to block GC progression and peritoneal metastasis.

The E2F1-HOXB9/PBX2-CDK6 axis drives gastric tumorigenesis and serves as a therapeutic target in gastric cancer.

Homeobox genes include HOX and non-HOX genes. HOX proteins play fundamental roles during ontogenesis by interacting with other non-HOX gene-encoded partners and performing transcriptional functions, whereas aberrant activation of HOX family members drives tumorigenesis. In this study, gastric cancer (GC) expression microarray data indicated that HOXB9 is a prominent upregulated HOX member in GC samples significantly associated with clinical outcomes and advanced TNM stages. However, the functional role of HOXB9 in GC remains contradictory in previous reports, and the regulatory mechanisms are elusive. By in silico and experimental analyses, we found that HOXB9 was upregulated by a vital cell cycle-related transcription factor, E2F1. Depleting HOXB9 causes G1-phase cell cycle arrest by downregulating CDK6 and a subset of cell cycle-related genes. Meanwhile, HOXB9 contributes to cell division and maintains the cytoskeleton in GC cells. We verified that HOXB9 interacts with PBX2 to form a heterodimer, which transcriptionally upregulates CDK6. Knocking down CDK6 can phenocopy the tumor-suppressive effects caused by HOXB9 depletion. Blocking HOXB9 can enhance the anti-tumor effect of CDK6 inhibitors. In conclusion, we elucidate the oncogenic role of HOXB9 in GC and reveal CDK6 as its potent downstream effector. The E2F1-HOXB9/PBX2-CDK6 axis represents a novel mechanism driving gastric carcinogenesis and conveys prognostic and therapeutic implications. © 2023 The Pathological Society of Great Britain and Ireland.

Changes of physicochemical properties and bioactivities of resveratrol-loaded core-shell biopolymer nanoparticles during in vitro gastrointestinal digestion.

Resveratrol loaded nanoparticles (nano-resveratrol) containing a zein core surrounded by surfactant (Tween-NPs) or carboxymethyl chitosan (CMCS-NPs) shell were fabricated with different particle sizes, surface charges and colloidal stabilities. Changes of physicochemical properties for the two nano-resveratrols, as well as their antioxidant potentials and cytotoxicity were investigated during a static in vitro gastrointestinal tract (GIT) digestion. Results showed that the Tween-NPs had a much higher bioaccessibility (84.1 ± 19.2%) than that of CMCS-NPs (36.6 ± 4.2%) after the GIT digestion, which was expected due to the steric barrier of the CMCS coating. Both nano-resveratrols could sustained their antioxidant activities after digestion. However, the Tween-NPs had a significantly higher cytotoxicity against MCF-7 cells than CMCS-NPs and free resveratrol, while a reduction in cytotoxicity of Tween-NPs was observed after the digestion. The bioactivities results were well correlated with the physicochemical properties and dissolution of resveratrol under environmental stress.

Cancer-associated fibroblasts potentiate colorectal cancer progression by crosstalk of the IGF2-IGF1R and Hippo-YAP1 signaling pathways.

Colorectal cancer (CRC) is one of the most common cancers worldwide. The tumor microenvironment exerts crucial effects in driving CRC progression. Cancer-associated fibroblasts (CAFs) serve as one of the most important tumor microenvironment components promoting CRC progression. This study aimed to elucidate the novel molecular mechanisms of CAF-secreted insulin-like growth factor (IGF) 2 in colorectal carcinogenesis. Our results indicated that IGF2 was a prominent factor upregulated in CAFs compared with normal fibroblasts. CAF-derived conditioned media (CM) promoted tumor growth, migration, and invasion of HCT 116 and DLD-1 cells. IGF1R expression is significantly increased in CRC, serving as a potent receptor in response to IGF2 stimulation and predicting unfavorable outcomes for CRC patients. Apart from the PI3K-AKT pathway, RNA-seq analysis revealed that the YAP1-target signature serves as a prominent downstream effector to mediate the oncogenic signaling of IGF2-IGF1R. By single-cell RNA sequencing (scRNA-seq) and immunohistochemical validation, IGF2 was found to be predominantly secreted by CAFs, whereas IGF1R was expressed mainly by cancer cells. IGF2 triggers the nuclear accumulation of YAP1 and upregulates YAP1 target signatures; however, these effects were abolished by either IGF1R knockdown or inhibition with picropodophyllin (PPP), an IGF1R inhibitor. Using CRC organoid and in vivo studies, we found that cotargeting IGF1R and YAP1 with PPP and verteporfin (VP), a YAP1 inhibitor, enhanced antitumor effects compared with PPP treatment alone. In conclusion, this study revealed a novel molecular mechanism by which CAFs promote CRC progression. The findings highlight the translational potential of the IGF2-IGF1R-YAP1 axis as a prognostic biomarker and therapeutic target for CRC. © 2022 The Pathological Society of Great Britain and Ireland.

A Narrative Review of Nutritional Therapy for Gastrointestinal Cancer Patients Underwent Surgery.

Background: Patients with gastrointestinal cancer often suffer from malnutrition during tumor progression. Malnutrition is associated with postoperative complications and decreased quality of life. Supporting cancer patients with proper nutrition is vital for improving their prognoses.Method: Google scholar and PubMed database searches were performed. Selection criteria included gastrointestinal cancer, surgery, ω - 3 fatty acids, randomized clinical trials from 2007 to August 2022.Conclusion: Nutritional therapy includes nutritional counseling, enteral nutrition, parenteral nutrition, and oral nutritional supplements. Immune nutrients like glutamine and ω-3 fatty acid have been demonstrated with benefits in reducing inflammatory responses and postoperative complications, regulating immune function and improving prognosis.

Targeting the Hippo Pathway in Gastric Cancer and Other Malignancies in the Digestive System: From Bench to Bedside.

The Hippo pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration under physiological conditions, and its aberrations have been well studied to promote tumor initiation and progression. Dysregulation of the Hippo tumor suppressor signaling frequently occurs in gastric cancer (GC) and other solid tumors and contributes to cancer development through modulating multiple aspects, including cell proliferation, survival, metastasis, and oncotherapy resistance. In the clinic, Hippo components also possess diagnostic and prognostic values for cancer patients. Considering its crucial role in driving tumorigenesis, targeting the Hippo pathway may greatly benefit developing novel cancer therapies. This review summarizes the current research progress regarding the core components and regulation of the Hippo pathway, as well as the mechanism and functional roles of their dysregulation in gastrointestinal malignancies, especially in GC, and discusses the therapeutic potential of targeting the Hippo pathway against cancers.

Glutamatergic and GABAergic neurons in the preoptic area of the hypothalamus play key roles in menopausal hot flashes.

During menopause, when estrogen levels are low, abnormalities in the hypothalamic preoptic area (POA) of the thermoregulatory center can cause hot flashes. However, the involved neural population has not been identified. Proteomics showed that under low estrogen, differentially expressed proteins in the hypothalamus were associated with glutamatergic and GABAergic synapses. RNAscope, Western blotting and qRT-PCR indicated that the number of glutamatergic neurons in the POA was decreased, while the number of GABAergic neurons was increased. Chemogenetics showed that the rat body temperature decreased slowly after glutamatergic neurons were activated and increased quickly after glutamatergic neurons were inhibited, while it increased quickly after GABAergic neurons were activated and decreased slowly after GABAergic neurons were inhibited. RNAscope, immunofluorescence, Western blotting and qRT-PCR further showed that glutamate decarboxylase (GAD) 1 expression in the POA was increased, while GAD2 expression in the POA was decreased; that thermosensitive transient receptor potential protein (ThermoTRP) M (TRPM) 2 expression in glutamatergic neurons was decreased, while TRPM8 expression in GABAergic neurons was increased; and that estrogen receptor (ER) α and ß expression in the POA was decreased, and ERα and ERß expressed in both glutamatergic and GABAergic neurons. Estrogen therapy corrected these abnormalities. In addition, CUT&Tag and Western blot after injection of agonists and inhibitors of ERs showed that ERα and ERß were both transcription factors in glutamatergic and GABAergic synapses. Mechanistically, during menopause, estrogen may regulate the transcription and expression of GADs and ThermoTRPs through ERs, impacting the number and function of glutamatergic and GABAergic neurons, resulting in unbalanced heat dissipation and production in the POA and ultimately triggering hot flashes.

MCM6 is a critical transcriptional target of YAP to promote gastric tumorigenesis and serves as a therapeutic target.

Rationale: Hyperactivation of Hippo-Yes-associated protein (YAP) signaling pathway governs tumorigenesis of gastric cancer (GC). Here we reveal that minichromosome maintenance complex component 6 (MCM6) is a critical transcriptional target of YAP in GC. We aim to investigate the function, mechanism of action, and clinical implication of MCM6 in GC. Methods: The downstream targets of YAP were screened by RNA sequencing (RNA-seq) and microarray, and further validated by chromatin immunoprecipitation PCR and luciferase reporter assays. The clinical implication of MCM6 was assessed in multiple GC cohorts. Biological function of MCM6 was evaluated in vitro, in patient-derived organoids, and in vivo. RNA-seq was performed to unravel downstream signaling of MCM6. Potential MCM6 inhibitor was identified and the effect of MCM6 inhibition on GC growth was evaluated. Results: Integrative RNA sequencing and microarray analyses revealed MCM6 as a potential YAP downstream target in GC. The YAP-TEAD complex bound to the promoter of MCM6 to induce its transcription. Increased MCM6 expression was commonly observed in human GC tissues and predicted poor patients survival. MCM6 knockdown suppressed proliferation and migration of GC cells and patient-derived organoids, and attenuated xenograft growth and peritoneal metastasis in mice. Mechanistically, MCM6 activated PI3K/Akt/GSK3ß signaling to support YAP-potentiated gastric tumorigenicity and metastasis. Furthermore, MCM6 deficiency sensitized GC cells to chemo- or radiotherapy by causing DNA breaks and blocking ATR/Chk1-mediated DNA damage response (DDR), leading to exacerbated cell death and tumor regression. As there are no available MCM6 inhibitors, we performed high-throughput virtual screening and identified purpureaside C as a novel MCM6 inhibitor. Purpureaside C not only suppressed GC growth but also synergized with 5-fluorouracil to induce cell death. Conclusions: Hyperactivated YAP in GC induces MCM6 transcription via binding to its promoter. YAP-MCM6 axis facilitates GC progression by inducing PI3K/Akt signaling. Targeting MCM6 suppresses GC growth and sensitizes GC cells to genotoxic agents by modulating ATR/Chk1-dependent DDR, providing a promising strategy for GC treatment.

MicroRNA-7a2 Contributes to Estrogen Synthesis and Is Modulated by FSH via the JNK Signaling Pathway in Ovarian Granulosa Cells.

MicroRNA-7a2 (miR-7a2) plays fundamental roles in the female reproductive axis, and estrogen is indispensable for maintaining ovary function. However, the interaction between miR-7a2 and ovarian function is unclear. The present study aimed to determine whether and how miR-7a2 functions in estrogen synthesis. Firstly, the results verified that miR-7a was highly expressed in ovarian granulosa cells. The knockout (KO) of miR-7a2 caused infertility and abnormal ovarian function in mice. Concomitantly, the Cyp19a1 expression and estrogen synthesis were significantly inhibited, which was validated in primary granulosa cells. The mice transplanted with miR-7a2 KO ovaries showed similar results; however, estrogen supplementation reversed infertility. In the in vitro experiment, follicle-stimulating hormone (FSH) significantly improved the expression of miR-7a and Cyp19a1 and the synthesis of estrogen. However, the miR-7a2 KO markedly reversed the function of FSH. Also, FSH upregulated miR-7a by activating the (c-Jun N-terminal kinase) JNK signaling pathway. In addition, Golgi apparatus protein 1 (Glg1) was shown to be the target gene of miR-7a2. These findings indicated that miR-7a2 is essential for ovarian functions with respect to estrogen synthesis through the targeted inhibition of the expression of Glg1 and then promoting Cyp19a1 expression; the physiological process was positively regulated by FSH via the JNK signaling pathway in granulosa cells.

Novel Colorimetric and NIR Fluorescent Probe for Bisulfite/Sulfite Detection in Food and Water Samples and Living Cells Based on the PET Mechanism.

Despite their status of being widely used as food additives, bisulfite (HSO3-)/sulfite (SO32-) can pose serious health risks when they are excessively added. Therefore, it is vital to develop a new method for detecting HSO3-/SO32- in foodstuff. In this paper, a benzopyran-benzothiazole derivative (probe DCA-Btl) with near-infrared emission was designed and synthesized by constructing a "push-pull" electronic system. DCA-Btl can selectively recognize HSO3-/SO32- via a colorimetric and fluorescence dual channel in DMF/PBS (1:1, v/v, pH = 8.4), and the emission wavelength of DCA-Btl can reach 710 nm. The fluorescence quenching of DCA-Btl after recognition of HSO3- is attributed to the photoinduced electron transfer (PET) process of the adduct DCA-Btl-HSO3- as evaluated by the DFT/TD-DFT method. In addition, DCA-Btl has many advantages, including a large Stokes shift (95 nm), good anti-interference ability, and little cytotoxicity. What's more, DCA-Btl has been successfully applied for the detection of HSO3-/SO32- in actual water samples and food samples such as sugar, red wine, and biscuits with satisfying results, as well as for fluorescent imaging of HSO3- in living MCF-7 cells.

Changes in vesicular glutamate transporter 2 (Vglut2) and vesicular GABA transporter 1 (Vgat1) in the orofacial pain and temperature perception pathway under low estrogen conditions.

OBJECTIVE: To investigate the effects of estrogen on the threshold and temperature of orofacial pain and explore the influence on the function of glutamate and GABA neurons in the orofacial pain temperature perception pathway by observing the expression of vesicular glutamate transporter 2 (Vglut2) and vesicular GABA transporter 1 (Vgat1). METHODS: A total of 24 adult female Sprague-Dawley rats were divided into three groups: sham operation (SHAM), ovariectomized (OVX) and ovariectomized plus estrogen intervention (OVX+E) (n = 8 per group). The threshold of mechanical pain of the orofacial region was assessed with von Frey filaments, and the temperature of the rat orofacial region was monitored by infrared thermography. Changes in the expression of Vglut2 and Vgat1 in glutamatergic and GABAergic neurons in the trigeminal ganglion (TG), spinal trigeminal nucleus (Sp5C), lateral parabrachial nucleus (LPB) and ventral posteromedial nucleus of the thalamus (VPM) were assessed by immunostaining and Western blotting. RESULTS: Under low-estrogen conditions, the mechanical pain threshold of the orofacial region of rats decreased significantly, and the temperature of the orofacial region increased significantly. The expression of Vglut2 and Vgat1 in the TG and Sp5C showed a downward trend, and the decline in Vgat1 was greater than that in Vglut2. Conversely, both proteins were upregulated in the LPB and VPM, and the magnitude of the changes in Vglut2 was greater than that in Vgat1. Estrogen therapy reversed these changes. CONCLUSION: Under low-estrogen conditions, the proportion of glutamate and GABA neurons in the orofacial pain and temperature sensation pathway changes, which leads to the imbalance of neurotransmission function and the enhancement of excitatory transmission of these two kinds of neurons and finally leads to a decrease in the orofacial pain threshold and an increase in temperature.

MicroRNA-7a2 is Required for the Development of Pituitary Stem Cells.

The pituitary gland is inhabited by a subpopulation of SOX2+ stem cells. However, the regulatory mechanisms underlying pituitary stem cell development remain poorly understood. In this study, we demonstrate that microRNA-7a (miR-7a) is enriched in the developing pituitary and is spatiotemporally expressed in the pituitary stem cells. Constitutive deletion of mir-7a2 in mice results in pituitary dysplasia emerging during birth, which is primarily manifested as malformed anterior lobes. Using immunofluorescence, immunohistochemistry, or in situ hybridization, we observe that the specification of hormone-expressing cells is not impeded post mir-7a2 deletion at birth, although the terminal differentiation of gonadotropes is inhibited. Further investigation of neonatal and adult pituitaries in mir-7a2 knockout mice reveals an expansion of the SOX2+ pituitary stem cell compartment. The inhibition of epithelial-mesenchymal like transition seems to be responsible for this phenotype, rather than abnormal proliferation or apoptosis. Furthermore, our data suggest that Gli3 and Ckap4 are potential targets of miR-7a in pituitary stem cells. In summary, our results identify miR-7a2 as a crucial factor involved in pituitary stem cell development.