Golm1 facilitates the CaO2-DOPC-DSPE200-PEI -CsPbBr3 QDs -induced apoptotic death of hepatocytes through the stimulation of mitochondrial autophagy and mitochondrial reactive oxygen species production through interactions with P53/Beclin-1/Bcl-2.

Mitophagy is a distinct physiological process that can have beneficial or deleterious effects in particular tissues. Prior research suggests that mitophagic activity can be triggered by CaO2-PM-CsPbBr3 QDs, yet the specific role that mitophagy plays in hepatic injury induced by CaO2-PM-CsPbBr3 QDs has yet to be established. Accordingly, in this study a series of mouse model- and cell-based experiments were performed that revealed the ability of CaO2-PM-CsPbBr3 QDs to activate mitophagic activity. Golm1 was upregulated in response to CaO2-PM-CsPbBr3 QDs treatment, and overexpressing Golm1 induced autophagic flux in the murine liver and hepatocytes, whereas knocking down Golm1 had the opposite effect. CaO2-PM-CsPbBr3 QDs were also able to Golm1 expression, in turn promoting the degradation of P53 and decreasing the half-life of this protein. Overexpressing Golm1 was sufficient to suppress the apoptotic death of hepatocytes in vitro and in vivo, whereas the knockdown of Golm1 had the opposite effect. The ability of Golm1 to promote p53-mediated autophagy was found to be associated with the disruption of Beclin-1 binding to Bcl-2, and the Golm1 N-terminal domain was determined to be required for p53 interactions, inducing autophagic activity in a manner independent of helicase activity or RNA binding. Together, these results indicate that inhibiting Golm1 can promote p53-dependent autophagy via disrupting Beclin-1 binding to Bcl-2, highlighting a novel approach to mitigating liver injury induced by CaO2-PM-CsPbBr3 QDs.

Th17/Treg balance: the bloom and wane in the pathophysiology of sepsis.

Sepsis is a multi-organ dysfunction characterized by an unregulated host response to infection. It is associated with high morbidity, rapid disease progression, and high mortality. Current therapies mainly focus on symptomatic treatment, such as blood volume supplementation and antibiotic use, but their effectiveness is limited. Th17/Treg balance, based on its inflammatory property, plays a crucial role in determining the direction of the inflammatory response and the regression of organ damage in sepsis patients. This review provides a summary of the changes in T-helper (Th) 17 cell and regulatory T (Treg) cell differentiation and function during sepsis, the heterogeneity of Th17/Treg balance in the inflammatory response, and the relationship between Th17/Treg balance and organ damage. Th17/Treg balance exerts significant control over the bloom and wanes in host inflammatory response throughout sepsis.

Polygonum cuspidatum polysaccharide: A review of its extraction and purification, structure analysis, and biological activity.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum cuspidatum Sieb. et Zucc. is mainly distributed in Shanxi, Gansu, and Sichuan province of China. It is also found in Korea and Japan. Its dried roots and rhizomes are used as medicinal herbs and have been used to treat hyperglycemia and various inflammatory disorders. AIM OF THE REVIEW: This paper aims to provide an up-to-date review of the developments in the studies involving the extraction and purification, structure analysis, pharmacological effects, and potential applications of polysaccharides obtained from Polygonum cuspidatum. Additionally, the possible future research directions of this plant are discussed. MATERIALS AND METHODS: This article used "Polygonum cuspidatum polysaccharide (PCP)" and "Polygonum cuspidatum" as the keywords and gathered relevant data on Polygonum cuspidatum using electronic databases (Elsevier, PubMed, ACS, CNKI, Google Scholar, Baidu Scholar, Web of Science), relevant books, and classic literature about Chinese herb. RESULTS: Excluding irrelevant and repetitive documents, 278 documents were finally included, of which 88 were in Chinese and 190 were in English. The CiteSpace software was used to visualize the trends and keywords in this research field. We concluded that the main extraction methods for Polygonum cuspidatum polysaccharide are water extraction and alcohol precipitation, microwave-assisted extraction, ultrasound-assisted extraction, and microjet extraction. High-performance liquid chromatography and column chromatography are also commonly used in the separation and purification of PCP. PCP has antitumor, immunomodulatory, hypoglycemic, and antioxidant effects. This paper provides an updated and deeper understanding of PCP, serving as a theoretical foundation for the further optimization of polysaccharide structures and the development of PCP as a novel functional material for clinical application.

A Novel pH-Responsive Iron Oxide Core-Shell Magnetic Mesoporous Silica Nanoparticle (M-MSN) System Encapsulating Doxorubicin (DOX) and Glucose Oxidase (Gox) for Pancreatic Cancer Treatment.

Introduction: This study developed a pancreatic cancer targeted drug delivery system that responds to changes in acidity. The system was based on iron oxide core-shell magnetic mesoporous silica nanoparticles (M-MSNs) to treat pancreatic cancer through combined chemotherapy and starvation therapy. Methods: Glucose oxidase (Gox) was coupled to the cancer cell surface to reduce glucose availability for cancer cells, exacerbating the heterogeneity of the tumor microenvironment. Reduced pH accelerated the depolymerization of pH-sensitive polydopamine (PDA), thereby controlling the spatial distribution of Gox and release of doxorubicin (DOX) within tumor cells. Results: Characterization results showed the successful synthesis of DG@M-MSN-PDA-PEG-FA (DG@NPs) with a diameter of 66.02 ± 3.6 nm. In vitro data indicated DG@NPs were highly effective and stable with good cellular uptake shown by confocal laser scanning microscopy (CLSM). DG@NPs exhibited high cytotoxicity and induced apoptosis. Additionally, in vivo experiments confirmed DG@NPs effectively inhibited tumor growth in nude mice with good biosafety. The combination of starvation therapy and chemotherapy facilitated drug release, suggesting DG@NPs as a novel drug delivery system for pancreatic cancer treatment. Conclusion: This study successfully constructed a doxorubicin release system responsive to acidity changes for targeted delivery in pancreatic cancer, providing a new strategy for combination therapy.

PINK1-PTEN axis promotes metastasis and chemoresistance in ovarian cancer via non-canonical pathway.

BACKGROUND: Ovarian cancer is commonly associated with a poor prognosis due to metastasis and chemoresistance. PINK1 (PTEN-induced kinase 1) is a serine/threonine kinase that plays a crucial part in regulating various physiological and pathophysiological processes in cancer cells. METHODS: The ATdb database and "CuratedOvarianData" were used to evaluate the effect of kinases on ovarian cancer survival. The gene expression in ovarian cancer cells was detected by Western blot and quantitative real-time PCR. The effects of gene knockdown or overexpression in vitro were evaluated by wound healing assay, cell transwell assay, immunofluorescence staining, immunohistochemistry, and flow cytometry analysis. Mass spectrometry analysis, protein structure analysis, co-immunoprecipitation assay, nuclear-cytoplasmic separation, and in vitro kinase assay were applied to demonstrate the PINK1-PTEN (phosphatase and tensin homolog) interaction and the effect of this interaction. The metastasis experiments for ovarian cancer xenografts were performed in female BALB/c nude mice. RESULTS: PINK1 was strongly associated with a poor prognosis in ovarian cancer patients and promoted metastasis and chemoresistance in ovarian cancer cells. Although the canonical PINK1/PRKN (parkin RBR E3 ubiquitin protein ligase) pathway showed weak effects in ovarian cancer, PINK1 was identified to interact with PTEN and phosphorylate it at Serine179. Remarkably, the phosphorylation of PTEN resulted in the inactivation of the phosphatase activity, leading to an increase in AKT (AKT serine/threonine kinase) activity. Moreover, PINK1-mediated phosphorylation of PTEN impaired the nuclear import of PTEN, thereby enhancing the cancer cells' ability to resist chemotherapy and metastasize. CONCLUSIONS: PINK1 interacts with and phosphorylates PTEN at Serine179, resulting in the activation of AKT and the inhibition of PTEN nuclear import. PINK1 promotes ovarian cancer metastasis and chemotherapy resistance through the regulation of PTEN. These findings offer new potential therapeutic targets for ovarian cancer management.

cRGD-Conjugated GdIO Nanoclusters for the Theranostics of Pancreatic Cancer through the Combination of T1-T2 Dual-Modal MRI and DTX Delivery.

Clinically, magnetic resonance imaging (MRI) often uses contrast agents (CAs) to improve image contrast, but single-signal MRI CAs are often susceptible to calcification, hemorrhage, and magnetic sensitivity. Herein, iron acetylacetone and gadolinium acetylacetone were used as raw materials to synthesize a T1-T2 dual-mode imaging gadolinium-doped iron oxide (GdIO) nanocluster. Moreover, to endow the nanoclusters with targeting properties and achieve antitumor effects, the cyclic Arg-Gly-Asp (cRGD) peptide and docetaxel (DTX) were attached to the nanocluster surface, and the efficacy of the decorated nanoclusters against pancreatic cancer was evaluated. The final synthesized material cRGD-GdIO-DTX actively targeted αvß3 on the surface of Panc-1 pancreatic cancer cells. Compared with conventional passive targeting, the enrichment of cRGD-GdIO-DTX in tumor tissues improved, and the diagnostic accuracy was significantly enhanced. Moreover, the acidic tumor microenvironment triggered the release of DTX from cRGD-GdIO-DTX, thus achieving tumor treatment. The inhibition of the proliferation of SW1990 and Panc-1 pancreatic cancer cells by cRGD-GdIO-DTX was much stronger than that by the untargeted GdIO-DTX and free DTX in vitro. In addition, in a human pancreatic cancer xenograft model, cRGD-GdIO-DTX considerably slowed tumor development and demonstrated excellent magnetic resonance enhancement. Our results suggest that cRGD-GdIO-DTX has potential applications for the precise diagnosis and efficient treatment of pancreatic cancer.

Nutritional Profile Changes in an Insect-Fungus Complex of Antheraea pernyi Pupa Infected by Samsoniella hepiali.

Historically, some edible insects have been processed into a complex of insect and fungus, such as Antherea pernyi and Samsoniella hepiali. Until now, the dynamics of the nutritional changes due to this infection were unclear. This study reveals the dynamic changes in nutritional components of Antherea pernyi pupa after infection with Samsoniella hepiali at post-infection time points of 0 d, 10 d, 20 d, and 30 d. The dynamic analysis of the components at different post-infection times showed that the content of polysaccharides and cordycepin increased with time while the content of fats and chitin decreased. The content of proteins showed a trend of decreasing at the beginning and then increasing. The essential amino acids (EAAs) decreased at the beginning and then increased, and non-essential amino acids (NEAA) changed similarly. The essential amino acid index showed a slight continuous decrease. Although the crude fat decreased dramatically due to the infection, from a value of 30.75% to 7.2%, the infection of S. hepiali produced five new fatty acids (14-methyl-pentadecanoic acid, docosanoic acid, succinic acid, arachidonic acid, and myristic acid) while the content of the seven fatty acids was greatly reduced after infection. Therefore, after being infected by S. hepiali and combined with it, the nutritional profile of A pernyi pupa was changed significantly and there were different characteristics at different infection stages. The above findings provide scientifically fundamental data to understand the nutritional value of the insect-fungus complex as human food and animal feed.

Functionalized europium-doped hollow mesoporous silica nanospheres as a cell imaging and drug delivery agents.

In an effort to enhance the antitumor efficacy of breast cancer treatment, the chemotherapeutic agent Paclitaxel (PTX) was encapsulated within hyaluronic acid (HA) modified hollow mesoporous silica (HMSNs). In vitro drug release assays showed that the resulting formulation, Eu-HMSNs-HA-PTX, exhibited enzyme-responsive drug release. In addition, cell cytotoxicity and hemolysis assays demonstrated the favorable biocompatibility of both Eu-HMSNs and Eu-HMSNs-HA. Notably, compared to Eu-HMSNs alone, Eu-HMSNs-HA showed enhanced accumulation within CD44-expressing cancer cells (MDA-MB-231). As anticipated, apoptosis experiments indicated that Eu-HMSNs-HA-PTX displayed significantly greater cytotoxicity toward MDA-MB-231 cells than non-targeted Eu-HMSNs-PTX and free PTX. In conclusion, Eu-HMSNs-HA-PTX demonstrated excellent anticancer effects and holds promise as a potent candidate for the efficient therapy of breast cancer.

Effect of Various Lasers With or Without Systemp.desensitizer on Dentine Tubules: An In Vitro Scanning Electron Microscopy Analysis.

Objective: The current study was carried out to evaluate the effects of laser and Systemp.desensitizer therapy. Further, scanning electron microscopy (SEM) was used to determine the effects of individual or combined desensitizers on human dentinal tubules. Background: The most common clinical condition that makes people uncomfortable is dentin hypersensitivity (DH). Both lasers and drugs that reduce sensitivity have been used to treat DH. Materials and methods: A total of 100 dentinal samples were taken from newly extracted third molars (affected) and divided into 10 groups (A to J), that is, control (A); Systemp.desensitizer (B); diode laser (980 nm) (C); Nd:YAG laser (D); Er:YAG laser (E); Er,Cr:YSGG laser (F); Systemp.desensitizer + diode laser (G); Systemp.desensitizer + Nd:YAG laser (H); Systemp.desensitizer + Er:YAG laser (I); and Systemp.desensitizer + Er,Cr:YSGG laser (J). SEM was used to evaluate the dentinal specimens in each group (longitudinal and transverse portions), and then images of each sample were captured (20 images/sample). In addition, the number of open dentinal tubules was counted and then the occlusion depth in dentinal tubules was measured. Mann-Whitney and Kruskal-Wallis tests were employed to analyze the obtained data. Results: All treatment procedures and protocols were effective in blocking dentinal tubules (p < 0.05). Compared with the other groups, dentinal tubules in the laser and laser combination therapy groups were significantly obstructed (p < 0.05). Diode and Nd:YAG lasers with or without Systemp.desensitizer showed significantly more tubule occlusion and greater sealing depth than Er:YAG and Er,Cr:YSGG lasers with or without Systemp.desensitizer (p < 0.05). Conclusions: In summary, lasers alone or in combination can play a significant role in occluding the dentinal tubules. However, combining the diode or Nd:YAG laser with Systemp.desensitizers is a more effective treatment strategy and may have immediate and long-lasting effects.

Cases of Yolk sac tumor associated with gynecological malignant tumor.

BACKGROUND: Yolk sac tumour (YST) is the second most common ovarian germ cell tumour and usually presents in children and young women. However, tumours rarely occur as malignant gynaecological tumours with YST components. CASE PRESENTATION: We present one case of endometrioid carcinoma and clear cell carcinoma with YST components and two other cases of YSTs associated with high-grade serous carcinoma of the ovary in females. After surgery and adjuvant chemotherapy, the patient with endometrioid carcinoma had progressive disease and died 20 months later, and the other two were still alive at the last follow-up. CONCLUSIONS: To our knowledge, these mixed neoplasm associations are unusual, and these cases illustrate the diagnosis and prognosis of YST associated with malignant gynaecological tumours, emphasizing early recognition and aggressive treatment.

Magnetic resonance/fluorescence dual-modality contrast agents targeting αvß6-overexpressing tumors based on A20FMDV2 peptide as a ligand.

Pancreatic ductal adenocarcinoma (PDAC) is a malignant digestive system tumor with a poor late-stage prognosis. This study aimed to identify new methods for the early detection of PDAC. The nanoprobe A20FMDV2-Gd-5-FAM was developed using A20FMDV2 (N1AVPNLRGDLQVLAQKVART20-NH2, A20FMDV2) as the ligand and characterized using dynamic light scattering, transmission electron microscopy, Fourier transform infrared analysis, and UV absorption spectroscopy. The binding of pancreatic cancer cells AsPC-1, MIA PaCa-2, and normal human pancreatic H6C7 cells (HPDE6-C7) to the probe was verified using laser confocal microscopy, and the biocompatibility of the probe was evaluated in vivo. In vivo magnetic resonance and fluorescence imaging were also performed on nude mice with subcutaneous pancreatic tumor xenografts to verify the bimodal imaging performance of the probe. The probe exhibited good stability and biocompatibility and an enhanced relaxation rate (25.46 ± 1.32 mM-1 s-1) than Gd-DTPA. Confocal laser scanning microscopy results revealed that the A20FMDV2-Gd-5-FAM probe could be successfully ingested and internalized, and infrared analysis results demonstrated that the probe was linked successfully. Finally, magnetic resonance T1WI imaging and intravital fluorescence imaging demonstrated the specific signal enhancement of the probe at the tumor site. In conclusion, the bimodal molecular probe A20FMDV2-Gd-5-FAM showed a stable magnetic resonance and fluorescence bimodal imaging performance and is a promising new approach for diagnosing early-stage cancers with a high integrin αvß6 expression.

MAP4K4 promotes ovarian cancer metastasis through diminishing ADAM10-dependent N-cadherin cleavage.

Peritoneal metastasis is a key feature of advanced ovarian cancer, but the critical protein required for ovarian cancer metastasis and progression is yet to be defined. Thus, an unbiased high throughput and in-depth study is warranted to unmask the mechanism. Transcriptomic sequencing of paired primary ovarian tumors and metastases unveiled that MAP4K4, a serine/threonine kinase belongs to the Ste20 family of kinases, was highly expressed in metastatic sites. Increased MAP4K4 expression in metastasis was further validated in other independent patients, with higher MAP4K4 expression associated with poorer survival, higher level of CA125 and more advanced FIGO stage. Down regulation of MAP4K4 inhibited cancer cell adhesion, migration, and invasion. Notably, MAP4K4 was found to stabilize N-cadherin. Further results showed that MAP4K4 mediated phosphorylation of ADAM10 at Ser436 results in suppression of N-cadherin cleavage by ADAM10, leading to N-cadherin stabilization. Pharmacologic inhibition of MAP4K4 abrogated peritoneal metastases. Overall, our data reveal MAP4K4 as a significant promoter in ovarian cancer metastasis. Targeting MAP4K4 may be a potential therapeutic approach for ovarian cancer patients.

Interdisciplinary management of combined periodontal-endodontic lesions with palatogingival grooves of the maxillary lateral incisors: a case report.

A palatogingival groove of the maxillary lateral incisor is an anatomic malformation, which always predisposes the tooth to pulpal and periodontal disease. The diagnosis and treatment planning become complicated, with uncertain prognosis. Herein, we present an effective interdisciplinary management of a case of combined periodontal-endodontic lesions caused by palatogingival grooves. A series of treatment modalities were undertaken to preserve the two teeth, including root canal treatment, periodontal initial therapy, splinting the mobile teeth, occlusal adjustment, apical microsurgery, grinding and sealing grooves, and guided tissue regeneration. An apparent healing of the lesions was visible after 12 months. Therefore, interdisciplinary management of combined periodontal-endodontic lesions with palatogingival grooves of the maxillary lateral incisors is necessary for a favourable long-term outcome.

Protection of adipose-derived mesenchymal stromal cells during acute lung injury requires autophagy maintained by mTOR.

Previous studies suggest that mesenchymal stem cells may represent a promising cellular therapy for acute lung injury (ALI); however, the underlying relevant molecular mechanisms remain unclear. Adipose-derived mesenchymal stem cells (ADSCs) were isolated and characterized by alizarin red staining, oil red staining, and flow cytometry. Lung injury and inflammatory cell infiltration were determined using the Evans blue method, wet/dry weight ratio, and H&E staining. An ELISA was used to detect the concentrations of IFN-γ, IL-2, and TNF-α. Autophagy was detected with an mRFP-GFP-LC3 dual-fluorescence autophagy indicator system, Western blotting, and electron microscopy. We first demonstrated that ADSCs did alleviate the inflammatory responses and tissue damage in lipopolysaccharide (LPS)-induced ALI. Next, we further demonstrated in vivo that autophagy plays a key role in the maintenance of ADSC therapeutic efficacy. In vitro experiments demonstrated that ADSCs co-cultured with alveolar epithelial cells depend on autophagy for significant anti-inflammatory functions. Moreover, the mammalian target of rapamycin (mTOR) is a key regulator of autophagy. Taken together, our findings demonstrate that the effect of ADSC on ALI, especially on alveolar epithelial cells, is dependent on mTOR-mediated autophagy maintenance. The significance of our study for ALI therapy is discussed with respect to a more complete understanding of the therapeutic strategy paradigm.

A sesquiterpene isolated from the stems and leaves of Dioscorea opposita thunb. Transforms the composition of immune cells through ERß in a mouse model of LPS-induced lung injury.

Acute lung injury (ALI) is a common critical disease with a high mortality rate. Natural products have marked efficacy in the prevention and treatment of ALI, in addition, estrogen and its receptors are involved in the pathogenesis and development of lung injury. Our previous research shows that sesquiterpenes isolated from the stems and leaves of Dioscorea opposita Thunb. have anti-inflammatory and estrogenic-like activity. In the present study, sesquiterpene (A1) is a natural extract from the stems and leaves of Dioscorea opposita Thunb. with a view to determining whether A1 can improve lung function in a mouse model of LPS-induced ALI and exploring the involvement of the estrogen receptor ß (ERß) pathway. A1 (20 or 40 mg/kg, i. g., 2 times/day) was administered for 3 d, followed by the induction of ALI via an intratracheal LPS drip (5 mg/kg/2 h). The lung function and levels of inflammation, immune cells, apoptosis, and ERß expression were examined. The antagonistic activity of specific ERß blocker (THC, 1 µM) against A1 (20 µM) in co-cultured BEAS-2B cells and splenic lymphocytes induced with LPS (1 µg/mL, 24 h) was also investigated to assess whether the observed effects of A1 were mediated by ERß. A1 improved lung function, regulated the immune system, and decreased inflammation and apoptosis. Moreover, A1 increased the expression of ERß in LPS-induced mice, and antagonism of ERß decreased the protective effects of A1 in a co-culture system. A1 had anti-ALI effects that might partially mediated through ERß signaling. Our data provide molecular justification for the use of A1 in the treatment of ALI.

Application of fluoride disturbs plaque microecology and promotes remineralization of enamel initial caries.

Background: The caries-preventive effect of topical fluoride application has been corroborated by a number of clinical studies. However, the effect of fluoride on oral microecology remains unclear. Objective: To monitor the effect of fluoride on dental plaque microecology and demineralization/remineralization balance of enamel initial caries. Methods: Three-year-old children were enrolled and treated with fluoride at baseline and 6 months. International Caries Detection and Assessment System II indices of 52 subjects were measured at baseline, 3, 6, and 12 months. Supragingival plaque samples of 12 subjects were collected at baseline, 3 and 14 days for 16S rRNA sequencing. Results: Changes in microbial community structure were observed at 3 days after fluoridation. Significant changes in the relative abundance of microorganisms were observed after fluoride application, especially Capnocytophaga, unidentified Prevotellaceae and Rothia. Functional prediction revealed that cell movement, carbohydrate and energy metabolism were affected significantly after fluoride application. Fluoride significantly inhibited enamel demineralization and promoted remineralization of early demineralized caries enamel at 3 months. Conclusion: Fluoride application significantly inhibited the progression of enamel initial caries and reversed the demineralization process, possibly by disturbing dental plaque microecology and modulating the physicochemical action of demineralization/remineralization. This deepened our understanding of caries-preventive effects and mechanisms of fluoride.

Thymidine and 2'-deoxyuridine reduce microglial activation and improve oxidative stress damage by modulating glycolytic metabolism on the Aß25-35-induced brain injury.

Alzheimer's disease (AD) is a progressive disease with a long duration and complicated pathogenesis. Thymidine (Thy) and 2'-deoxyuridine (2'-De) are pyrimidines nucleotides that are associated with nervous system diseases. However, it remains unclear whether Thy and 2'-De exert neuroprotective effects in AD. Therefore, this study was conducted to explore the interventional effects and mechanisms of Thy and 2'-De on the Aß25-35-induced brain injury. Donepezil (Do, 10 mg/kg/d), Thy (20 mg/kg/d), and 2'-De (20 mg/kg/d) were administered for 4 weeks after the injection of Aß25-35 peptides (200 µM, i.c.v.) to mice. UPLC-MS/MS method was performed to quantify Thy and 2'-De in the hippocampus of mice brain. The cognition ability, neuronal and mitochondria damage, and levels of Aß1-42/Aß1-40, p-Tau, Na+ K+-ATPase, apoptosis, oxidative stress, immune cells, and Iba 1+ were measured in Aß25-35-induced mice. The oxygen consumption (OCR) and extracellular acidification rate (ECAR) were measured using a seahorse analyzer in Aß25-35-induced N9 cells. Moreover, 2-Deoxy-D-glucose (2-DG), a glycolysis inhibitor, was added to explore the mechanisms underlying the effects of Thy and 2'-De on Aß25-35-induced N9 cells. The expression of Iba 1+ and levels of CD11b+ and reactive oxygen species (ROS) were measured after treatment with Thy (5 µM) and 2'-De (10 µM) against 2-DG (5 mM) in Aß25-35-induced N9 cells. The results suggested that Do, Thy, and 2'-De improved the cognition ability, attenuated the damage to hippocampus and mitochondria, downregulated the levels of Aß1-42/Aß1-40, p-Tau, Na+ K+-ATPase, apoptosis, oxidative stress, and Iba 1+, and regulated the immune response induced by Aß25-35 against the brain injury. Furthermore, Do, Thy, and 2'-De increased ATP production and inhibited glycolysis in Aß25-35-induced N9 cells. Moreover, 2-DG enhanced the effects of drugs, reduced microglial activation, and attenuated oxidative stress to interfere with Aß25-35-induced N9 cells. In conclusion, Thy and 2'-De reduced microglial activation and improved oxidative stress damage by modulating glycolytic metabolism on the Aß25-35-induced brain injury.

MicroRNA-22 suppresses NLRP3/CASP1 inflammasome pathway-mediated proinflammatory cytokine production by targeting the HIF-1α and NLRP3 in human dental pulp fibroblasts.

AIM: To investigate the synergetic regulatory effect of miR-22 on HIF-1α and NLRP3, subsequently regulating the production of the NLRP3/CASP1 inflammasome pathway-mediated proinflammatory cytokines IL-1ß and IL-18 in human dental pulp fibroblasts (HDPFs) during the progression of pulpitis. METHODOLOGY: Fluorescence in situ hybridization (FISH) and immunofluorescence (IF) were performed to determine the localization of miR-22-3p, NLRP3 and HIF-1α in human dental pulp tissues (HDPTs). The miR-22 mimics and inhibitor or plasmid of NLRP3 or HIF-1α were used to upregulate or downregulate miR-22 or NLRP3 or HIF-1α in HDPFs, respectively. Computational prediction via TargetScan 5.1 and a luciferase reporter assay were conducted to confirm target association. The mRNA and protein expression of HIF-1α, NLRP3, caspase-1, IL-1ß and IL-18 were determined by qRT-PCR and western blotting, respectively. The release of IL-1ß and IL-18 was analysed by ELISA. The significance of the differences between the experimental and control groups was determined by one-way analysis of variance, p < .05 indicated statistical significance. RESULTS: A decrease in miR-22 and an increase in HIF-1α and NLRP3 in HDPTs occurred during the transformation of reversible pulpitis into irreversible pulpitis compared with that in the healthy pulp tissues (p < .05). In the normal HDPTs, miR-22-3p was extensively expressed in dental pulp cells. HIF-1α and NLRP3 were mainly expressed in the odontoblasts and vascular endothelial cells. Whereas in the inflamed HDPTs, the odontoblast layers were disrupted. HDPFs were positive for miR-22-3p, HIF-1α and NLRP3. Computational prediction via TargetScan 5.1 and luciferase reporter assays confirmed that both NLRP3 and HIF-1α were direct targets of miR-22 in HDPFs. The miR-22 inhibitor further promoted the activation of NLRP3/CASP1 inflammasome pathway induced by ATP plus LPS and hypoxia (p < .05). In contrast, the miR-22 mimic significantly inhibited the NLRP3/CASP1 inflammasome pathway activation induced by ATP plus LPS and hypoxia (p < .05). CONCLUSION: MiR-22, as a synergetic negative regulator, is involved in controlling the secretion of proinflammatory cytokines mediated by the NLRP3/CASP1 inflammasome pathway by targeting NLRP3 and HIF-1α. These results provide a novel function and mechanism of miR-22-HIF-1α-NLRP3 signalling in the control of proinflammatory cytokine secretion, thus indicating a potential therapeutic strategy for future endodontic treatment.

Eriodictyol and Homoeriodictyol Improve Memory Impairment in Aß25-35-Induced Mice by Inhibiting the NLRP3 Inflammasome.

(1) Alzheimer's disease (AD) is a neurodegenerative disorder, and it is now widely accepted that neuroinflammation plays a key role in its pathogenesis. Eriodictyol (Eri) and homoeriodictyol (Hom), dihydroflavonoids extracted from a variety of plants, have been confirmed to display a relationship with neuroprotection. (2) Methods: An AD mouse model was constructed by intracerebroventricular (ICV) injection of the Aß25-35 peptide, and Eri and Hom were administered orally for 4 weeks. UPLC-MS/MS was used to determine whether Eri and Hom cross the blood-brain barrier to exert their therapeutic effects. Histological changes in the brain and levels of Aß were evaluated, and Y-maze and new object recognition experiments were conducted to assess the effects of Eri and Hom on Aß25-35-induced memory impairment in mice. The levels of oxidative stress and apoptosis in peripheral immune cells and progenitor cells in the hippocampal region were analyzed by flow cytometry and in vitro assays. Western blotting and enzyme-linked immunosorbent assays (ELISA) were used to measure the expression levels of NLRP3 inflammasome-related proteins and inflammatory factors in the brain. The effect of nigericin (an agonist of the NLRP3 inflammasome) on Eri and Hom intervention in LPS-induced N9 microglia was examined using a High Content Screening System. (3) Results: Eri and Hom reduced neuronal damage in mouse brain tissue, decreased Aß levels in the brain, downregulated oxidative stress and apoptosis levels, and improved learning and memory capacity by crossing the blood-brain barrier to exert its effects. Moreover, Eri and Hom inhibited NLRP3 inflammasome activation and ameliorated immune cell disorder. Furthermore, the effect of Eri and Hom on LPS-induced N9 microglia disappeared after the addition of nigericin to agonize NLRP3 receptors. (4) Conclusions: Eri and Hom improved Aß25-35-induced memory impairment in mice by inhibiting the NLRP3 inflammasome.

LncRNA CASC15, MiR-23b Cluster and SMAD3 form a Novel Positive Feedback Loop to promote Epithelial-Mesenchymal Transition and Metastasis in Ovarian Cancer.

Cancer Susceptibility Candidate 15 (CASC15), which is a newly identified long noncoding RNA crucial for epigenetic regulation in human tumors, was found to be associated with poor prognosis of the patients with ovarian cancer by utilizing The Cancer Genome Atlas and Gene Expression Omnibus database. Therefore, the purpose of this paper was to explore the functional role and latent molecular mechanism of CASC15 in the progression of ovarian cancer. In vitro and in vivo experiments validated CASC15 as an oncogenic lncRNA in ovarian cancer, which could enhance metastasis through TGF-ß-induced epithelial-mesenchymal transition progress. MiR-23b-3p and miR-24-3p, which are members of the miR-23b cluster, were identified to directly target CASC15 through luciferase assays. Further mechanistic investigations indicated that CASC15-mediated miR-23b-3p/miR-24-3p sequestration cooperatively upregulated SMAD3 expression, which, in turn, would permit increased CASC15 mRNA level as a transcription activation factor. This study first described a miR-23b-3p/miR-24-3p-mediated positive feedback loop between CASC15 and SMAD3, which may reflect the underlying molecular mechanism of CASC15's oncogenic function in ovarian cancer.