The effect and mechanism of palmar ginseng in type 2 diabetic cognitive impairment.

Objective: To investigate the therapeutic effect of palmar ginseng on cognitive impairment in rats with type 2 diabetes, evaluate its neuroprotective effects, and explore its underlying mechanism. Methods: A rat model of diabetic cognitive impairment (DCI) was established by feeding with homemade high-fat, high-sugar chow combined with intraperitoneal injection of streptozotocin (STZ). Rats were continually fed high-fat, high-sugar chow for 60 days after successful induction of the model. Palmar ginseng was administered via gavage. The Morris test was performed after 30 days of treatment. At the end of the test, blood samples were collected, and the activities of IL-6, IL-10, TNF-α, and IL-1ß in rat serum. Pathological changes in hippocampal tissues were observed by Haematoxylin-eosin (HE) staining of the brain, activation of microglia in hippocampal tissues was detected by immunofluorescence, and the expression of PI3K/Akt/mTOR and JAK2/STAT3 proteins in the hippocampal tissues by Western blot. Results: During the administration of palmar Ginseng, the body weight and blood glucose levels of DCI rats were measured weekly, with results showing that Palmar Ginseng effectively reduced blood glucose levels and body weight of DCI rats. Behavioural tests in the water maze indicated that palmar ginseng effectively improved the learning and memory ability of DCI rats. HE and immunofluorescence staining showed that palmar ginseng improved DCI in rats, ameliorated hippocampal neuronal damage, and improved microglial activation. ELISA showed that palmar ginseng significantly reduced the expression of pro-inflammatory factors in the serum of DCI rats. Increased expression of anti-inflammatory factors was observed, and Western blot analysis showed that Palmar Ginseng regulated PI3K/Akt/mTOR and JAK2/STAT3 protein expression, promoted the phosphorylation of PI3K/Akt/mTOR, and inhibited JAK2/STAT3 protein phosphorylation in rat hippocampal tissues as well as in BV2 cells. Conclusions: Palmar ginseng may improve the onset and development of DCI by upregulating the phosphorylation of proteins in the PI3K/Akt/mTOR pathway.

Targeting the PI3K/AKT/mTOR pathway offer a promising therapeutic strategy for cholangiocarcinoma patients with high doublecortin-like kinase 1 expression.

BACKGROUND: Cholangiocarcinoma (CCA), characterized by high heterogeneity and extreme malignancy, has a poor prognosis. Doublecortin-like kinase 1 (DCLK1) promotes a variety of malignant cancers in their progression. Targeting DCLK1 or its associated regulatory pathways can prevent the generation and deterioration of several malignancies. However, the role of DCLK1 in CCA progression and its molecular mechanisms remain unknown. Therefore, we aimed to investigate whether and how DCLK1 contributes to CCA progression. METHODS: The expression of DCLK1 in CCA patients was detected using Immunohistochemistry (IHC). We established DCLK1 knockout and DCLK1 overexpression cell lines for Colony Formation Assay and Transwell experiments to explore the tumor-promoting role of DCLK1. RT-PCR, Western blot and multiple fluorescent staining were used to assess the association between DCLK1 and epithelial-mesenchymal transition (EMT) markers. RNA sequencing and bioinformatics analysis were performed to identify the underlying mechanisms by which DCLK1 regulates CCA progression and the EMT program. RESULTS: DCLK1 was overexpressed in CCA tissues and was associated with poor prognosis. DCLK1 overexpression facilitated CCA cell invasion, migration, and proliferation, whereas DCLK1 knockdown reversed the malignant tendencies of CCA cells, which had been confirmed both in vivo and in vitro. Furthermore, we demonstrated that DCLK1 was substantially linked to the advancement of the EMT program, which included the overexpression of mesenchymal markers and the downregulation of epithelial markers. For the underlying mechanism, we proposed that the PI3K/AKT/mTOR pathway is the key process for the role of DCLK1 in tumor progression and the occurrence of the EMT program. When administered with LY294002, an inhibitor of the PI3K/AKT/mTOR pathway, the tumor's ability to proliferate, migrate, and invade was greatly suppressed, and the EMT process was generally reversed. CONCLUSIONS: DCLK1 facilitates the malignant biological behavior of CCA cells through the PI3K/AKT/mTOR pathway. In individuals with cholangiocarcinoma who express DCLK1 at high levels, inhibitors of the PI3K/AKT/mTOR signaling pathway may be an effective therapeutic approach.

Unilateral focal palmoplantar keratoderma associated with a postzygotic variant in PIK3CA and activation of the PI3K/AKT/mTOR pathway.

Palmoplantar keratoderma (PPK) is a group of -disorders with genetic and phenotypic heterogeneity featuring skin thickening of the palms and soles. More than 60 genes involved in various biological processes are implicated in PPK. PIK3CA is an oncogene encoding p110α, and its somatic variants contribute to a spectrum of congenital overgrowth disorders, including epidermal nevi (EN). To identify the genetic basis and elucidate the pathogenesis of a patient with unilateral focal PPK. Whole-exome sequencing and Sanger sequencing combined with laser capture microdissection (LCM) were performed on genomic DNA extracted from the patient's peripheral blood and skin lesion. Skin biopsies were taken from the lesion of the patient and normal controls for immunofluorescence. Molecular docking was performed using Alphafold2-multimer. A three-year-old girl presented with unilateral focal PPK with an identified missense -variant (c.3140A>G, p.His1047Arg) in PIK3CA from affected tissue. This variant only existed in the lesional epidermis. Elevated PI3K/AKT/mTOR signalling in the affected epidermis and an increased number of Ki67-positive keratinocytes were demonstrated. Molecular docking indicated instability of the p110α-p85α dimer caused by the PIK3CA His1047Arg variant. We describe the first PPK case associated with a variant in PIK3CA, which expands the spectrum of PIK3CA-related disorders. Our study further underscores the importance of the PI3K/AKT/mTOR pathway in the homeostasis of skin keratinization.

B. glomerulata promotes neuroprotection against ischemic stroke by inhibiting apoptosis through the activation of PI3K/AKT/mTOR pathway.

BACKGROUND: Brassaiopsis glomerulata (Blum) Regel (B.glomerulata) is recognized as a traditional Chinese medicine (TCM) primarily used for promoting blood circulation and removing stasis. It is frequently utilized in the treatment of injuries resulting from falls and bumps. PURPOSE: Despite its effective use in clinical treatment for ischemic stroke (IS), there are currently no reports on its composition and mechanism of action, which affects its promotion. The study investigated the chemical components and molecular mechanisms of B.glomerulata, with the following components: UPLC-Q-TOF-MS, network pharmacology Analysis and experimental verification in vivo and vitro. METHODS: The effect of B.glomerulata on interfering with ischemic stroke was assessed on MCAO/R rats and ORD cell model. Then the compositional analysis was conducted using UPLC-Q-TOF-MS. Furthermore, network pharmacology and molecular docking techniques were explored to identify potential targets and pathways. The predicted mechanisms of action were ultimately confirmed by immunohistochemistry and protein blotting. RESULTS: B. glomerulata exhibited neuroprotective effects in MCAO/R rats by reductions in hippocampal and cortical neuronal damage, brain infarction, and cerebral edema. Both in vivo and in vitro experiments demonstrated that it decreased ROS and MDA levels, increased SOD and GSH levels, thereby inhibiting oxidative stress. Moreover, the improvements in neuronal morphology and the modulation of Nissl bodies suggested a potential mechanism underlying its neuroprotective action. Additionally, B.glomerulata exhibited concentration-dependent reductions in Bax and Caspase-3 expressions, along with increases in GFAP, Bcl2/Bax ratio, p-PI3K, p-AKT, and p-mTOR levels. CONCLUSION: B.glomerulata exhibited neuroprotective effects against cerebral ischemia-reperfusion injury both in vivo and in vitro. It prevented oxidative stress damage and inhibited apoptosis of ischemic stroke through the PI3K/AKT/mTOR pathway.

Bisphenol S (BPS) induces glioblastoma progression via regulation of EZH2-mediated PI3K/AKT/mTOR pathway in U87-MG cells.

Bisphenol S (BPS), an alternative to bisphenol A (BPA), exerts proliferative effects similar to those of BPA. BPS is a representative endocrine disruptor associated with cancer progression. However, the mechanisms underlying BPS-induced glioblastoma progression are not fully understood. To investigate the effects of BPS on glioblastoma, U-87 MG cancer cell lines were exposed to BPS. The study focused on analyzing the proliferation and migration of U-87 MG cells. Furthermore, the involvement of the enhancer of the zeste homolog 2 (EZH2)-mediated phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of the rapamycin (mTOR) pathway was examined. Pharmacological approaches were employed to inhibit EZH2 activity and observe its effects on BPS-induced changes. The results indicated that BPS promoted the proliferation and migration of U-87 MG cells at a concentration of 0.1µM. These changes appeared to be linked to the activation of the EZH2-mediated PI3K/AKT/mTOR pathway. Moreover, inhibiting EZH2 activity using pharmacological approaches restored the BPS-mediated induction of proliferation and migration. In conclusion, the results of this study indicated that BPS induces glioblastoma progression through EZH2 upregulation. Therefore, targeting the EZH2-mediated PI3K/AKT/mTOR pathway could be considered a potential therapeutic strategy for the treatment of glioblastoma.

Extracellular vesicle-mediated regulation of imatinib resistance in chronic myeloid leukemia via the miR-629-5p/SENP2/PI3K/AKT/mTOR axis.

BACKGROUND: Imatinib (IM) is the primary treatment for patients with chronic-phase CML (CML-CP). However, an increasing number of CML-CP patients have developed resistance to IM. Our study aims to explore the expression of miR-629-5p in extracellular vesicles (EVs) from both IM-sensitive (K562) and resistant (K562-Re) CML cell lines and to investigate the impact of regulating miR-629-5p expression on the biological characteristics of K562 and K562-Re cells. METHODS: Assess miR-629-5p expression levels in IM-sensitive and resistant CML cell lines. Separate EVs and verify it. EVs from K562-Re cells were co-cultured with K562 cells to detect the expression level of miR-629-5p. Target genes of miR-629-5p were determined and validated through luciferase experiments. Examined by manipulating miR-629-5p expression in cells using transfection techniques. The expression level of phosphorylated proteins in the PI3K/AKT/mTOR signaling pathway after IM was detected in CML cell lines. In K562-Re cells, the expression level of phosphorylated protein in the PI3K/AKT/mTOR signaling pathway was detected after single transfection of miR-629-5p inhibitor and cotransfection of miR-629-5p inhibitor and siSENP2. RESULTS: Increasing concentrations of EVs from K562-Re cells elevated miR-629-5p expression levels. The expression levels of miR-629-5p in CML cells varied with IM concentration and influenced the biological characteristics of cells. SENP2 was identified as a target gene of miR-629-5p. Furthermore, miR-629-5p was found to modulate the SENP2/PI3K/AKT/mTOR pathway, impacting IM resistance in CML cells. CONCLUSION: EVs from IM-resistant CML cells alter the expression of miR-629-5p in sensitive cells, activating the SENP2/PI3K/AKT/mTOR pathway and leading to IM resistance.

Arnicolide D Inhibits Proliferation and Induces Apoptosis of Osteosarcoma Cells through PI3K/Akt/mTOR Pathway.

BACKGROUND: Osteosarcoma is considered as the most prevalent form of primary malignant bone cancer, prompting a pressing need for novel therapeutic options. Arnicolide D, a sesquiterpene lactone derived from the traditional Chinese herbal medicine Centipeda minima (known as E Bu Shi Cao in Chinese), showed anticancer efficacy against several kinds of cancers. However, its effect on osteosarcoma remains unclear. OBJECTIVE: This study aimed to investigate the anticancer activity of arnicolide D and the underlying molecular mechanism of its action in osteosarcoma cells, MG63 and U2OS. METHODS: Cell viability and proliferation were evaluated through MTT assay and colony formation assay following 24 h and 48 h treatment with different concentrations of arnicolide D. Flow cytometry was employed to examine cell cycle progression and apoptosis after 24 h treatment of arnicolide D. Western blotting was performed to determine the expression of the PI3k, Akt and m-TOR and their phosphorylated forms. RESULTS: Our findings revealed that arnicolide D treatment resulted in a significant reduction in cell viability, the inhibition of proliferation, and the induction of apoptosis and cell cycle arrest in the G2/M phase. Furthermore, arnicolide D could inhibit the activation of PI3K/Akt/mTOR pathway in osteosarcoma cells. CONCLUSION: Based on our results, arnicolide D demonstrated significant anti-osteosarcoma activity and held the potential to be considered as a therapeutic candidate for osteosarcoma in the future.

AURKB targets DHX9 to promote hepatocellular carcinoma progression via PI3K/AKT/mTOR pathway.

Aurora kinase B (AURKB) is known to play a carcinogenic role in a variety of cancers, but its underlying mechanism in liver cancer is unknown. This study aimed to investigate the role of AURKB in hepatocellular carcinoma (HCC) and its underlying molecular mechanism. Bioinformatics analysis revealed that AURKB was significantly overexpressed in HCC tissues and cell lines, and its high expression was associated with a poorer prognosis in HCC patients. Furthermore, downregulation of AURKB inhibited HCC cell proliferation, migration, and invasion, induced apoptosis, and caused cell cycle arrest. Moreover, AURKB downregulation also inhibited lung metastasis of HCC. AURKB interacted with DExH-Box helicase 9 (DHX9) and targeted its expression in HCC cells. Rescue experiments further demonstrated that AURKB targeting DHX9 promoted HCC progression through the PI3K/AKT/mTOR pathway. Our results suggest that AURKB is significantly highly expressed in HCC and correlates with patient prognosis. Targeting DHX9 with AURKB promotes HCC progression via the PI3K/AKT/mTOR pathway.

Biomarkers and Signaling Pathways Implicated in the Pathogenesis of Idiopathic Multicentric Castleman Disease/Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, Renal Insufficiency, and Organomegaly (TAFRO) Syndrome.

Idiopathic multicentric Castleman disease (iMCD) and TAFRO syndrome present a variety of symptoms thought to be caused by excessive inflammatory cytokines and chemokines, but the underlying mechanisms are unknown. iMCD is broadly classified into two types: iMCD-NOS and iMCD-TAFRO, which have distinct laboratory findings, pathological features, and responses to treatments. It is thought that iMCD-NOS, particularly the IPL type, responds favorably to IL-6 inhibitors due to its IL-6-centric profile. iMCD-TAFRO frequently progresses acutely and seriously, similar to TAFRO syndrome. Elevated levels of cytokines, including IL-1ß, TNF-α, IL-10, and IL-23, as well as chemokines like CXCL13 and CXCL-10 (especially in iMCD-TAFRO), SAA, and VEGF, have been linked to the disease's pathology. Recent research has identified key signaling pathways including PI3K/Akt/mTOR and JAK-STAT3, as well as those regulated by type I IFN, as crucial in iMCD-TAFRO. These results suggest that dominant pathways may vary between subtypes. Further research into the peripheral blood and lymph nodes is required to determine the disease spectrum of iMCD-NOS/iMCD-TAFRO/TAFRO syndrome.

Kaempferol Inhibits Cervical Cancer Cells by Inducing Apoptosis and Autophagy via Inactivation of the PI3K/AKT/mTOR Signaling Pathway.

BACKGROUND/AIM: Kaempferol, a natural flavonoid, occurs abundantly in fruits and vegetables. It has various bioactivities, with antioxidant, anti-inflammatory, and other beneficial properties. The aim of this study was to investigate the in vitro effects of kaempferol on the proliferation, apoptosis, and autophagy of KB cells, a human cervical cancer cell line, and the corresponding action mechanisms. MATERIALS AND METHODS: The inhibitory efficacy of kaempferol on KB cervical cancer cells was investigated through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, migration assay, 4',6-diamidino-2-phenylindole staining, flow cytometry, acridine orange staining and western blotting. RESULTS: Kaempferol reduced KB cell viability and migration in a dose-dependent manner. Additionally, kaempferol-induced apoptosis was confirmed, and kaempferol treatment influenced levels of apoptotic proteins. Autophagy was detected upon visualization of characteristic autophagic vacuoles and acidic vesicular organelles, and verified using western blotting, which revealed elevated levels of autophagy-related proteins. Kaempferol-mediated apoptosis and autophagy were evidently attributable to reduced phosphorylation in the phosphoinositide 3-kinase (PI3K)/serine/threonine kinase 1 (AKT)/mammalian target of rapamycin (mTOR) pathway. This finding was validated using a pharmacological inhibition assay with the PI3K pathway inhibitor LY294002, which promoted KB cell apoptosis and autophagy. CONCLUSION: Our results suggest that kaempferol induces apoptosis and autophagy by inhibiting the PI3K/AKT/mTOR pathway in human cervical cancer cells, empirically showing the anticancer effects of kaempferol, and thereby presenting it as a potential anticancer therapeutic agent.

Unveiling the role of UPF3B in hepatocellular carcinoma: Potential therapeutic target.

RNA-binding proteins can regulate nucleotide metabolism and gene expression. UPF3B regulator of nonsense mediated mRNA decay (UPF3B) exhibits dysfunction in cancers. However, its role in the progression of hepatocellular carcinoma (HCC) is still insufficiently understood. Here, we found that UPF3B was markedly upregulated in HCC samples and associated with adverse prognosis in patients. UPF3B dramatically promoted HCC growth both in vivo and in vitro. Mechanistically, UPF3B was found to bind to PPP2R2C, a regulatory subunit of PP2A, boosting its mRNA degradation and activating the PI3K/AKT/mTOR pathway. E2F transcription factor 6 (E2F6) directly binds to the UPF3B promoter to facilitate its transcription. Together, the E2F6/UPF3B/PPP2R2C axis promotes HCC growth through the PI3K/AKT/mTOR pathway. Hence, it could be a promising therapeutic target for treating HCC.

Identification of 8 candidate microsatellite instability loci in colorectal cancer and validation of the ACVR2A mechanism in the tumor progression.

This study probes the utility of biomarkers for microsatellite instability (MSI) detection and elucidates the molecular dynamics propelling colorectal cancer (CRC) progression. We synthesized a primer panel targeting 725 MSI loci, informed by The Cancer Genome Atlas (TCGA) and ancillary databases, to construct an amplicon library for next-generation sequencing (NGS). K-means clustering facilitated the distillation of 8 prime MSI loci, including activin A receptor type 2A (ACVR2A). Subsequently, we explored ACVR2A's influence on CRC advancement through in vivo tumor experiments and hematoxylin-eosin (HE) staining. Transwell assays gauged ACVR2A's role in CRC cell migration and invasion, while colony formation assays appraised cell proliferation. Western blotting illuminated the impact of ACVR2A suppression on CRC's PI3K/AKT/mTOR pathway protein expressions under hypoxia. Additionally, ACVR2A's influence on CRC-induced angiogenesis was quantified via angiogenesis assays. K-means clustering of NGS data pinpointed 32 MSI loci specific to tumor and DNA mismatch repair deficiency (dMMR) tissues. ACVR2A emerged as a pivotal biomarker, discerning MSI-H tissues with 90.97% sensitivity. A curated 8-loci set demonstrated 100% sensitivity and specificity for MSI-H detection in CRC. In vitro analyses corroborated ACVR2A's critical role, revealing its suppression of CRC proliferation, migration, and invasion. Moreover, ACVR2A inhibition under CRC-induced hypoxia markedly escalated MMP3, CyclinA, CyclinD1, and HIF1α protein expressions, alongside angiogenesis, by triggering the PI3K/AKT/mTOR cascade. The 8-loci ensemble stands as the optimal marker for MSI-H identification in CRC. ACVR2A, a central element within this group, deters CRC progression, while its suppression amplifies PI3K/AKT/mTOR signaling and angiogenesis under hypoxic stress.

Synthesis of novel carbazole hydrazine-carbothioamide scaffold as potent antioxidant, anticancer and antimicrobial agents.

BACKGROUND: Carbazole-based molecules containing thiosemicarbazide functional groups are recognized for their diverse biological activities, particularly in enhancing therapeutic anticancer effects through inhibiting crucial pathways. These derivatives also exhibit noteworthy antioxidant properties. OBJECTIVES: This study aims to synthesize, characterize, and evaluate the antioxidant and anticancer activities of 18 novel carbazole derivatives. METHODS: The radical scavenging capabilities of the compounds were assessed using the 2,2-diphenyl-1-picrylhydrazyl assay. Antiproliferative activities were evaluated on MCF-7 cancer cell lines through viability assays. Additionally, the modulation of the PI3K/Akt/mTOR pathway, apoptosis/necrosis induction, and cell cycle analysis were conducted for the most promising anticancer agents. RESULTS: nine compounds showed potent antioxidant activities with IC50 values lower than the positive control acarbose, with compounds 4 h and 4y exhibiting the highest potency (IC50 values of 0.73 and 0.38 µM, respectively). Furthermore, compounds 4o and 4r displayed significant anticancer effects, with IC50 values of 2.02 and 4.99 µM, respectively. Compound 4o, in particular, exhibited promising activity by targeting the PI3K/Akt/mTOR signaling pathway, inhibiting tumor survival, inducing apoptosis, and causing cell cycle arrest in MCF-7 cell lines. Furthermore, compound 4o was showed significant antimicrobial activities against S. aureus and E. coli, and antifungal effect against C. albicans. Its potential to overcome drug resistance through this pathway inhibition highlights its promise as an anticancer agent. Molecular docking simulations supported these findings, revealing favorable binding profiles and interactions within the active sites of the enzymes PI3K, AKT1, and mTOR. Moreover, assessing the druggability of the newly synthesized thiosemicarbazide derivatives demonstrated optimal physicochemical properties, further endorsing their potential as drug candidates.

Bioactive components and potential mechanisms of Biqi Capsule in the treatment of osteoarthritis: based on chondroprotective and anti-inflammatory activity.

Cartilage damage and synovial inflammation are vital pathological changes in osteoarthritis (OA). Biqi Capsule, a traditional Chinese medicine formula used for the clinical treatment of arthritis in China, yields advantages in attenuating OA progression. The drawback here is that the bioactive components and pharmacological mechanisms by which Biqi Capsule exerts its anti-inflammatory and chondroprotective effects have yet to be fully clarified. For in vivo studies, a papain-induced OA rat model was established to explore the pharmacological effects and potential mechanisms of Biqi Capsule against OA. Biqi Capsule alleviated articular cartilage degeneration and chondrocyte damage in OA rats and inhibited the phosphorylation of NF-κB and the expression of pro-inflammatory cytokines in synovial tissue. Network pharmacology analysis suggested that the primary biological processes regulated by Biqi Capsule are inflammation and oxidative stress, and the critical pathway regulated is the PI3K/AKT signaling pathway. The result of this analysis was later verified on SW1353 cells. The in vitro studies demonstrated that Glycyrrhizic Acid and Liquiritin in Biqi Capsule attenuated H2O2-stimulated SW1353 chondrocyte damage via activation of PI3K/AKT/mTOR pathway. Moreover, Biqi Capsule alleviated inflammatory responses in LPS-stimulated RAW264.7 macrophages via the NF-κB/IL-6 pathway. These observations were suggested to have been facilitated by Brucine, Liquiritin, Salvianolic Acid B, Glycyrrhizic Acid, Cryptotanshinone, and Tanshinone ⅡA. Put together, this study partially clarifies the pharmacological mechanisms and the bioactive components of Biqi capsules against OA and suggests that it is a promising therapeutic option for the treatment of OA. Chemical compounds studied in this article. Strychnine (Pubchem CID:441071); Brucine (Pubchem CID:442021); Liquiritin (Pubchem CID:503737); Salvianolic Acid B (Pubchem CID:6451084); Glycyrrhizic Acid (Pubchem CID:14982); Cryptotanshinone (Pubchem CID:160254); Tanshinone ⅡA (Pubchem CID:164676).

Fermented dietary fiber from soy sauce residue exerts antidiabetic effects through regulating the PI3K/AKT signaling pathway and gut microbiota-SCFAs-GPRs axis in type 2 diabetic mellitus mice.

The gut plays a crucial role in the development and progression of metabolic disorders, particularly in relation to type 2 diabetes mellitus (T2DM). While a high intake of dietary fiber is inversely associated with the risk of T2DM, the specific effects of various dietary fibers on T2DM are not fully understood. This study investigated the anti-diabetic properties of fermented dietary fiber (FDF) derived from soy sauce residue in T2DM mice, demonstrating its ability to lower blood glucose levels and ameliorate insulin resistance. Our findings revealed that FDF could enhance hepatic glucose metabolism via the IRS-1/PI3K/AKT/mTOR pathway. Additionally, the anti-diabetic effect of FDF was correlated with alterations in gut microbiota composition in T2DM mice, promoting a healthier gut environment. Specifically, FDF increased the abundance of beneficial flora such as Dubosiella, Butyricimonas, Lachnospiraceae_NK4A136_group, Lactobacillus and Osillibacter, while reducing harmful bacteria including Bilophila, Parabacteroides and Enterorhabdus. Further analysis of microbial metabolites, including short-chain fatty acids (SCFAs) and bile acids (BAs), provided evidence of FDF's regulatory effects on cecal contents in T2DM mice. Importantly, FDF treatment significantly restored the G-protein-coupled receptors (GPRs) expression in the colon of T2DM mice. In conclusion, our study suggests that the anti-diabetic effects of FDF are associated with the regulation of both the liver-gut axis and the gut microbiota-SCFAs-GPRs axis.

Elucidating the mechanism of action of Radix Angelica sinensis (Oliv.) Diels and Radix Astragalus mongholicus Bunge ultrafiltration extract on radiation-induced myocardial fibrosis based on network pharmacology and experimental research.

Myocardial fibrosis can induce cardiac dysfunction and remodeling. Great attention has been paid to traditional chinese medicine (TCM) 's effectiveness in treating MF. Radix Angelica sinensis (Oliv.) Diels and Radix Astragalus mongholicus Bunge ultrafiltration extract (RAS-RA), which is a key TCM compound preparation, have high efficacy in regulating inflammation. However, studies on its therapeutic effect on radiation-induced myocardial fibrosis (RIMF) are rare. In this study, RAS-RA had therapeutic efficacy in RIMF and elucidated its mechanism of action. First, we formulated the prediction network that described the relation of RAS-RA with RIMF according to data obtained in different databases. Then, we conducted functional enrichment to investigate the functions and pathways associated with potential RIMF targets for RAS-RA. In vivo experiments were also performed to verify these functions and pathways. Second, small animal ultrasound examinations, H&E staining, Masson staining, transmission electron microscopy, Enzyme-linked immunosorbent assay (ELISA), Western-blotting, Immunohistochemical method and biochemical assays were conducted to investigate the possible key anti-RIMF pathway in RAS-RA. In total, 440 targets were detected in those 21 effective components of RAS-RA; meanwhile, 1,646 RIMF-related disease targets were also discovered. After that, PPI network analysis was conducted to identify 20 key targets based on 215 overlap gene targets. As indicated by the gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analysis results, inflammation and PI3K/AKT/mTOR pathways might have important effects on the therapeutic effects on RIMF. Molecular docking analysis revealed high binding of effective components to targets (affinity < -6 kcal/mol). Based on experimental verification results, RAS-RA greatly mitigated myocardial fibrosis while recovering the cardiac activity of rats caused by X-rays. According to relevant protein expression profiles, the PI3K/AKT/mTOR pathway was important for anti-fibrosis effect of RAS-RA. Experimental studies showed that RAS-RA improved cardiac function, decreased pathological damage and collagen fiber deposition in cardiac tissues, and improved the mitochondrial structure of the heart of rats. RAS-RA also downregulated TNF-α, IL-6, and IL-1ß levels. Additionally, RAS-RA improved the liver and kidney functions and pathological injury of rat kidney and liver tissues, enhanced liver and kidney functions, and protected the liver and kidneys. RAS-RA also increased PI3K, AKT and mTOR protein levels within cardiac tissues and downregulated α-SMA, Collagen I, and Collagen III. The findings of this study suggested that RAS-RA decreased RIMF by suppressing collagen deposition and inflammatory response by inhibiting the PI3K/AKT/mTOR pathway. Thus, RAS-RA was the potential therapeutic agent used to alleviate RIMF.

Down-regulation of long noncoding RNA HOXA11-AS nullifies the impact of microRNA-506-3p on chondrocytes proliferation and apoptosis in osteoarthritis.

OBJECTIVES: This study was directed towards exploring the impacts of lncRNA HOXA11-AS-mediated microRNA (miR)-506-3p on chondrocytes proliferation and apoptosis in osteoarthritis (OA). METHODS: The articular cartilages were provided by OA patients who received total knee arthroplasty, and Human Chondrocyte (HC)-OA (HCOA) was also attained. The miR-506-3p and HOXA11-AS expressions in articular cartilages from OA patients and HCOA cells were analyzed via qPCR. After gain- and loss-of-function assays in HCOA cells, MTT assay and flow cytometry (FC) were used for assessing cell viability and apoptosis, accordingly. The levels of PIK3CA, AKT, and mTOR as well as AKT and mTOR phosphorylation levels assessed using western blotting (WB). The targeting correlation of HOXA11-AS and miR-506-3p as well as miR-506-3p and PIK3CA was assessed through Dual-Luciferase Reporter gene Assay (DLRA). RESULT: The articular cartilages from OA patients and Human Chondrocyte (HC)-OA (HCOA) cells showed increased HOXA11-AS and decreased miR-506-3p. Mechanistically, HOXA11-AS was capable of binding to miR-506-3p to increase PIK3CA, the target gene of miR-506-3p. miR-506-3p suppression facilitated HCOA cell proliferation and reduced their apoptosis, which was nullified by further silencing HOXA11-AS or silencing PIK3CA. The down-regulation of HOXA11-AS disrupted the PI3K/AKT/mTOR pathway, which was counteracted by further miR-506-3p inhibition. CONCLUSION: The silencing of HOXA11-AS might block the PI3K/AKT/mTOR pathway through miR-506-3p up-regulation, thereby restricting HCOA cell proliferation and provoking apoptosis.

Exploiting new strategies in combating head and neck carcinoma: A comprehensive review on phytochemical approaches passing through PI3K/Akt/mTOR signaling pathway.

Recently, malignant neoplasms have growingly caused human morbidity and mortality. Head and neck cancer (HNC) constitutes a substantial group of malignancies occurring in various anatomical regions of the head and neck, including lips, mouth, throat, larynx, nose, sinuses, oropharynx, hypopharynx, nasopharynx, and salivary glands. The present study addresses the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway as a possible therapeutic target in cancer therapy. Finding new multitargeting agents capable of modulating PI3K/Akt/mTOR and cross-linked mediators could be viewed as an effective strategy in combating HNC. Recent studies have introduced phytochemicals as multitargeting agents and rich sources for finding and developing new therapeutic agents. Phytochemicals have exhibited immense anticancer effects, including targeting different stages of HNC through the modulation of several signaling pathways. Moreover, phenolic/polyphenolic compounds, alkaloids, terpenes/terpenoids, and other secondary metabolites have demonstrated promising anticancer activities because of their diverse pharmacological and biological properties like antiproliferative, antineoplastic, antioxidant, and anti-inflammatory activities. The current review is mainly focused on new therapeutic strategies for HNC passing through the PI3K/Akt/mTOR pathway as new strategies in combating HNC.

IGF2BP2 regulates the proliferation and migration of endometrial stromal cells through the PI3K/AKT/mTOR signaling pathway in Hu sheep.

Insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), a significant member of the conserved RNA-binding protein family, plays various roles in numerous physiological and pathological processes. However, the specific function of IGF2BP2 in regulating endometrial function in sheep remains largely unknown. In this study, we observed a significant upregulation in IGF2BP2 mRNA abundance in the endometrium during the luteal phase compared to the follicular phase in Hu sheep. The knockdown of IGF2BP2 resulted in accelerated cell proliferation and migration of Hu sheep endometrial stromal cells (ESCs). Moreover, RNA sequencing analysis revealed that genes with significantly altered expression in IGF2BP2 knockdown cells were predominantly enriched in endometrial receptivity-related signaling pathways, such as cytokine-cytokine receptor interaction, NOD-like receptor, PI3K-AKT, and JAK-STAT signaling pathway. Additionally, the knockdown of IGF2BP2 significantly increased the expression of matrix metalloprotein 9 (MMP9), vascular endothelial growth factor, and prolactin (PRL) in ESCs. The knockdown of IGF2BP2 was also observed to stimulate the PI3K/AKT/mTOR pathway by upregulating integrin ß4 (ITGB4) expression. Notably, the downregulation of ITGB4 attenuates IGF2BP2 knockdown-induced facilitation of proliferation and migration of Hu sheep ESCs by inhibiting the PI3K/AKT/mTOR pathway. Collectively, these findings highlight the important role of IGF2BP2 in regulating endometrial function, particularly through the modulation of ESC proliferation and migration via the PI3K/AKT/mTOR pathway.

The maintenance of normal physiological functionality of the endometrium is crucial for successful embryo implantation. Endometrial stromal cells (ESCs), as the principal components of the endometrium, play a key role in establishing optimal endometrial receptivity for embryo implantation. Despite the well-established role of IGF2BP2 in the pathogenesis of endometriosis in women, its functional impact on endometrial activity in ruminants, particularly in ovine species, remains undefined. In this study, we investigated the expression pattern of IGF2BP2 in the reproductive organs of female sheep and evaluated the potential roles and underlying mechanisms of IGF2BP2 in the function of sheep ESCs. This experiment confirmed the important role of IGF2BP2 in regulating endometrial function by modulating the proliferation and migration of Hu sheep ESCs.

Endometriosis-Related Ovarian Cancer: Where Are We Now? A Narrative Review towards a Pragmatic Approach.

BACKGROUND: Endometriosis affects more than 10% of reproductive-aged women, causing pelvic pain and infertility. Despite the benign nature of endometriosis, ovarian endometriomas carry a higher risk of developing endometrioid carcinomas (EnOCs) and clear cell ovarian carcinomas (CCCs). Atypical endometriosis, defined as cytological atypia resembling intraepithelial cancer, is considered the precursor of endometriosis-associated ovarian cancer (EAOC). This narrative review aims to provide an overview of EAOC, proposing a practical approach to clinical and therapeutic decision making. METHODS: An electronic literature search was conducted from inception up to January 2023, using the MEDLINE database via PubMed to evaluate the existing literature on EAOC, including its pathogenesis, the diagnostic process, and the therapeutic possibilities, with articles not relevant to the topic or lacking scientific merit being excluded. RESULTS: Eighty-one articles were included in the review to present the current state of the art regarding EAOC. A pragmatic clinical flowchart is proposed to guide therapeutic decisions and improve patient outcomes. CONCLUSIONS: Endometriosis patients may have an increased risk of developing EAOC (either EnOC or CCC). Despite not being fully accepted, the concept of AE may reshape the endometriosis-ovarian cancer relationship. Further research is needed to understand the unaddressed issues.