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Cancer development is closely associated with immunosuppressive tumor microenvironment (TME) that attenuates antitumor immune responses and promotes tumor cell immunologic escape. The sequential conversion of extracellular ATP into adenosine by two important cell-surface ectonucleosidases CD39 and CD73 play critical roles in reshaping an immunosuppressive TME. The accumulated extracellular adenosine mediates its regulatory functions by binding to one of four adenosine receptors (A1R, A2AR, A2BR and A3R). The A2AR elicits its profound immunosuppressive function via regulating cAMP signaling. The increasing evidence suggests that CD39, CD73 and A2AR could be used as novel therapeutic targets for manipulating the antitumor immunity. In recent years, monoclonal antibodies or small molecule inhibitors targeting the CD39/CD73/A2AR pathway have been investigated in clinical trials as single agents or in combination with anti-PD-1/PD-L1 therapies. In this review, we provide an updated summary about the pathophysiological function of the adenosinergic pathway in cancer development, metastasis and drug resistance. The targeting of one or more components of the adenosinergic pathway for cancer therapy and circumvention of immunotherapy resistance are also discussed. Emerging biomarkers that may be used to guide the selection of CD39/CD73/A2AR-targeting treatment strategies for individual cancer patients is also deliberated. [ABSTRACT FROM AUTHOR]

Abstract The molecular mechanisms underlying the antineoplastic properties of metformin combined with nelfinavir remain elusive. To explore this question, transmission electron microscopy (TEM) was used to observe the combinatorial effect of inducing autophagosome formation in human cervical cancer cells. Western blotting respectively assayed protein expression of LC3I, LC3II, Beclin-1, Autophagy-related protein 7 (Atg7), Autophagy-related protein 3 (Atg3), NAD-dependent deacetylase sirtuin-3 (SIRT3) and major histocompatibility complex class I chain-related gene A (MICA). Lactate dehydrogenase (LDH) cytotoxicity assay evaluated natural killer (NK) cell cytotoxicity in the presence of metformin and nelfinavir in combination or each drug alone. Using tumor xenografts in a nude mouse model, antitumor efficacy of the drug combination was assessed. We found that the drug combination could induce autophagosome formation in human cervical cancer cells. The biomarker proteins of autophagy, including Beclin-1, Atg7 and Atg3, decreased, but the ratios of LC3I/II increased. We also found that this drug combination sensitizes human cervical cancer cells to NK cell-mediated lysis by increasing the protein of SIRT3 and MICA. Moreover, this drug combination markedly induced autophagy of SiHa xenografts in nude mice. Therefore, it can be concluded that metformin, in combination with nelfinavir, can induce SIRT3/mROS-dependent autophagy and sensitize NK cell-mediated lysis in human cervical cancer cells and cervical cancer cell xenografts in nude mice. Thus, our findings have revealed the detailed molecular mechanisms underlying the antitumor effects of metformin in combination with nelfinavir in cervical cancer. [ABSTRACT FROM AUTHOR]

The molecular mechanisms underlying the anti-neoplastic properties of metformin, a first-line drug for type 2 diabetes, remain elusive. To explore the novel anti-neoplastic mechanisms of metformin, the transwell chamber and wound-healing assays were used to evaluate its effects on the migration and invasion of human cervical cancer cells. Real-time PCR and Western blotting were used to measure the gene and protein expression, respectively, of microRNA (miRNA) miR-142-3p, long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript-1 (MALAT1), and high-mobility group AT-hook 2 (HMGA2). The dual-luciferase reporter assay system was used to examine the direct interaction between miR-142-3p and lncRNA MALAT1 and HMGA2. Immunofluorescence was used to detect the protein expression of HMGA2. In addition, tumor xenografts in a nude mouse model were developed to evaluate the anti-tumor efficacy of metformin. We found that metformin could suppress cervical cancer migration and invasion. During the process of tumor metastasis, miR-142-3p was significantly upregulated, whereas lncRNA MATAL1 and HMGA2 were suppressed by metformin. The binding site that allow the direct interaction between miR-142-3p and MALAT1 were located in the 3′ untranslated region (3′ UTR) of lncRNA MATAL1 and HMGA2 at base pairs (bp) 4452–5255, while that between miR-142-3p and HMGA2 was located at bp 1562–2521 of HMGA2. Metformin markedly inhibited the growth and angiogenesis of SiHa xenografts in nude mice. In conclusion, this study provides evidence that metformin can prevent the MALAT1/miR-142-3p sponge from developing anti-neoplastic properties in human cervical cancer cells and cervical cancer cell xenografts in nude mice. Thus, our findings demonstrate the novel anti-tumor effects of metformin in cervical cancer. [ABSTRACT FROM AUTHOR]

Neuronal cell dysfunction and apoptosis are the main causes of the invasion of the central nervous system by human immunodeficiency virus type 1 (HIV-1), although the underlying mechanism has not been well understood. Recent research has shown that curcumin might play an important role in regulating HIV-1 development. Heat shock protein 70 (HSP70), a protein induced by heat, was reported to inhibit apoptosis through various cell signaling pathways in brain. Overexpression of HSP70 could effectively protected neurons in many animal and cellular models of dementia. In the present study, the expression of HSP70 in the gp120 V3 loop peptide-induced neuronal apoptosis was investigated. Our results demonstrated that gp120 V3 loop peptide could induce primary rat cortical neuronal apoptosis. We also found that curcumin could increase HSP70 expression. In addition, the expression level of both HSP70 mRNA and HSP70 protein were dependent on the curcumin dose in the rat cortical neurons. Curcumin could improve HSP70 expression in gp120 V3 loop peptide-induced primary rat cortical neuronal apoptosis. In general, our results indicated that curcumin played an important role in the gp120 V3 loop peptide induced neuronal apoptosis by regulating HSP70. [ABSTRACT FROM AUTHOR]

Infertility is an area of increasing in life science research. Although follicular maturation disorders and anovulation are the primary causations of infertility, its molecular mechanism is not well understood. Recent research has shown that microRNAs (miRNAs) might play an important role in the regulation of ovarian follicle development and maturation. In this study, the expression of miRNAs in metaphase I (MI) oocytes treated with or without insulin-like growth factor 1 (IGF-1) was observed by microRNA microarray analysis. Results show that 145 miRNAs were up-regulated and 200 miRNAs were down-regulated in MI oocytes after IGF-1 treatment. MiR-133b, which was up-regulated more than 30-fold, was chosen for further research. As a potential target of miR133b, transgelin 2 (TAGLN2) gene was down-regulated, at both transcription and translation levels, in miR-133b- over-expressed 293T cells, but TAGLN2 was up-regulated when the expression of miR-133b was inhibited. Furthermore, the expression level of TAGLN2 in the ovaries of 8-week- old mice was higher than that observed in 4-week-old mice. Immunofluorescence experiments showed that TAGLN2 was located in the cytoplasm. In general, our results indicate that miR-133b may play important roles in the growth and maturation of oocytes by regulating its potential target, TAGLN2, at both transcription and translation levels. Therefore, our research provides a potential new target for infertility therapy. [ABSTRACT FROM AUTHOR]

Abstract: Neurological complications associated with HIV-1 are being recognized as a common disorder in AIDS patients, especially patients with HIV-associated dementia (HAD). However, our knowledge of the complicated pathogenesis and clinical symptoms of HAD is limited by an incomplete understanding of the biology of HIV-1 in the nervous system. Therefore, this review focuses on the pathogenesis of HAD in the context of novel highly active antiretroviral therapy (HARRT) regimens. [Copyright &y& Elsevier]

Background: Early pregnancy loss (EPL) presents as sporadic or recurrent miscarriage during the first trimester. In addition to chromosomal defects, EPL may result from impairment of the placental-decidual interface at early gestational age due to gene-environmental interactions. Methods: To better understand the pathogenesis associated with this impairment, cell development in chorionic villi and decidua of different forms of EPL (sporadic or recurrent) was investigated with single-cell RNA sequencing and compared to that of normal first-trimester tissue. Results: Unique gene expression signatures were obtained for the different forms of EPL and for normal tissue and the composition of placental and decidual cell clusters in each form was established. In particular, the involvement of macrophages in the EPL phenotypes was identified revealing an immunoactive state. Conclusion: Differential gene expression and unique marker genes among cell clusters from chorionic villi and decidua of miscarried and normal pregnancies, may lead to identification of biomarker for EPL. [ABSTRACT FROM AUTHOR]

Background: Multidrug resistance (MDR) is a complex phenomenon that frequently leads to chemotherapy failure during cancer treatment. The overexpression of ATP-binding cassette (ABC) transporters represents the major mechanism contributing to MDR. To date, no effective MDR modulator has been applied in clinic. Adagrasib (MRTX849), a specific inhibitor targeting KRAS G12C mutant, is currently under investigation in clinical trials for the treatment of non-small cell lung cancer (NSCLC). This study focused on investigating the circumvention of MDR by MRTX849. Methods: The cytotoxicity and MDR reversal effect of MRTX849 were assessed by MTT assay. Drug accumulation and drug efflux were evaluated by flow cytometry. The MDR reversal by MRTX849 in vivo was investigated in two ABCB1-overexpressing tumor xenograft models in nude mice. The interaction between MRTX849 and ABCB1 substrate binding sites was studied by the [125I]-IAAP-photoaffinity labeling assay. The vanadate-sensitive ATPase assay was performed to identify whether MRTX849 would change ABCB1 ATPase activity. The effect of MRTX849 on expression of ABCB1 and PI3K/AKT signaling molecules was examined by flow cytometry, Western blot and Quantitative Real-time PCR analyses. Results: MRTX849 was shown to enhance the anticancer efficacy of ABCB1 substrate drugs in the transporter-overexpressing cells both in vitro and in vivo. The MDR reversal effect was specific against ABCB1 because no similar effect was observed in the parental sensitive cells or in ABCG2-mediated MDR cells. Mechanistically, MRTX849 increased the cellular accumulation of ABCB1 substrates including doxorubicin (Dox) and rhodamine 123 (Rho123) in ABCB1-overexpressing MDR cells by suppressing ABCB1 efflux activity. Additionally, MRTX849 stimulated ABCB1 ATPase activity and competed with [125I]-IAAP for photolabeling of ABCB1 in a concentration-dependent manner. However, MRTX849 did not alter ABCB1 expression or phosphorylation of AKT/ERK at the effective MDR reversal drug concentrations. Conclusions: In summary, MRTX849 was found to overcome ABCB1-mediated MDR both in vitro and in vivo by specifically attenuating ABCB1 efflux activity in drug-resistant cancer cells. Further studies are warranted to translate the combination of MRTX849 and conventional chemotherapy to clinical application for circumvention of MDR. 3A9j1Q87GL5CKdhmy4Ppap Video Abstract [ABSTRACT FROM AUTHOR]

Objective To study the mechanism of polypeptide-induced PC12 nervous cell apoptosis in the area of HIV-1 gp120. Methods The adrenal gland chromaffin tumor cell (PC12) by cultivation in vitro was detected the apoptosis by Annexin V combined with PI and flow cytometry. Obtaining the model of cell apoptosis, it adopted Western blotting to inspect the polypeptide-disposed cells from gp120 with the concerntrations of 0, 100, 200, 400 and 800 nmol/L and the influence on PC12 cells' PLK-1 expression of 400 nmol/L polypeptide at the time of 4th, 12th, 24th, 36th, 48th hour. Results After the apoptosis of polypeptide-induced PC12 cells,The expression of polo-like kinases-1 was decreased and demonstrated dependence of concentration-time. Conclusion The apoptosis of polypeptide-induced PC12 cells in the area of HIV-1 gp120 V3 is involved in PLK-1. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Activation of AMPK inhibits cervical cancer growth by hyperacetylation of H3K9 through PCAF." The authors of the original article noticed an error in the order of the figures and have provided the correct order. The article discusses the role of AMPK activation in inhibiting cervical cancer growth through the hyperacetylation of H3K9. The study explores the molecular mechanism of this process and provides evidence of the effectiveness of metformin, an AMPK agonist, in exerting cytotoxic and anti-tumor effects on cervical cancer cells. [Extracted from the article]

Background: Dysregulation in histone acetylation, a significant epigenetic alteration closely associated with major pathologies including cancer, promotes tumorigenesis, inactivating tumor-suppressor genes and activating oncogenic pathways. AMP-activated protein kinase (AMPK) is a cellular energy sensor that regulates a multitude of biological processes. Although a number of studies have identified the mechanisms by which AMPK regulates cancer growth, the underlying epigenetic mechanisms remain unknown. Methods: The impact of metformin, an AMPK activator, on cervical cancer was evaluated through assessments of cell viability, tumor xenograft model, pan-acetylation analysis, and the role of the AMPK-PCAF-H3K9ac signaling pathway. Using label-free quantitative acetylproteomics and chromatin immunoprecipitation-sequencing (ChIP) technology, the activation of AMPK-induced H3K9 acetylation was further investigated. Results: In this study, we found that metformin, acting as an AMPK agonist, activates AMPK, thereby inhibiting the proliferation of cervical cancer both in vitro and in vivo. Mechanistically, AMPK activation induces H3K9 acetylation at epigenetic level, leading to chromatin remodeling in cervical cancer. This also enhances the binding of H3K9ac to the promoter regions of multiple tumor suppressor genes, thereby promoting their transcriptional activation. Furthermore, the absence of PCAF renders AMPK activation incapable of inducing H3K9 acetylation. Conclusions: In conclusion, our findings demonstrate that AMPK mediates the inhibition of cervical cancer growth through PCAF-dependent H3K9 acetylation. This discovery not only facilitates the clinical application of metformin but also underscores the essential role of PCAF in AMPK activation-induced H3K9 hyperacetylation. [ABSTRACT FROM AUTHOR]

Vorinostat has good therapeutic efficacy against primary cutaneous T-cell lymphoma in the refractory stage. However, the molecular mechanism by which it inhibits solid tumors has not been clarified. To investigate the tumor inhibitory mechanism of vorinostat in cervical cancer, this study used Cell Counting Kit-8, flow cytometry, cell invasion and migration assays and the wound healing assay to evaluate the effects of vorinostat on cervical cancer cell proliferation, apoptosis, cell cycle, migration, and invasion. Real-time quantitative PCR and immunoblotting were used to detect gene and protein expression, respectively, of major histocompatibility class I-related chain A, phosphoinositide 3-kinase, phosphorylated PI3K p55 (Tyr199), and p-Akt (Ser473). The lactate dehydrogenase cytotoxicity assay was used to evaluate the ability of natural killer-92 cells to lyse cervical cancer cells. A xenograft nude mouse model was established to analyze the anti-tumor effect of vorinostat in vivo. Our results showed that vorinostat inhibited the proliferation, migration, and invasion of cervical cancer cells. Vorinostat also induced apoptosis and cell-cycle arrest in the S phase, inhibited PI3K (p110α), p-PI3K p55 (Tyr199), and p-Akt (Ser473) protein expression and upregulated MICA expression in vitro and in vivo, and promoted NK-92 cell-mediated cervical cancer cell lysis. The ability of vorinostat to upregulate MICA expression in cervical cancer cells was related to PI3K/Akt signaling. In brief, vorinostat upregulated MICA through the PI3K/Akt pathway and enhanced the sensitivity of cervical cancer cells to the NK cell-mediated cytolytic reaction. The results of this study demonstrate that vorinostat has anti-solid tumor effects on cervical cancer. [ABSTRACT FROM AUTHOR]

In recent years the anti-diabetic drug metformin has been shown to inhibit tumor growth, but the underlying mechanism is unclear. Our previous results showed that metformin can destroy the sponge effect of long-chain non-coding RNA MALAT1/miR-142-3p and inhibit the proliferation of cervical cancer cells. Metformin can inhibit the PI3K/Akt signaling pathway and synergizes with Nelfinavir to inhibit the proliferation and invasion of cervical cancer cells. In this study, we used iTRAQ-based proteomics, mass spectrometry-based targeted proteomics, immunoblotting, and bioinformatics to analyze the molecular mechanism by which metformin inhibits the proliferation and invasion of cervical cancer cells. We found that 53 proteins were differentially expressed in cervical cancer cells after metformin treatment, of which 20 were up-regulated and 33 were down-regulated. Bioinformatics analysis showed that the 53 differentially expressed proteins are negative regulators of receptor signaling that inhibit cell growth and are mainly enriched in cell growth and apoptosis signaling pathways. We performed PRM verification on 11 of the differentially expressed proteins and found that they were all associated with apoptosis. We also found that metformin up-regulated the expression of the tumor suppressor IGFBP7 to inhibit the proliferation and invasion of cervical cancer cells. Our results indicate that metformin mainly regulates the insulin signaling pathway and interferes with cell proliferation and apoptosis to inhibit proliferation and invasion of cervical cancer cells. These differentially expressed proteins may become new targets for the treatment of cervical cancer. [ABSTRACT FROM AUTHOR]

Exosomes are nano-scale extracellular vesicles that are found widely in various biological fluids. As messengers, exosomes deliver characteristic biological information from donor cells, facilitating their accumulation and subsequent transfer of information to tumor immune cells. Immunotherapy is a cutting-edge strategy for cancer therapy, but it has not yet reached its full potential owing to severe side effects and limited efficacy. Exosomes possess antigens and immunostimulatory molecules and can serve as cell-free vaccines to induce antitumor immunity. In addition, given their stability, low immunogenicity, and targeting ability, exosomes represent ideal drug delivery systems in tumor immunotherapy by delivering cargoes, including non-coding ribonucleic acids (RNAs), membrane proteins, chemotherapeutic agents, and immune cell death inducers. Exosomes can also be engineered to precisely target tumor cells. However, as a rising star in tumor immunotherapy, exosomes are also impeded by some challenges, including the lack of uniform technical standards for their isolation and purification, the need to improve exosomal cargo loading for efficient exosome delivery, and the expansion of clinical trials, which are currently in their infancy. Long-term, multi-center, and large-scale clinical trials are needed to evaluate the performance of exosomes in the future. Nonetheless, exosomes have demonstrated encouraging performance in tumor immunotherapy. In this review, we summarize the potential and challenges of exosomes in tumor immunotherapy, with the aim to shed light on exosomes as new-era tumor immunotherapy tools. [Display omitted] [ABSTRACT FROM AUTHOR]

Cancer stem-like cells (CSCs), a subpopulation of cancer cells, possess remarkable capability in proliferation, self-renewal, and differentiation. Their presence is recognized as a crucial factor contributing to tumor progression and metastasis. CSCs have garnered significant attention as a therapeutic focus and an etiologic root of treatment-resistant cells. Increasing evidence indicated that specific biomarkers, aberrant activated pathways, immunosuppressive tumor microenvironment (TME), and immunoevasion are considered the culprits in the occurrence of CSCs and the maintenance of CSCs properties including multi-directional differentiation. Targeting CSC biomarkers, stemness-associated pathways, TME, immunoevasion and inducing CSCs differentiation improve CSCs eradication and, therefore, cancer treatment. This review comprehensively summarized these targeted therapies, along with their current status in clinical trials. By exploring and implementing strategies aimed at eradicating CSCs, researchers aim to improve cancer treatment outcomes and overcome the challenges posed by CSC-mediated therapy resistance. [ABSTRACT FROM AUTHOR]

Cancer stem-like cells (CSCs), a subpopulation of cancer cells, possess remarkable capability in proliferation, self-renewal, and differentiation. Their presence is recognized as a crucial factor contributing to tumor progression and metastasis. CSCs have garnered significant attention as a therapeutic focus and an etiologic root of treatment-resistant cells. Increasing evidence indicated that specific biomarkers, aberrant activated pathways, immunosuppressive tumor microenvironment (TME), and immunoevasion are considered the culprits in the occurrence of CSCs and the maintenance of CSCs properties including multi-directional differentiation. Targeting CSC biomarkers, stemness-associated pathways, TME, immunoevasion and inducing CSCs differentiation improve CSCs eradication and, therefore, cancer treatment. This review comprehensively summarized these targeted therapies, along with their current status in clinical trials. By exploring and implementing strategies aimed at eradicating CSCs, researchers aim to improve cancer treatment outcomes and overcome the challenges posed by CSC-mediated therapy resistance. [ABSTRACT FROM AUTHOR]

Human cervical cancer is the fourth most common carcinoma in women worldwide. However, the emergence of drug resistance calls for continuously developing new anticancer drugs and combination chemotherapy regimens. The present study aimed to investigate the anti-cervical cancer effects of metformin, a first-line therapeutic drug for type 2 diabetes mellitus, and nelfinavir, an HIV protease inhibitor, when used alone or in combination. We found that both metformin and nelfinavir, when used alone, were moderately effective in inhibiting proliferation, inducing apoptosis and suppressing migration and invasion of human cervical cell lines HeLa, SiHa and CaSki. When used in combination, these two drugs acted synergistically to inhibit the growth of human cervical cancer cells in vitro and cervical cancer cell xenograft in vivo in nude mice, and suppress cervical cancer cell migration and invasion. The protein expression of phosphoinositide 3-kinase catalytic subunit PI3K(p110α), which can promote tumor growth, was remarkably downregulated, while the tumor suppressor proteins p53 and p21 were substantially upregulated following the combinational treatment in vitro and in vivo. These results suggest that clinical use of metformin and nelfinavir in combination is expected to have synergistic antitumor efficacy and significant potential for the treatment of human cervical cancer. [ABSTRACT FROM AUTHOR]

Drug resistance is still an obstacle in cancer therapy, leading to the failure of tumor treatment. The emergence of tumor drug resistance has always been a main concern of oncologists. Therefore, overcoming tumor drug resistance and looking for new strategies for tumor treatment is a major focus in the field of tumor research. Natural products serve as effective substances against drug resistance because of their diverse chemical structures and pharmacological effects. We reviewed the signaling pathways involved in the development of tumor drug resistance, including Epidermal growth factor receptor (EGFR), Renin-angiotensin system (Ras), Phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), Wnt, Notch, Transforming growth factor-beta (TGF-β), and their specific signaling pathway inhibitors derived from natural products. This can provide new ideas for the prevention of drug resistance in cancer therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • FIR treatment improved adjuvant arthritis in rats. • FIR exposure inhibited the inflammatory genes expression of synovial tissues in AIA rats. • FIR exposure down-regulated inflammatory genes expression mainly through transcription factors AP-1, CEBPα, CEBPβ, c-Fos, GR, HNF-3β, USF-1, and USF-2. • FIR irradiation may exhibit anti-arthritic effects through inactivation of the MAPK, PI3K-Akt, and NF-κB signaling pathways. Far-infrared radiation (FIR) is widely used in the treatment of various diseases such as insomnia and cardiovascular risk. Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease in which the therapeutic potential of FIR in RA is unclear. To determine the therapeutic potential and mechanistic actions of FIR in treatment of RA. Adjuvant-induced arthritis (AIA) rat models were established to assess the therapeutic potency of FIR in RA treatment. The scoring parameters such as arthritis score, swelling of the hind paw, spleen and thymus indices, micro-CT analysis indices were adopted to estimate the beneficial effects of FIR during RA treatment in AIA model. PCR gene expression arrays were used to analyze inflammatory and autoimmune genes expression profiles in rat synovium. The inflammatory and immunity genes profiling was further analyzed through transcription factor prediction using PROMO. A signaling network map of possible molecular circuits connecting the identified differential genes to the RA's pathogenesis was constructed based on extensive literature reviews, and the major signaling pathways were validated by Western blotting. Thirty minutes of FIR treatment significantly improved the symptoms of AIA in rats. Gene expression profiling indicated that 27 out of 370 genes were down-regulated by FIR. AP-1, CEBPα, CEBPβ, c-Fos, GR, HNF-3β, USF-1, and USF-2 were predicted as key transcription factors that regulated the identified differential genes. In addition, MAPK, PI3K-Akt, and NF-κB signaling are the major molecular pathways down-regulated by FIR treatment. FIR may provide beneficial effects on the AIA rat model of arthritis by suppression of the MAPK, PI3K-Akt and NF-κB signaling pathways. Therefore, we believe that FIR may provide an alternative non-pharmacological and non-surgical therapeutic approach for the treatment of RA. [ABSTRACT FROM AUTHOR]

• AGAP2-AS1 levels in psoriatic skin were higher than those in healthy controls. • AGAP2-AS1 expression was increased via an m6A-YTHDF2-dependent manner. • AGAP2-AS1 promotes keratinocyte proliferation through miR-424–5p/AKT3 axis. Psoriasis is a chronic, complicated, and recurrent inflammatory skin disease. However, the precise molecular mechanisms remain largely elusive and the present treatment is unsatisfactory. This study aimed to unravel the functions of long noncoding RNA (lncRNA) AGAP2-AS1 and its biological mechanism in psoriasis pathogenesis, hinting for the new therapeutic targets in psoriasis. The expression of AGAP2-AS1 in the skin tissue of psoriasis patients and healthy controls were detected by qRT-PCR and RNAscope®. Cell Counting Kit‑8 (CCK8) and clone formation assays were utilized to assess proliferation. Methylated RNA immunoprecipitation (MeRIP) was performed to detect the N6-methyladenosine (m6A) modification. RNA immunoprecipitation (RIP) was used to detect the interaction of AGAP2-AS1 with YTH domain family 2(YTHDF2). The relationships among AGAP2-AS1, miR-424–5p and AKT3 were examined by dual-luciferase reporter assay and RIP assay. We found that AGAP2-AS1 level was upregulated in the skin tissue of psoriasis patients than that of healthy controls and AGAP2-AS1 could promote proliferation and inhibit apoptosis of keratinocytes. Methyltransferase like 3(METTL3)-mediated m6A modification suppressed the expression of AGAP2-AS1 via YTHDF2-dependent AGAP2-AS1 stability. Thus, downregulation of METTL3 resulted in the upregulation of AGAP2-AS1 in psoriasis. AGAP2-AS1 functioned as a competitive endogenous RNA by sponging miR-424–5p to upregulate AKT3, activate AKT/mTOR pathway, as well as promote cell proliferation in keratinocytes. AGAP2-AS1 is upregulated in the skin tissue of psoriasis patients and m6A methylation was involved in its upregulation. AGAP2-AS1 promotes keratinocyte proliferation through miR-424–5p/AKT/mTOR axis and may be a promising target for psoriasis therapy. [ABSTRACT FROM AUTHOR]

Background: Aberrant expression of Aldo-Keto reductase family 1 member B10 (AKR1B10) was associated with tumor size and metastasis of breast cancer in our published preliminary studies. However, little is known about the detailed function and underlying molecular mechanism of AKR1B10 in the pathological process of breast cancer. Methods: The relationship between elevated AKR1B10 expression and the overall survival and disease-free survival of breast cancer patients was analyzed by Kaplan–Meier Plotter database. Breast cancer cell lines overexpressing AKR1B10 (MCF-7/AKR1B10) and breast cancer cell lines with knockdown of AKR1B10 (BT-20/shAKR1B10) were constructed to analyze the impact of AKR1B10 expression on cell proliferation and migration of breast cancer. The expression levels of AKR1B10 were detected and compared in the breast cancer cell lines and tissues by RT-qPCR, western blot and immunohistochemistry. The proliferation of breast cancer cells was monitored by CCK8 cell proliferation assay, and the migration and invasion of breast cancer cells was observed by cell scratch test and transwell assay. The proliferation- and EMT-related proteins including cyclinD1, c-myc, Survivin, Twist, SNAI1, SLUG, ZEB1, E-cadherin, PI3K, p-PI3K, AKT, p-AKT, IKBα, p-IKBα, NF-κB p65, p-NF-κB p65 were detected by western blot in breast cancer cells. MCF-7/AKR1B10 cells were treated with LY294002, a PI3K inhibitor, to consider the impact of AKR1B10 overexpression on the PI3K/AKT/NF-κB signal cascade and the presence of NF-κB p65 in nuclear. In vivo tumor xenograft experiments were used to observe the role of AKR1B10 in breast cancer growth in mice. Results: AKR1B10 expression was significantly greater in breast cancer tissue compared to paired non-cancerous tissue. The expression of AKR1B10 positively correlated with lymph node metastasis, tumor size, Ki67 expression, and p53 expression, but inversely correlated with overall and disease-free survival rates. Gene Ontology analysis showed that AKR1B10 activity contributes to cell proliferation. Overexpression of AKR1B10 facilitated the proliferation of MCF-7 cells, and induced the migration and invasion of MCF-7 cells in vitro in association with induction of epithelial-mesenchymal transition (EMT). Conversely, knockdown of AKR1B10 inhibited these effects in BT-20 cells. Mechanistically, AKR1B10 activated PI3K, AKT, and NF-κB p65, and induced nuclear translocation of NF-κB p65, and expression of proliferation-related proteins including c-myc, cyclinD1, Survivin, and EMT-related proteins including ZEB1, SLUG, Twist, but downregulated E-cadherin expression in MCF-7 cells. AKR1B10 silencing reduced the phosphorylation of PI3K, AKT, and NF-κB p65, the nuclear translocation of NF-κB p65, and the expression of proliferation- and migration-related proteins in BT-20 cells. LY294002, a PI3K inhibitor, attenuated the phosphorylation of PI3K, AKT, and NF-κB p65, and the nuclear translocation of NF-κB p65. In vivo tumor xenograft experiments confirmed that AKR1B10 promoted breast cancer growth in mice. Conclusions: AKR1B10 promotes the proliferation, migration and invasion of breast cancer cells via the PI3K/AKT/NF-κB signaling pathway and represents a novel prognostic indicator as well as a potential therapeutic target in breast cancer. [ABSTRACT FROM AUTHOR]

Background. The number of hepatocellular carcinoma (HCC) cases worldwide has increased significantly. As a traditional Chinese medicine (TCM) with a long history, Ecliptae herba (EH) has been widely used in HCC patients in China, but its hepatoprotective mechanism is still unclear. Methods. In this study, we applied a network pharmacology-based strategy and experimental verification to systematically unravel the underlying mechanisms of EH against HCC. First, six active ingredients of EH were screened from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) by the ADME method. Subsequently, 52 potential targets of 6 active ingredients acting on HCC were screened from various databases, including TCMSP, DGIdb, SwissTargetPrediction, CTD, and GeneCards. Then, by constructing protein-protein interaction (PPI) network from STRING, we displayed the intricate connections among these 52 targets through Cytoscape software. We also applied enrichment analysis, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, to provide an outline and set of concepts for describing gene functions and the advanced functions of biological systems of these 52 targets from genomic and molecular level information. Finally, molecular docking and biological experiments were used to reconfirm these results. Results. We hypothesized that EH might exert anti-HCC activity by acting on hub genes, including RELA, MMP9, PTGS2, ESR1, EGFR, AR, AKT1, HIF1A, AHR, CYP3A4, ABCG2, and MMP2. Moreover, based on GO and KEGG analysis, we speculated that EH may exert hepatoprotective effects on HCC through the following mechanisms: regulation of the PI3K-AKT signaling pathway to promote apoptosis and inhibit the abnormal proliferation of HCC, downregulation of HIF-1A expression by activating the HIF-1 signaling pathway, prevention of HCC by regulating lipid metabolism, and inhibition of nonalcoholic fatty liver disease (NAFLD) by the cytochrome P450 subfamily. Subsequent biological experiments verified that EH inhibits the PI3K-AKT signaling pathway through its active ingredients, quercetin, and wedelolactone, thereby inhibiting the proliferation of HCC cells and promoting the apoptosis of HCC cells. Conclusions. The network pharmacological strategy provides an efficient method to systematically explore the pharmacological mechanism of EH in HCC. Our study demonstrated that the anti-HCC proliferation activity of EH is mainly exerted by two active ingredients (quercetin and wedelolactone), which inhibit the proliferation of HCC cells (HepG2 and Huh-7) by inhibiting PI3K-AKT signaling. [ABSTRACT FROM AUTHOR]

Revolutionary all-in-one RPA-CRISPR assays are rapidly becoming the most sought-after tools for point-of-care testing (POCT) due to their high sensitivity and ease of use. Despite the availability of one-pot methods for specific targets, the development of more efficient methods for new targets remains a significant challenge. In this study, we present a rapid and universal approach to establishing an all-in-one RPA-Cas12a method CORDSv2 based on rational balancing amplification and Cas12a cleavage, which achieves ultrasensitive detection of several targets, including SARS-CoV-2, ASFV, HPV16, and HPV18. CORDSv2 demonstrates a limit of detection (LOD) of 0.6 cp/μL and 100% sensitivity for SARS-CoV-2, comparable to qPCR. Combining with our portable device(hippo-CORDS), it has a visual detection LOD of 6 cp/μL and a sensitivity up to 100% for SARS-CoV-2 and 97% for Ct<35 ASFV samples, surpassing most one-pot visual methods. To simplify and accelerate the process for new targets, we also develop a de novo autodesigner by which the optimal couples of primers and crRNA can be selected rapidly. As a universal all-in-one RPA-CRISPR method for on-site testing, CORDSv2 becomes an attractive choice for rapid and accurate diagnosis in resource-limited settings. [Display omitted] • Rapid detection of DNA and RNA viruses using all-in-one CORDSv2 platform. • Primer and crRNA designing with AutoCORDSv2 allowed CORDSv2 establishment in 1 week. • Visual LOD of 6 cp/μL and sensitivity of 100%, 97% for SARS-CoV-2, ASFV samples. [ABSTRACT FROM AUTHOR]

The neuroprotective effects of Er-Zhi-Wan (EZW), a well-known traditional Chinese formulation, in MPTP-induced Parkinson's disease (PD) models are poorly understood and require evaluation. A model of PD induced by MPTP was used to evaluate the neuroprotective effects of EZW in mice. The underlying pharmacological mechanisms of EZW for the prevention and treatment of PD were then explored using a combination of multilevel databases, network pharmacology, biological experiments, and LC MS/MS. In vivo data showed that pretreatment with EZW can be neuroprotective against MPTP-induced motor dysfunction and can effectively rescue dopaminergic neurons from MPTP-induced degeneration in mice. Furthermore, data from combined multilevel databases and network pharmacology analysis strategies suggested that the neuroprotective activity of EZW in the treatment of PD is mediated by a complicated multicomponent, multitarget network. Genes such as Grm2, Grm5, Drd2, and Grik2 were identified as important therapeutic targets. Subsequent experimental validation showed that EZW can broadly regulate the mRNA levels of these receptor genes as well as BDNF, and consequently increase the phosphorylation levels of CREB to stimulate CREB signaling. These targets and signaling systems may be responsible for the reversal of neuronal death by EZW after MPTP exposure. The LC-MS/MS results also identified a wide range of chemical components of EZW, including at least 53 precise compounds, further demonstrating the complexity of the network in which EZW exerts its neuroprotective activity. Our work provides evidence for the mechanism of EZW in MPTP-PD models and supports the neuroprotective function of EZW in neurodegenerative diseases. [Display omitted] • EZW contains a complex system of at least 53 compounds identified by LC-MS/MS. • EZW attenuated PD-like phenotypes in MPTP-induced PD mice model. • EZW alleviated the dopaminergic neuron damage in MPTP-induced PD mice model. • EZW alters mRNA expression of multiple PD-associated receptors (mGluRs/Drd2/Grik2). • EZW exerts neuroprotective effects via the BDNF/CREB pathway. [ABSTRACT FROM AUTHOR]

Potassium channels play an important role in human physiological function. Recently, various molecular mechanisms have implicated abnormal functioning of potassium channels in the proliferation, migration, invasion, apoptosis, and cancer stem cell phenotype formation. Potassium channels also mediate the association of tumor cells with the tumor microenvironment. Meanwhile, potassium channels are important targets for cancer chemotherapy. A variety of drugs exert anti-cancer effects by modulating potassium channels in tumor cells. Therefore, there is a need to understand how potassium channels participate in tumor development and progression, which could reveal new, novel targets for cancer diagnosis and treatment. This review summarizes the roles of voltage-gated potassium channels, calcium-activated potassium channels, inwardly rectifying potassium channels, and two-pore domain potassium channels in tumorigenesis and the underlying mechanism of potassium channel-targeted drugs. Therefore, the study lays the foundation for rational and effective drug design and individualized clinical therapeutics. [Display omitted] • Potassium channels play an important role in tumorigenesis. • Potassium channels are involved in tumor proliferation, metastasis, and apoptosis through multiple molecular pathways. • Drugs exert anticancer effects by targeting potassium channels. [ABSTRACT FROM AUTHOR]

Objectives Transforming growth factor-beta 1 (TGF-β1) is one of the multifunctional cytokine families. It takes part in a series of physiological and pathological processes in the human body, including wound healing, tissue fibrosis and embryonic development. Recent studies have shown that TGF-β1 participates in the development of polycystic ovary syndrome (PCOS). This study was therefore designed to investigate the association of TGF-β1 polymorphism with the risk of PCOS. Study design We enrolled 328 PCOS patients and 358 healthy individuals in this study. Five single nucleotide polymorphisms (SNPs) – rs4803457C/T, rs11466313 deletion/AGG, rs2217130C/T, rs1800469C/T and rs1800470C/T – were detected using Snapshot technology. Linkage disequilibrium and haplotype analysis was conducted among the five SNPs. The relationship between genotypes and haplotypes and the risk of PCOS was also explored. Results The TT/CT/CC genotype frequencies of rs4803457 in the PCOS group and the control group were 0.2805/0.4878/0.2317 and 0.3659/0.4749/0.1592 respectively. The C/T allele frequencies in the PCOS group and control group were 0.3813/0.6187 and 0.3966/0.6034 respectively. There were significant differences in genotype distribution frequencies and allele frequencies between these two groups ( P = 0.018). Logistic regression analysis showed that CC genotype had higher risk of PCOS than the no CC genotype in rs4803457 loci (OR = 1.75, 95%CI = 1.11–2.75). Haplotype analysis further showed that the haplotypes “T-del-C-C-C”, “C-del-C-C-C” and “C-del-C-T-C” were associated with the highest risk of PCOS. However, for rs11466313 deletion/AGG, rs2217130C/T, rs1800469C/T and rs1800470C/T, no significant association with PCOS risk was observed. Conclusion The TGF-β1 gene rs4803457C/T polymorphism is associated with susceptibility to PCOS, and is the key contributor for the development of PCOS in Chinese Han women. The haplotypes T-del-C-C-C, C-del-C-C-C and C-del-C-T-C are also risk factors for PCOS susceptibility among Chinese Han women. [ABSTRACT FROM AUTHOR]

Patchouli Essential Oil (PEO) has been used as a scent for various healing purposes since the ancient Egyptian period. The primary source of the oil is Pogostemon cablin (PC), a medicinal plant for treating gastrointestinal symptoms. However, the pharmacological function has not been addressed. Here, we report the cancer prevention and gut microbiota (GM) modulating property of PEO and its derivatives patchouli alcohol (PA) and pogostone (PO) in the Apc Min /+ colorectal cancer mice model. We found that PEO, PA, and PO significantly reduced the tumor burden. At the same time, it strengthened the epithelial barrier, evidenced by substantially increasing the number of the goblet and Paneth cells and upregulation of tight junction and adhesion molecules. In addition, PEO, PA, and PO shifted M1 to M2 macrophage phenotypes and remodeled the inflammatory milieu of Apc Min /+ mice. We also found suppression of CD4+CD25+ and stimulation CD4+ CD8+ cells in the spleen, blood, mesenteric lymph nodes (MLNs), and Peyer's patches (PPs) of the treated mice. The composition of the gut microbiome of the drug-treated mice was distinct from the control mice. The drugs stimulated the short-chain fatty acids (SCFAs)-producers and the key SCFA-sensing receptors (GPR41, GPR43, and GPR109a). The activation of SCFAs/GPSs also triggered the alterations of PPAR-γ, PYY, and HSDCs signaling mediators in the treated mice. Our work showed that PEO and its derivatives exert potent anti-cancer effects by modulating gut microbiota and improving the intestinal microenvironment of the ApcM min /+ mice. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Theaflavins are the major components of tea polyphenols in brewed black tea. We previously reported that theaflavin derivatives, such as TF3, inhibited HIV-1 entry by targeting gp41. However, it is difficult to purify the individual theaflavins and the purified compounds are highly unstable. To develop theaflavins as affordable anti-HIV-1 microbide for preventing HIV sexual transmission, we intended to use an economic natural preparation containing 90% of theaflavins (TFmix). Its antiviral activity against HIV-1 strains was evaluated in vitro using p24 production and luciferase assays. The mechanism by which TFmix inhibits HIV-1 infection was investigated using time-of-addition, cell-cell fusion and biophysical assays. The data suggested TFmix exhibited potent anti-HIV-1 activity on lab-adapted and primary HIV-1 strains with IC50 less than 1.20μM. It also effectively inhibited infection by T-20 resistant HIV-1 strains. The mechanism studies suggest that TFmix mainly inhibit the HIV-1 entry by targeting gp41 since it is effective in inhibiting gp41 six-helix bundle (6-HB) formation and HIV-1 envelope protein-mediated cell-cell fusion. TFmix could also inhibit HIV-1 reverse transcriptase (RT) activity, but the IC50 is about 8-fold higher than that for inhibiting gp41 6-HB formation, suggesting RT is not a major target for TFmix. In conclusion, TFmix is an economic natural product preparation containing high content of theaflavins with potent anti-HIV-1 activity by targeting the viral entry step through the disruption of gp41 6-HB core structure. It has a potential to be developed as a safe and affordable topical microbicide for preventing sexual transmission of HIV. [Copyright &y& Elsevier]

Abstract: Intimal hyperplasia plays an important role in various types of vascular remodeling. Mechanical forces derived from blood flow are associated with the proliferation of vascular smooth muscle cells (VSMC). This contributes to many vascular disorders such as hypertension, atherosclerosis and restenosis after percutaneous transluminal angioplasty (PTA). In this study, we show that static pressure induces the proliferation of VSMC and activates its related signal pathway. VSMC from a rat aorta were treated with different pressures (0, 60, 90, 120, 150 and 180mm Hg) in a custom-made pressure incubator for 24h. The most active proliferation of VSMC was detected at a pressure of 120mm Hg. VSMC was also incubated under a static pressure of 120mm Hg for different time intervals (0, 2, 4, 8, 12 and 24h). We found that static pressure significantly stimulates VSMC proliferation. Extracellular signal-regulated kinases 1/2 (ERK1/2) activation showed a peak at the pressure of 120mm Hg at 4-h time point. Moreover, caveolin-1 expression was significantly inhibited by rising static pressure. Downregulation of VSMC proliferation could be found after PD98059 (ERK1/2 phosphorylation inhibitor) treatment. Our data also showed that a siRNA-mediated caveolin-1 knock down increased ERK1/2 phosphorylation and VSMC proliferation. These results demonstrate that static pressure promotes VSMC proliferation via the Caveolin-1/ERK1/2 pathway. [Copyright &y& Elsevier]

Vorinostat is a histone deacetylase inhibitor (HDACi) that was demonstrated in our previous study to inhibit the proliferation, migration, and invasion of cervical cancer cells by regulating the PI3K/Akt signaling pathway. However, the molecular mechanism of vorinostat in cervical cancer treatment remains to be further elucidated. A nude mouse xenograft model was established to analyze the antitumor effect of vorinostat in vivo. The combination of iTRAQ-based proteomics and parallel reaction monitoring (PRM) technology has proven to be an efficient and reliable method to identify potential targets for cancer chemotherapy. In this study, 254 differentially expressed proteins in vorinostat-treated cervical cancer cells, among which 180 were upregulated and 74 were downregulated, were identified by using an iTRAQ-based proteomic strategy. Subsequent bioinformatic and PRM analysis of these differentially expressed proteins indicated that UBE2C is a promising target of vorinostat in the inhibition of cervical cancer cell proliferation. We confirmed that the expression of endogenous UBE2C in cervical cancer cell lines was significantly higher than that in normal cervical epithelial cell lines. Additionally, we found that vorinostat downregulated the expression of UBE2C, SQSTM1/p62, N-cadherin, vimentin and upregulated E-cadherin in SiHa and HeLa cells. Our results also showed that vorinostat can downregulate the expression of SQSTM1/p62, N-cadherin, and vimentin during the treatment of cervical cancer cells by regulating UBE2C, while upregulating the expression of E-cadherin. In conclusion, vorinostat reverses epithelial-mesenchymal transition by targeting UBE2C and controls the proliferation of cervical cancer cells through the ubiquitination pathway. UBE2C can be used as a promising target for the development of vorinostat treatment strategies. [ABSTRACT FROM AUTHOR]

We previously reported the neuroprotective effects of icariin in rat cortical neurons. Here, we present a study on icariin's anti-aging effect in 24-month aged mice by treating them with a single daily dose of 100 mg/kg of icariin for 15 consecutive days. Icariin treatment improved motor coordination and learning skills while lowered oxidative stress biomarkers in the serum, brain, kidney, and liver of the aged mice. In addition, icariin improved the intestinal integrity of the aged mice by upregulating tight junction adhesion molecules and the Paneth and goblet cells, along with the reduction of iNOS and pro-inflammatory cytokines (IL-1β, TNF-α, IL-2 and IL-6, and IL-12). Icariin treatments also significantly upregulated aging-related signaling molecules, Sirt 1, 3 & 6, Pot1α, BUB1b, FOXO1, Ep300, ANXA3, Calb1, SNAP25, and BDNF in old mice. Through gut microbiota (GM) analysis, we observed icariin-associated improvements in GM composition of aged mice by reinstating bacteria found in the young mice, while suppressing some bacteria found in the untreated old mice. To clarify whether icariin's anti-aging effect is rooted in the GM, we performed fecal microbiota transfer (FMT) from icariin-treated old mice to the old mice. FMT-recipients exhibited similar improvements in the rotarod score and age-related biomarkers as observed in the icariin-treated old mice. Equal or better improvement on the youth-like features was noticed when aged mice were FMT with feces from young mice. Our study shows that both direct treatments with icariin and fecal transplant from the icariin-treated aged mice produce similar anti-aging phenotypes in the aged mice. We prove that GM plays a pivotal role in the healing abilities of icariin. Icariin has the potentials to be developed as a medicine for the wellness of the aged adults. [Display omitted] [ABSTRACT FROM AUTHOR]

Schematic diagram of the proposed molecular targets and mechanisms of celastrol in induction of autophagic cell death and inhibition of P-glycoprotein. Multidrug resistance (MDR) represents an obstacle in anti-cancer therapy. MDR is caused by multiple mechanisms, involving ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), which reduces intracellular drug levels to sub-therapeutic concentrations. Therefore, sensitizing agents retaining effectiveness against apoptosis- or drug-resistant cancers are desired for the treatment of MDR cancers. The sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) pump is an emerging target to overcome MDR, because of its continuous expression and because the calcium transport function is crucial to the survival of tumor cells. Previous studies showed that SERCA inhibitors exhibit anti-cancer effects in Bax-Bak-deficient, apoptosis-resistant and MDR cancers, whereas specific P-gp inhibitors reverse the MDR phenotype of cancer cells by blocking efflux of chemotherapeutic agents. Here, we unraveled SERCA and P-gp as double targets of the triterpenoid, celastrol to reverse MDR. Celastrol inhibited both SERCA and P-gp to stimulate calcium-mediated autophagy and ATP depletion, thereby induced collateral sensitivity in MDR cancer cells. In vivo studies further confirmed that celastrol suppressed tumor growth and metastasis by SERCA-mediated calcium mobilization. To the best of our knowledge, our findings demonstrate collateral sensitivity in MDR cancer cells by simultaneous inhibition of SERCA and P-gp for the first time. [ABSTRACT FROM AUTHOR]