Akt Pathway Research Articles

Caffeine regulates both osteoclast and osteoblast differentiation via the AKT, NF-κB, and MAPK pathways

Caffeine regulates both osteoclast and osteoblast differentiation via the AKT, NF-κB, and MAPK pathways

Unraveling the intricate relationship between lipid metabolism and oncogenic signaling pathways.

Lipids, the primary constituents of the cell membrane, play essential roles in nearly all cellular functions, such as cell-cell recognition, signaling transduction, and energy provision. Lipid metabolism is necessary for the maintenance of life since it regulates the balance between the processes of synthesis and breakdown. Increasing evidence suggests that cancer cells exhibit abnormal lipid metabolism, significantly affecting their malignant characteristics, including self-renewal, differentiation, invasion, metastasis, and drug sensitivity and resistance. Prominent oncogenic signaling pathways that modulate metabolic gene expression and elevate metabolic enzyme activity include phosphoinositide 3-kinase (PI3K)/AKT, MAPK, NF-kB, Wnt, Notch, and Hippo pathway. Conversely, when metabolic processes are not regulated, they can lead to malfunctions in cellular signal transduction pathways. This, in turn, enables uncontrolled cancer cell growth by providing the necessary energy, building blocks, and redox potentials. Therefore, targeting lipid metabolism-associated oncogenic signaling pathways could be an effective therapeutic approach to decrease cancer incidence and promote survival. This review sheds light on the interactions between lipid reprogramming and signaling pathways in cancer. Exploring lipid metabolism as a target could provide a promising approach for creating anticancer treatments by identifying metabolic inhibitors. Additionally, we have also provided an overview of the drugs targeting lipid metabolism in cancer in this review.

Induction of CX3CL1 expression by LPS and its impact on invasion and migration in oral squamous cell carcinoma.

Purpose: This study aimed to explore the expression of CX3CL1 induced by lipopolysaccharide (LPS) in oral squamous cell carcinoma (OSCC) and its impact on biological characteristics such as invasion and migration, taking the foundation for new targets for the treatment and prognosis of OSCC. Methods: This study utilized a variety of techniques, including bioinformatics, molecular biology, and cell experiments, to investigate the expression of CX3CL1 and its receptor CX3CR1 in OSCC patients' cancer tissues or OSCC cell lines. Extracting, organizing, and analyzing the TCGA database on the expression of CX3CL1 and its receptor CX3CR1 in cancer tissues and corresponding paracancerous normal tissues of OSCC patients by bioinformatics methods. The expression of CX3CL1 in cancerous and normal tissues of OSCC patients was verified by IHC, and the changes in mRNA and protein expression of CX3CL1 and its receptor CX3CR1 in OSCC cell lines were detected before and after lipopolysaccharide LPS stimulation by RT-PCR, ELISA, and WB. Changes in cell biological behavior by overexpression of CX3CL1 in OSCC cell lines were detected by CCK-8, Transwell, scratch healing assay, and cloning assay. The effects of overexpressing cell lines on the AKT pathway and Epithelial-mesenchymal Transition (EMT)-related protein expression before and after LPS stimulation were detected by Western Blot. Results: (1) CX3CL1 and its receptor CX3CR1 were found to be downregulated in OSCC tissues of patients or OSCC cell lines. (2) After LPS stimulation, CX3CL1 gene expression increased in both OSCC cell lines, while CX3CR1 expression remained unchanged. (3) OSCC cell lines overexpressing CX3CL1 showed changes in cell biological characteristics, including decreased proliferation, invasion, migration, and stemness, which were more pronounced after LPS stimulation. (4) Overexpression of CX3CL1 in OSCC cell lines decreased EMT-related protein expression and AKT phosphorylation. On the contrary were promoted by LPS stimulation. Conclusion: CX3CL1 and CX3CR1 are downregulated in OSCC cancer tissues and cell lines compared to adjacent normal tissues and cells. LPS stimulation increases CX3CL1 expression in OSCC cell lines, suggesting that inflammation may induce CX3CL1 expression and that the CX3CL1 gene may play an important role in OSCC progression. Overexpression of CX3CL1 inhibits OSCC cell proliferation, migration, invasion, and stemness, suggesting that CX3CL1 plays a critical role in suppressing OSCC development. CX3CL1 suppresses OSCC invasion and migration by affecting EMT progression and AKT phosphorylation, and partially reverse the process that LPS causes and affects the development of OSCC.

FOXO3a/PI3K/Akt pathway participates in the ROS- induced apoptosis triggered by α-ZEL and β-ZEL

Zearalenone (ZEN), an estrogenic mycotoxin, is one of the most common food and feed contaminants. Also, its metabolites α-zearalenol (α-ZEL) and β-zearalenol (β-ZEL) are considered to induce oxidative stress, however its effect in prostate cells is not known yet. Our previous observations showed that forehead box transcription factor 3a (FOXO3a) expression is modified in hormone- sensitive cells in the response to mycotoxins, similar to the phosphoinositide 3-kinase (PI3K)/ protein kinase B (Akt) pathway. Thus, this study evaluated the direct molecular effect of α-ZEL and β-ZEL in a dose of 30 µM in hormone-dependent human prostate cancer (PCa) cells with the focus of the involvement of FOXO3a and PI3K/Akt signaling pathway in that effect. We observed that both active metabolites of ZEN reduced cell viability, induced oxidative stress, cell cycle arrest and apoptosis in PCa cells. Furthermore, we observed that FOXO3a as well as PI3K/Akt signaling pathway participate in ZELs induced toxicity in PCa cells, indicating that this signaling pathway might be a regulator of mycotoxin-induced toxicity generally.

Exploring the mechanism of fraxetin against acute myeloid leukemia through cell experiments and network pharmacology

ObjectivePrevious studies have shown that fraxetin has antitumor activity in a variety of tumors, but its role in acute myeloid leukemia (AML) remains unclear. In this study, we aimed to evaluate the anti-AML effect of fraxetin through cell experiments and network pharmacology analysis.MethodsThe inhibitory and apoptotic effects of fraxetin on AML cells were determined by CCK-8 and flow cytometry experiments. Potential targets of fraxetin and AML-related targets were screened using public databases. PPI network, GO functional enrichment and KEGG pathway enrichment analyses were performed to predict the hub targets and signaling pathways by which fraxetin alleviates AML. Molecular docking was used to determine the fraxetin binding sites on hub targets. Using the GEPIA database, the expression of hub targets was analyzed in relation to the overall survival of AML patients.ResultsCell experiments showed that fraxetin inhibits AML cell proliferation and induces apoptosis. To explore the potential mechanism of fraxetin, 29 shared targets of fraxetin and AML were obtained through screening online public databases. Among them, AKT1, TNF, SRC, etc., are related to AML cell apoptosis. The expression levels of SRC, NOS3, VAV1, LYN, and PTGS1 were associated with the overall survival of AML patients (p value < 0.05). The enrichment analysis results identified the main pathways, namely, focal adhesion and the PI3K-AKT signaling pathway, that affected the proliferation and apoptosis of AML cells. The analysis of hub targets of the PPI network showed that AKT1, TNF, CTNNB1, etc., were hub targets, which were related to the proliferation and apoptosis of AML cells. The results of molecular docking showed that the hub targets had good binding with fraxetin.ConclusionFraxetin may inhibit AML cell proliferation and induce AML cell apoptosis through multiple targets, such as AKT1, SRC, and EGFR, and multiple pathways, such as focal adhesion and the PI3K-AKT signaling pathway.

Marine algae-derived oligosaccharide via protein crotonylation of key targeting for management of type 2 diabetes mellitus in the elderly

Global aging is a tendency of the world, as is the increasing prevalence of diabetes, and the two are closely linked. In our early research, Enteromorpha prolifera oligosaccharide (EPO) possesses the excellent ability of anti-oxidative, anti-inflammatory, and anti-diabetic. We aim to further explore the deeper mechanism of how EPO delays aging and regulates glycometabolism. EPO effectively impacts crotonylation procession to enhance glucose metabolism and reduce cell senescence in aging diabetic rats. Crotonylation modification of XPO1 influences the expression of critical genes, including p53, CDK1, and CCNB1, which affect cell cycle regulation and aging. Additionally, EPO improves glucose metabolism by inhibiting the crotonylation modification of HSPA8-K126 and activating the AKT pathway. EPO promotes crotonylation of histones in intestinal cells, influencing the aging process by increasing the butyric acid-producing bacteria Ruminococcaceae. The observed enhancement in pyrimidine metabolism underscores EPO’s potential role in regulating intestinal health, presenting a promising avenue for delaying aging. In summary, our findings affirm EPO as a naturally bioactive ingredient with significant potential for anti-aging and antidiabetic interventions.

C-type natriuretic peptide/cGMP/FoxO3 signaling attenuates hyperproliferation of pericytes from patients with pulmonary arterial hypertension

Pericyte dysfunction, with excessive migration, hyperproliferation, and differentiation into smooth muscle-like cells contributes to vascular remodeling in Pulmonary Arterial Hypertension (PAH). Augmented expression and action of growth factors trigger these pathological changes. Endogenous factors opposing such alterations are barely known. Here, we examine whether and how the endothelial hormone C-type natriuretic peptide (CNP), signaling through the cyclic guanosine monophosphate (cGMP) -producing guanylyl cyclase B (GC-B) receptor, attenuates the pericyte dysfunction observed in PAH. The results demonstrate that CNP/GC-B/cGMP signaling is preserved in lung pericytes from patients with PAH and prevents their growth factor-induced proliferation, migration, and transdifferentiation. The anti-proliferative effect of CNP is mediated by cGMP-dependent protein kinase I and inhibition of the Phosphoinositide 3-kinase (PI3K)/AKT pathway, ultimately leading to the nuclear stabilization and activation of the Forkhead Box O 3 (FoxO3) transcription factor. Augmentation of the CNP/GC-B/cGMP/FoxO3 signaling pathway might be a target for novel therapeutics in the field of PAH.

Canthin-6-one analogs block Newcastle disease virus proliferation via suppressing the Akt and ERK pathways

Newcastle disease virus, a member of the Paramyxoviridae family, causes significant economic losses in poultry worldwide. To identify novel antiviral agents against NDV, 36 canthin-6-one analogs were evaluated in this study. Our data showed that 8 compounds exhibited excellent inhibitory effects on NDV replication with IC50 values in the range of 5.26 to 11.76 μM. Besides, these analogs inhibited multiple NDV strains with IC50 values within 12 μM and exerted antiviral activity against peste des petits ruminants virus (PPRV) and canine distemper virus (CDV). Among these analogs, 16 presented the strongest anti-NDV activity (IC50 = 5.26 μM) and minimum cytotoxicity (CC50 > 200 μM) in DF-1 cells. Furthermore, 16 displayed antiviral activity in different cell lines. Our results showed that 16 did not affect the viral adsorption while it can inhibit the entry of NDV by suppressing the Akt pathway. Further study found that 16-treatment inhibited the NDV-activated ERK pathway, thereby promoting the expression of interferon-related genes. Our findings reveal an antiviral mechanism of canthin-6-one analogs through inhibition of the Akt and ERK signaling pathways. These results point to the potential value of canthin-6-one analogs to serve as candidate antiviral agents for NDV.

Protective effects of baicalin against phenylarsine oxide-induced cytotoxicity in human skin keratinocytes

Phenylarsine oxide (PAO) is a known environmental pollutant and skin keratinocytes are most seriously affected. Baicalin (BCN) was reported to have antioxidant and anti-inflammatory effects, but its protective effect against PAO toxicity is unknown. This study aimed at exploring whether baicalin can reverse the toxicity of human epidermal keratinocytes that are subjected to PAO exposure and underlying mechanisms. In silico analysis from a publicly accessible HaCaT cell transcriptome dataset exposed to chronic Arsenic showed significant differential expression of several genes, including the genes related to DNA replication. Later, we performed in vitro experiments, in which HaCaT cells were exposed to PAO (500 nM) in the existence of BCN (10–50 µM). Treatment of PAO alone induces the JNK, p38 and caspase-3 activation, which were engaged in the apoptosis induction, while the activity of AKT was significantly inhibited, which was engaged in the suppression of apoptosis. PAO suppressed SIRT3 expression and induced intracellular reactive oxygen species (ROS), causing a marked reduce in cell viability and apoptosis. However, BCN treatment restored the PAO-induced suppression of SIRT3 and AKT expression, reduced intracellular ROS generation, and markedly suppressed both caspase-3 activation and apoptosis induction. However, the protective effect of BCN was significantly attenuated after pretreatment with nicotinamide, an inhibitor of SIRT3. These findings indicate that BCN protects against cell death induced by PAO via inhibiting excessive intracellular ROS generation via restoring SIRT3 activity and reactivating downstream AKT pathway. In this study, we firstly shown that BCN is an efficient drug to prevent PAO-induced skin cytotoxicity, and these findings need to be confirmed by in vivo and clinical investigations.

Gedatolisib shows superior potency and efficacy versus single-node PI3K/AKT/mTOR inhibitors in breast cancer models

The PI3K, AKT, and mTOR (PAM) pathway is frequently dysregulated in breast cancer (BC) to accommodate high catabolic and anabolic activities driving tumor growth. Current therapeutic options for patients with hormone receptor (HR) + / HER2- advanced BC (ABC) include PAM inhibitors that selectively inhibit only one PAM pathway node, which can lead to drug resistance as cells rapidly adapt to maintain viability. We hypothesized that gedatolisib, which potently inhibits all Class I PI3K isoforms, as well as mTORC1 and mTORC2, may be more effective in BC cells than single-node PAM inhibitors by limiting adaptive resistances. By using multiple functional assays, a panel of BC cell lines was evaluated for their sensitivity to four different PAM inhibitors: gedatolisib (pan-PI3K/mTOR inhibitor), alpelisib (PI3Kα inhibitor), capivasertib (AKT inhibitor), and everolimus (mTORC1 inhibitor). Gedatolisib exhibited more potent and efficacious anti-proliferative and cytotoxic effects regardless of the PAM pathway mutational status of the cell lines compared to the single-node PAM inhibitors. The higher efficacy of gedatolisib was confirmed in three-dimensional culture and in BC PDX models. Mechanistically, gedatolisib decreased cell survival, DNA replication, cell migration and invasion, protein synthesis, glucose consumption, lactate production, and oxygen consumption more effectively than the other PAM inhibitors tested. These results indicate that inhibition of multiple PAM pathway nodes by a pan-PI3K/mTOR inhibitor like gedatolisib may be more effective at inducing anti-tumor activity than single-node PAM inhibitors. A global Phase 3 study is currently evaluating gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2− ABC.

Prevotella copri transplantation promotes neurorehabilitation in a mouse model of traumatic brain injury

BackgroundThe gut microbiota plays a critical role in regulating brain function through the microbiome-gut-brain axis (MGBA). Dysbiosis of the gut microbiota is associated with neurological impairment in Traumatic brain injury (TBI) patients. Our previous study found that TBI results in a decrease in the abundance of Prevotella copri (P. copri). P. copri has been shown to have antioxidant effects in various diseases. Meanwhile, guanosine (GUO) is a metabolite of intestinal microbiota that can alleviate oxidative stress after TBI by activating the PI3K/Akt pathway. In this study, we investigated the effect of P. copri transplantation on TBI and its relationship with GUO-PI3K/Akt pathway.MethodsIn this study, a controlled cortical impact (CCI) model was used to induce TBI in adult male C57BL/6J mice. Subsequently, P. copri was transplanted by intragastric gavage for 7 consecutive days. To investigate the effect of the GUO-PI3K/Akt pathway in P. copri transplantation therapy, guanosine (GUO) was administered 2 h after TBI for 7 consecutive days, and PI3K inhibitor (LY294002) was administered 30 min before TBI. Various techniques were used to assess the effects of these interventions, including quantitative PCR, neurological behavior tests, metabolite analysis, ELISA, Western blot analysis, immunofluorescence, Evans blue assays, transmission electron microscopy, FITC-dextran permeability assay, gastrointestinal transit assessment, and 16 S rDNA sequencing.ResultsP. copri abundance was significantly reduced after TBI. P. copri transplantation alleviated motor and cognitive deficits tested by the NSS, Morris’s water maze and open field test. P. copri transplantation attenuated oxidative stress and blood-brain barrier damage and reduced neuronal apoptosis after TBI. In addition, P. copri transplantation resulted in the reshaping of the intestinal flora, improved gastrointestinal motility and intestinal permeability. Metabolomics and ELISA analysis revealed a significant increase in GUO levels in feces, serum and injured brain after P. copri transplantation. Furthermore, the expression of p-PI3K and p-Akt was found to be increased after P. copri transplantation and GUO treatment. Notably, PI3K inhibitor LY294002 treatment attenuated the observed improvements.ConclusionsWe demonstrate for the first time that P. copri transplantation can improve GI functions and alter gut microbiota dysbiosis after TBI. Additionally, P. copri transplantation can ameliorate neurological deficits, possibly via the GUO-PI3K/Akt signaling pathway after TBI.

Human Amniotic Epithelial Stem Cells Alleviate Autoimmune Premature Ovarian Insufficiency in Mice by Targeting Granulosa Cells via AKT/ERK Pathways

Autoimmune factors play an important role in premature ovarian insufficiency (POI). Human amniotic epithelial stem cells (hAESCs) have recently shown promising treatment effects on chemotherapy-induced POI. However, the therapeutic efficacy and underlying mechanisms of hAESCs in autoimmune POI remain to be investigated. In this study, we showed for the first time that intravenous transplantation of hAESCs could reside in the ovary of zona pellucida 3 peptide (pZP3) induced autoimmune POI mice model for at least 4 weeks. hAESCs could improve ovarian function and fertility, alleviate inflammation and reduce apoptosis of granulosa cells (GCs) in autoimmune POI mice. The transcriptome analysis of mice ovaries and in vitro co-cultivation experiments suggest that activation of the AKT and ERK pathways may be the key mechanism in the therapeutic effect of hAESCs. Our work provides the theoretical and experimental foundation for optimizing the administration of hAESCs, as well as the clinical application of hAESCs in autoimmune POI patients.Graphical

An Update on Physiopathological Roles of Akt in the ReprodAKTive Mammalian Ovary.

The phosphoinositide 3-kinase (PI3K)/Akt pathway is a key signaling cascade responsible for the regulation of cell survival, proliferation, and metabolism in the ovarian microenvironment. The optimal finetuning of this pathway is essential for physiological processes concerning oogenesis, folliculogenesis, oocyte maturation, and embryo development. The dysregulation of PI3K/Akt can impair molecular and structural mechanisms that will lead to follicle atresia, or the inability of embryos to reach later stages of development. Due to its pivotal role in the control of cell proliferation, apoptosis, and survival mechanisms, the dysregulation of this molecular pathway can trigger the onset of pathological conditions. Among these, we will focus on diseases that can harm female fertility, such as polycystic ovary syndrome and premature ovarian failure, or women's general health, such as ovarian cancer. In this review, we report the functions of the PI3K/Akt pathway in both its physiological and pathological roles, and we address the existing application of inhibitors and activators for the balancing of the molecular cascade in ovarian pathological environments.

Downregulation of HIGD1B induces mitochondria-mediated apoptosis in gastric cancer cells by inactivating Akt and ERK pathways.

Gastric cancer (GC) is one of the most common malignancies worldwide. Hypoxia-inducible domain (HIGD) family members (e.g., HIGD1A) have been linked to tumor progression. However, the role of HIGD1B (another HIGD family member) in GC has yet to be fully understood. Based on data from TCGA_GC, GSE65801, and GSE65801 data sets, HIGD1B levels were evaluated in normal and GC tissues. Next, HIGD1B levels were validated by reverse transcription-quantitative PCR and western blot analysis analyses. Meanwhile, patients with GC in the TCGA_GC cohort were grouped into high- and low-HIGD1B level groups, and overall survival, functional enrichment, and immune infiltration were analyzed. Additionally, gain- and loss-of-function experiments were performed to determine the function of HIGD1B in GC cells. Compared to normal controls, HIGD1B mRNA levels were significantly elevated in GC tissues. Moreover, high HIGD1B levels may be an independent indicator of poor prognosis in patients with GC. Additionally, high HIGD1B levels were correlated with high stromal and ESTIMATE scores and elevated expression of immune checkpoints in patients with GC. Functional analyses showed that HIGD1B deficiency notably suppressed GC cell proliferation, migration, and invasion. Moreover, HIGD1B deficiency significantly induced mitochondria-mediated apoptosis in GC cells by inactivating Akt and ERK pathways. Collectively, HIGD1B may predict the prognosis of patients with GC and may function as an oncogene in GC. These findings suggest that HIGD1B may serve as a prognostic biomarker and potential therapeutic target in GC.

RONS-mediated redox signaling in skeletal muscle: Impact on glucose uptake through AMPK and AKT pathways

RONS-mediated redox signaling in skeletal muscle: Impact on glucose uptake through AMPK and AKT pathways

Pan-cancer analysis of DCTN2 and its tumour-promoting role in HCC by modulating the AKT pathway.

Dynactin subunit 2 (DCTN2) has been reported to play a role in progression of several tumours; however, the involvement of DCTN2 in potential mechanism or the tumour immune microenvironment among various cancers still remains largely unknown. Therefore, the objective of this study was to comprehensively investigate the expression status and potential function of DCTN2 in various malignancies through different database, such as The Cancer Genome Atlas, the Genotype-Tissue Expression and Gene Expression Omnimus databases. We discovered that DCTN2 expression was high in many type of tumours tissues compared to adjacent non-tumour ones. High DCTN2 signified poor prognosis for patients with tumours. Additionally, Gene Set Enrichment Analysis (GSEA) analysis revealed that DCTN2 was positively correlated with oncogenic pathways, including cell cycle, tumour metastasis-related pathway, while it was negatively with anti-tumour immune signalling pathway, such as INF-γ response. More importantly, we elucidated the functional impact of DCTN2 on hepatocellular carcinoma (HCC) progression and its underlying mechanisms. DCTN2 expression was much higher in HCC tissues than in adjacent non-tumour tissues. Silencing DCTN2 dramatically suppressed the proliferative and metastasis capacities of tumour cell invitro. Mechanistically, DCTN2 exerted tumour-promoting effects by modulating the AKT signalling pathway. DCTN2 knockdown in HCC cells inhibited AKT phosphorylation and its downstream targets as well. Rescue experiments revealed that the anti-tumour effects of DCTN2 knockdown were partially reversed upon AKT pathway activation. Overall, DCTN2 may be a potent biomarker signifying tumour prognosis and a promising therapeutic target for tumour treatment, particularly in HCC.

Apigenin's Modulation of Doxorubicin Efficacy in Breast Cancer.

Apigenin, a naturally derived flavonoid, is increasingly being acknowledged for its potential therapeutic applications, especially in oncology. This research explores apigenin's capacity to modulate cancer cell viability, emphasizing its roles beyond its minimal antioxidant activity attributed to its basic molecular structure devoid of hydroxyl groups. We investigated apigenin's effects on two breast cancer cell lines, estrogen-dependent MCF-7 and non-estrogen-dependent MDA-MB-231 cells. Our findings reveal that apigenin exerts a dose-dependent cytotoxic and anti-migratory impact on these cells. Interestingly, both apigenin and doxorubicin-a standard chemotherapeutic agent-induced lipid droplet accumulation in a dose-dependent manner in MDA-MB-231 cells. This phenomenon was absent in MCF-7 cells and not evident when doxorubicin and apigenin were used concurrently, suggesting distinct cellular responses to these treatments that imply that their synergistic effects might be mediated through mechanisms unrelated to lipid metabolism. A further chemoinformatics analysis indicated that apigenin and doxorubicin might interact primarily at the level of ATP-binding cassette (ABC) transporter proteins, with potential indirect influences from the AKT and MYC signaling pathways. These results highlight the importance of understanding the nuanced interactions between apigenin and conventional chemotherapeutic drugs, as they could lead to more effective strategies for cancer treatment. This study underscores apigenin's potential as a modulator of cancer cell dynamics through mechanisms independent of its direct antioxidant effects, thereby contributing to the development of flavonoid-based adjunct therapies in cancer management.

Research of active compounds from Allii Macrostemonis Bulbus and potential targets against Non-Hodgkin's Lymphoma based on Network pharmacology.

Non-Hodgkin's Lymphoma (NHL) is a series of lymphoid malignancies in some aggressive subtypes with unsatisfactory treatment effects. Allii Macrostemonis Bulbus (Xie Bai) is a traditional Chinese medicine with anti-cancer activities, which may potentially suppress aggressive NHL. This study tries to discover active components and targets of Xie Bai in treating NHL by network pharmacology-based approaches. Compounds and related targets of Xie Bai were collected from the Traditional Chinese Medicine Database and Analysis Platform. Target genes associated with NHL were searched by GeneCards and DisGeNET, then the overlapped targets were further analyzed by STRING tool, GO, and KEGG pathway enrichment analysis. Molecular docking was employed to verify the interaction between compounds and targets. 11 bioactive compounds were successfully identified, with 30 targets that were screened out for the treatment of NHL. Functional enrichment analysis suggested that Xie Bai exerted its potential effects against NHL via pathways in cancer, such as PI3K/ AKT, p53, and MAPK signaling pathways. Molecular docking results showed that 3 active compounds (quercetin, beta-sitosterol, and naringenin) had good affinity with selected 6 targets（TP53, AKT1, CASP3, CCND1, HPK1, and NLRP3). Identifying six potential genes could accurately be docked with Xie Bai and had close interactions with NHL, which may provide insight into further research and new treatment strategy.

Mechanism of Yupingfeng Powder on hepatic insulin resistance in type 2 diabetes mellitus rats by regulating IRS/PI3K/Akt pathway

Based on the insulin receptor substrate(IRS)/phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt) pathway, the intervention effect of Yupingfeng Powder on type 2 diabetes mellitus(T2DM) rats was studied, and the potential mechanism of improving T2DM hepatic insulin resistance was explored. A T2DM rat model was established by feeding with high-fat and high-sugar feed combined with intraperitoneal injection of streptozotocin. Successfully modeled rats were selected and divided into a model group, a positive control group(MET), and a Yupingfeng Powder group. At the same time, a blank group was set up, and corresponding drugs were given by gavage. The model group and blank group were given an equal amount of physiological saline by gavage. During the experiment, body mass and fasting blood glucose were regularly measured, and glucose tolerance and insulin tolerance were measured at the end of the experiment. After the experiment, the levels of blood glucose, insulin, blood lipids, and related liver function indicators were measured; changes in liver pathological damage were observed, levels of liver monoamine oxidase were detected, and qRT-PCR was used to detect mRNA expression levels of IRS/PI3K/Akt pathway related genes. Compared with the model group, the Yupingfeng Powder group had an increase in body weight, a decrease in fasting blood glucose, fasting insulin, and steady-state model evaluation index, a decrease in the area under the curve of glucose tolerance and insulin tolerance tests, a decrease in serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol content, and an increase in high-density lipoprotein cholesterol content. Compared with the model group, the Yupingfeng Powder group showed a decrease in liver monoamine oxidase levels, a decrease in serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total bilirubin levels, and an increase in total protein and albumin levels. Hematoxylin-eosin(HE) staining showed a reduction in pathological liver cell damage. Compared with the model group, the Yupingfeng Powder group showed a significant increase in the mRNA expression levels of IRS1, PI3K, and Akt in the liver of rats, as well as a significant decrease in the mRNA expression levels of interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α). This indicates that Yupingfeng Powder can regulate the IRS/PI3K/Akt signaling pathway and glucose and lipid metabolism disorders, increase insulin sensitivity, improve hepatic insulin resistance, and thus play a therapeutic role in T2DM.

Ring finger protein 216 loss-of-function induces white matter hyperintensities by inhibiting oligodendroglia proliferation.

White matter hyperintensities(WMHs) refer to a group of diseases with numerous etiologies while oligodendrocytes remain the centerpiece in the pathogenesis of WMHs. Ring Finger Protein 216 (RNF216) encodes a ubiquitin ligase, and its mutation begets WMHs, ataxia, and cognitive decline in patients. Yet no study has revealed the function of RNF216 in oligodendroglia and WHIs before. In this study, we summarized the phenotypes of RNF216-mutation cases and explored the normal distribution of RNF216 in distinct brain regions and neuronal cells by bioinformatic analysis. Furthermore, MO3.13, a human oligodendrocyte cell line, was applied to study the function alteration after RNF216 knockdown. As a result, WMHs were the most common symptom in RNF216-mutated diseases, and RNF216 was indeed relatively enriched in corpus callosum and oligodendroglia in humans. The downregulation of RNF216 in oligodendroglia remarkably hampered cell proliferation by inhibiting the Akt pathway while having no significant effect on cell injury and oligodendrocyte maturation. Combining clinical, bioinformatical, and experimental evidence, our study implied the pivotal role of RNF216 in WMHs which might serve as a potent target in the therapy of WMHs.