Yanggan Huayu granule (YGHY) is a formula of traditional Chinese medicine that has been widely used to treat patients with liver cancer. But its working mechanism is still poorly understood.

Endometriosis is an estrogen-dependent and progesterone-resistant gynecological inflammatory disease of reproductive-age women. The prevalence of endometriosis is ~5-10% in reproductive-age women, increasing to 20-30% in women with subfertility. The current anti-estrogen therapies can be prescribed only for a short time because of the undesirable side effects on menstruation, pregnancy, bone health, and failure to prevent a recurrence. The causes of endometriosis-associated infertility are multifactorial and poorly understood. The objective of the present study was to determine the inhibitory effects of AKT and/or ERK1/2 pathways on the microenvironment of the endometrium in a xenograft mouse model of endometriosis of human origin. Results indicate that dual inhibition of AKT and ERK1/2 pathways, but not inhibition of either AKT or ERK1/2 pathway, suppresses the growth of the endometriotic lesions in vivo. Dual inhibition of AKT and ERK1/2 pathways suppresses the production of proinflammatory cytokines, decreases E2 biosynthesis and signaling, and restores progesterone receptor-B signaling components in the epithelial and stromal cells of the endometrium in a cell-specific manner. These results together suggest that dual inhibition of AKT and ERK1/2 pathways suppresses the estrogen-dominant state and concomitantly increases the progesterone-responsive state of the endometrium. Therefore, dual inhibition of AKT and ERK1/2 pathways could emerge as long-term nonsteroidal therapy for endometriosis.

Intracerebral hemorrhage (ICH) is a severe stroke subtype with high disability and mortality, and no effective treatment is available. Previous research on intracerebral hemorrhage secondary brain injury drugs mainly targeted at cell apoptosis, inflammation and oxidative stress, but did not achieve good effects. In recent years, ferroptosis has become a focus concern in neurological diseases. Ferroptosis is a new type of programmed cell death caused by iron-dependent accumulation of lipid peroxides, in which glutathione peroxidase 4 (GPX4) is a key protein affecting ferroptosis. In this study, we used the STRING protein database to predict the proteins that may be co-expressed with GPX4, and studied the ability of Dauricine(Dau) to up-regulate the expression of GPX4 against ferroptosis and neuroprotection after intracerebral hemorrhage in normal cells in vitro, glutathione peroxidase 4 (GPX4) knockdown cells and collagenase injection in vivo in mouse models of intracerebral hemorrhage. The results showed that glutathione reductase (GSR) was a possible co-expression protein with GPX4. Dau could up-regulate the expression of glutathione peroxidase 4 (GPX4) in intracerebral hemorrhage(ICH) model, normal cells and GPX4 knockdown cells in vitro, and simultaneously up-regulate the expression of GSR in ICH mice. Dau could also reduce the levels of iron and lipid peroxidation, and have a neuroprotective effect on intracerebral hemorrhage(ICH) mice. It was tesified that Dauricine(Dau) could inhibit ferroptosis of nerve cells and alleviate brain injury after intracerebral hemorrhage by upregulating glutathione peroxidase 4 (GPX4) and glutathione reductase (GSR) co-expression. Therefore, Dau may be an effective drug for inhibiting ferroptosis and treating intracerebral hemorrhage.

Dihydrotanshinone (DIH) is an extract of Salvia miltiorrhiza Bunge. It has been reported that DIH could regulate NF-κB signaling pathway. The aim of this study was to investigate whether DIH could protect mice from lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. In this study, sixty mice were randomly divided into five groups, one group as blank control group, the second group as LPS control group, and the last three groups were pre-injected with different doses of DIH and then inhaled LPS for experimental comparison. After 12 h of LPS treatment, the wet-dry ratio, histopathlogical changes, and myeloperoxidase (MPO) activity of lungs were measured. In addition, ELISA kits were used to measure the levels of TNF-α and IL-1β inflammatory cytokines in bronchoalveolar lavage fluids (BALF), and western blot analysis was used to measure the activity of NF-κB signaling pathway. The results demonstrated that DIH could effectively reduce pulmonary edema, MPO activity, and improve the lung histopathlogical changes. Furthermore, DIH suppressed the levels of inflammatory cytokines in BALF, such as TNF-α and IL-1β. In addition, DIH could also downregulate the activity of NF-κB signaling pathway. We also found that DIH dose-dependently increased the expression of LXRα. In addition, DIH could inhibit LPS-induced IL-8 production and NF-κB activation in A549 cells. And the inhibitory effects were reversed by LXRα inhibitor geranylgeranyl pyrophosphate (GGPP). Therefore, we speculate that DIH regulates LPS-induced ALI in mice by increasing LXRα expression, which subsequently inhibiting NF-κB signaling pathway.

Sunitinib is the first-line drug for treating renal cell carcinoma (RCC), and it functions mainly through inhibition of tumor angiogenesis. However, the patients may become insensitive or develop resistance toward sunitinib treatment, but the underlying mechanisms have not yet been fully elucidated. Herein, it was found that sunitinib could have adverse effects of promoting RCC progression by increasing vascular mimicry (VM) formation of RCC cells. Mechanism dissection revealed that sunitinib can increase the expression of a long non-coding RNA (lncRNA), lncRNA-ECVSR, thereby enhancing the stability of estrogen receptor β (ERβ) mRNA. Subsequently, the increased ERβ expression can then function via transcriptional up-regulation of Hif2-α. Notably, sunitinib-increased lncRNA-ECVSR/ERβ/Hif2-α signaling resulted in an increased cancer stem cell (CSC) phenotype, thereby promoting VM formation. Furthermore, the sunitinib/lncRNA-ECVSR-increased ERβ expression can transcriptionally regulate lncRNA-ECVSR expression via a positive-feedback loop. Supportively, preclinical studies using RCC mouse xenografts demonstrated that combining sunitinib with the small molecule anti-estrogen PHTPP can increase sunitinib efficacy with reduced VM formation. Collectively, the findings of this study may aid in the development of potential biomarker(s) and novel therapies to better monitor and suppress RCC progression.

Prevention and management of myocardial ischemia/reperfusion (I/R) injury is a key step in coronary heart disease surgery. Luteolin is a falconoid compound that has an antioxidant effect, but its mechanism in I/R injury in vivo and in vitro is still under explored. This study attempted to reveal the role of luteolin (Lut) in I/R through mediation of the Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1)/Signal transducer and activator of transcription 3 (STAT3) pathway. To establish I/R rat models, the left anterior descending artery (LAD) was ligated for 30 min and re-perfused for 1 h in Lut-pretreated or nude rats. Comparisons between infarct area, cardiac dysfunction, and myocardial cell death and inflammatory reaction were performed in I/R-induced rats. Hypoxia/reoxygenation (H/R) cell models were established by stimulating H9c2 cells with 95% nitrogen and 5% carbon dioxide. Simultaneously, H/R-related cell death and inflammatory reactions were investigated following Lut treatment. The target protein of Lut was identified using western blotting. Pro-inflammatory cytokines were also measured in serum or Lut-pretreated cell culture medium. The results revealed that compared with the I/R group, Lut treatment could significantly decrease myocardial infarction (MI) area, increase left ventricular ejection fraction (LVEF), and decrease cell death and pro-inflammatory cytokines in the serum. Decreased apoptosis and inflammatory cytokines were also observed in H/R cells after Lut treatment. Lut treatment downregulated SHP-1 expression and subsequently upregulated STAT3 phosphorylation in both I/R rat heart tissue and H9c2 cells. The findings of the current study suggest that Lut can protect the heart and reduce MI area, cell apoptosis rate, and inflammatory level in I/R models.

Primary hyperparathyroidism (PHPT) results from the hypersecretion of parathyroid hormone from parathyroid tumors. A transcription factor, namely Paired box1 (PAX1), is active in parathyroid gland development.

At present, there are still many problems in the treatment of lung cancer, such as high cost, side effects and low quality of life. The advantages of traditional Chinese medicine (TCM) in the treatment of lung cancer are reflected. Berberine has been increasingly popular in colorectal cancer treatment, but little is known about its bioactivity against non-small cell lung cancer (NSCLC). Cell proliferation, cell apoptosis, cDNA microarray, gene and protein expression, and NSCLC transplanted tumour growth were performed. Berberine suppressed NSCLC cell proliferation and colony formation in vitro and inhibited NSCLC tumour growth in subcutaneously transplanted tumour lung tumour models, leading to prolonged survival of tumour-bearing mice. However, berberine did not induce the cleavage of Caspase 3 and PARP1, and could not induce apoptosis in all NSCLC cells. Moreover, 646 genes were differentially expressed upon berberine administration, which were involved in seven signal pathways, such as DNA replication. In cDNA microarray, berberine downregulated the expression of RRM1, RRM2, LIG1, POLE2 that involving DNA repair and replication. Our findings demonstrate that berberine inhibits NSCLC cells growth through repressing DNA repair and replication rather than through apoptosis. Berberine could be used as a promising therapeutic candidate for NSCLC patients.

The Frank-Starling response of the heart is known to be mediated by nitric oxide (NO) signaling, which is regulated by reduced glutathione (GSH) and hydrogen sulfide (H2S). We hypothesized that stimulation of endogenous H2S or GSH synthesis would improve the Frank-Starling response. Wistar male rats were injected with propargylglycine (PAG; 11.3 mg/kg, 40 min, n = 12), an inhibitor of H2S-producing enzyme (cystationine-γ-lyase), and l-cysteine (121 mg/kg, 30 min, n = 20), a precursor of H2S and GSH. Pretreatment with PAG or l-cysteine separately slightly improved the pressure-volume (P-V) dependence of the isolated rat heart, but the combination of PAG and l-cysteine (n = 12) improved heart contractile activity. H2S content, Ca2+-dependent NOS activity (cNOS) activity, nitrate reductase activity, and nitrite content increased by 2, 3.83, 2.5, and 1.3 times in cardiac mitochondria, and GSH and oxidized glutathione (GSSG) levels increased by 2.24 and 1.86 times in the heart homogenates of the PAG + l-cysteine group compared with the control (all P < 0.05). Inhibition of glutathione with DL-buthionine-sulfoximine (BSO; 22.2 mg/kg, 40 min, n = 6) drastically decreased Frank-Starling response of the heart and prevented PAG + l-cysteine-induced increase of GSH and GSSG levels (BSO + PAG + l-cysteine, n = 9). Inhibition of NOS, N-nitro-l-arginine-methylester hydrochloride (l-NAME; 40 min, 27 mg/kg) abolished positive inotropy induced by PAG+l-cysteine pretreatment (l-NAME + PAG + l-cysteine, n = 7). Thus, PAG + l-cysteine administration improves the Frank-Starling response by upregulating mitochondrial H2S, glutathione, and NO synthesis, which may be a promising approach in the treatment of myocardial dysfunction.

One cost-effective way for identifying novel cancer therapeutics is in the repositioning of available drugs for which current therapies are inadequate. Levofloxacin prevents DNA duplication in bacteria by inhibiting the activity of DNA helicase. As eukaryotic cells have similar intracellular biologic characteristics as prokaryotic cells, we speculate that antibiotics inhibiting DNA duplication in bacteria may also affect the survival of cancer cells. Here we report that levofloxacin significantly inhibited the proliferation and clone formation of cancer cells and xenograft tumor growth through cell cycle arrest at G2/M and by enhancing apoptosis. Levofloxacin significantly altered gene expression in a direction favoring anticancer activity. THBS1 and LAPTM5 were dose-dependently upregulated whereas SRD5A3, MFAP5 and P4HA1 were downregulated. Pathway analysis revealed that levofloxacin significantly regulated canonical oncogenic pathways. Specific network enrichment included a MAPK/apoptosis/cytokine-cytokine receptor interaction pathway network that associates with cell growth, differentiation, cell death, angiogenesis and development and repair processes and a bladder cancer/P53 signaling pathway network mediating the inhibition of angiogenesis and metastasis. THBS1 overlapped in 16 of the 22 enriched apoptotic pathways and the 2 pathways in the bladder cancer/P53 signaling pathway network. P4HA1 enriched in 7 of the top 10 molecular functions regulated by differential downregulated genes. Our results indicate that levofloxacin has broad-spectrum anticancer activity with the potential to benefit cancer patients already treated or requiring prophylaxis for an infectious syndrome. The efficacy we find with levofloxacin may provide insight into the discovery and the design of novel less toxic anticancer drugs.

Ischemia-reperfusion injury (IRI) is typically associated with a vigorous inflammatory and oxidative stress response to hypoxia and reperfusion that disturbs the function of the organ. The remote effects of renal IRI on the liver, however, require further study. Renal damage associated with liver disease is a common clinical problem. Colchicine, a polymerization inhibitor of microtubules, has been used as an anti-inflammatory and anti-fibrotic drug for liver diseases. The goal of the current study was to investigate the possible protective mechanisms of colchicine on liver injury following renal IRI. Forty rats were divided randomly into four groups: sham group, colchicine-treated group, IRI group, and colchicine-treated + IRI group. Treatment with colchicine significantly reduced hepatic toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB) transcription factor, myeloid differentiation factor 88 (MyD88), and tumor necrosis factor-alpha (TNF-α) contents; downregulated BCL2 associated X apoptosis regulator (BAX) gene expression, transforming growth factor-β (TGF-β) content, and upregulated hepatic B cell lymphoma 2 (Bcl-2) gene expression as compared with the IRI group. Finally, hepatic histopathological examinations have confirmed the biochemical results. Renal IRI-induced liver damage in rats was alleviated by colchicine through its anti-inflammatory, anti-apoptotic, and anti-fibrotic actions.

Aurora kinase A (AURKA) carries out an essential role in proliferation and involves in cisplatin resistance in various cancer cells. Overexpression of AURKA is associated with the poor prognosis of cancer patients. Thus, AURKA has been considered as a target for cancer therapy. Developing AURKA inhibitors became an important issue in cancer therapy. A natural compound emodin mainly extracted from rhubarbs possesses anti-cancer properties. However, the effect of emodin on AURKA has never been investigated. In the present study, molecular docking analysis indicated that emodin interacts with AURKA protein active site. We also found nine emodin analogues from Key Organic database by using ChemBioFinder software. Among that, one analogue 8L-902 showed a similar anti-cancer effect as emodin. The bindings of emodin and 8L-902 on AURKA protein were confirmed by cellular thermal shift assay. Furthermore, emodin inhibited the AURKA kinase activity in vitro and enhanced the cisplatin-DNA adduct level in a resistant ovarian cancer cell line. It seems that emodin may have the potential to inhibit cancer cell growth and enhance cisplatin therapy in cancer with resistance. Collectively, our finding reveals a novel AURKA inhibitor, emodin, which may be vulnerable to ovarian cancer therapy in the future.

Emodin is a natural bioactive compound from traditional Chinese herbs that exerts anti-inflammatory, antioxidant, anticancer, hepatoprotective, and neuroprotective effects. However, the protective effects of emodin in acetaminophen (APAP)-induced hepatotoxicity are not clear. The present study examined the effects of emodin on APAP-induced hepatotoxicity and investigated the potential molecular mechanisms. C57BL/6 mice were pretreated with emodin (15 and 30 mg/kg) for 5 consecutive days and then given APAP (300 mg/kg) to establish an APAP-induced liver injury model. Mice were sacrificed to detect the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and albumin (ALB) and the liver tissue levels of glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD). Histological assessment, Western blotting, and ELISA were performed. Emodin pretreatment significantly reduced the levels of ALT, AST, and ALP; increased the levels of ALB; alleviated hepatocellular damage and apoptosis; attenuated the exhaustion of GSH and SOD and the accumulation of MDA; and increased the expression of antioxidative enzymes, including nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO1). Emodin also inhibited the expression of NLRP3 and reduced the levels of pro-inflammatory factors, including interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α). Emodin inhibited interferon (IFN)-α, cyclic GMP-AMP synthase (cGAS), and its downstream signaling effector stimulator of interferon genes (STING) expression to protect the liver against APAP-induced inflammatory responses and apoptosis. These results suggest that emodin protected hepatocytes from APAP-induced liver injury via the upregulation of the Nrf2-mediated antioxidative stress pathway, the inhibition of the NLRP3 inflammasome, and the downregulation of the cGAS-STING signaling pathway.

Unfolded protein response (UPR) and endoplasmic reticulum (ER) stress are aspects of SARS-CoV-2-host cell interaction with proposed role in the cytopathic and inflammatory pathogenesis of this viral infection. The role of the NF-kB pathway in these cellular processes remains poorly characterized. When investigated in VERO-E6 cells, SARS-CoV-2 infection was found to markedly stimulate NF-kB protein expression and activity. NF-kB activation occurs early in the infection process (6 hpi) and it is associated with increased MAPK signaling and expression of the UPR inducer IRE-1α. These signal transduction processes characterize the cellular stress response to the virus promoting a pro-inflammatory environment and caspase activation in the host cell. Inhibition of viral replication by the viral protease inhibitor Nelfinavir reverts all these molecular changes also stimulating c-Jun expression, a key component of the JNK/AP-1 pathway with important role in the IRE-1α-mediated transcriptional regulation of stress response genes with anti-inflammatory and cytoprotection function. The present study demonstrates that UPR signaling and its interaction with cellular MAPKs and the NF-kB activity are important aspects of SARS-CoV-2-host cell interaction that deserve further investigation to identify more efficient therapies for this viral infection.

Peroxisome proliferator-activated receptor α (PPARα, NR1C1) is a ligand-activated nuclear receptor involved in the regulation of lipid catabolism and energy homeostasis. PPARα activation induces hepatomegaly and plays an important role in liver regeneration, but the underlying mechanisms remain unclear.

Parenteral nutrition (PN)-associated cholestasis (PNAC) complicates the care of patients with intestinal failure. In PNAC, phytosterol containing PN synergizes with intestinal injury and IL-1β derived from activated hepatic macrophages to suppress hepatocyte farnesoid X receptor (FXR) signaling and promote PNAC. We hypothesized that pharmacological activation of FXR would prevent PNAC in a mouse model.

Serine protease inhibitor Kazal-type 5 (SPINK5) has been indicated to act as a prognostic predictor for patients with head and neck squamous cell carcinoma. However, its specific role in nasopharyngeal carcinoma (NPC), a malignancy that has a high propensity for chemoresistance, remains largely obscure. We, thus, sought to investigate the importance of SPINK5 expression in regulating chemoresistance in NPC. Differentially expressed genes in NPC were screened using the cancer genome atlas-head and neck squamous cell carcinoma database and microarray analysis. SPINK5 was downregulated in NPC tissues and cells. After SPINK5 upregulation, the cells treated with cisplatin showed reduced cell survival and the ability to migrate, invade and metastasize. Mechanistically, the transcription factors regulating SPINK5 were queried through the JASPAR website, followed by dual-luciferase and Chromatin immunoprecipitation assay validation. CCAAT enhancer-binding protein (CEBP) beta (CEBPB) bound to the SPINK5 promoter region in NPC cells. The silencing of CEBPB enhanced the expression of SPINK5. CEBPB overexpression reversed the inhibitory effects of cisplatin on NPC cell malignant phenotype in the presence of SPINK5 overexpression. In conclusion, CEBPB silencing promoted chemoresistance of NPC cells via activating SPINK5, signifying that targeting CEBPB was a new approach to enhance the chemotherapy efficacy in NPC.

Circular RNAs (circRNAs) are important regulators that drive or inhibit cancer initiation and development. Here, we identified the expression and function of a circRNA, circ_KIAA1199, in colorectal cancer (CRC). The expression levels of circ_KIAA1199, microRNA-34c-5p (miR-34c-5p) and Musashi RNA-binding protein 1 (MSI1) mRNA were detected by quantitative real-time PCR. Cell proliferative capacity was assessed by colony formation assay, EdU assay and MTT assay. Cell apoptosis was determined by flow cytometry assay. Cell migration and cell invasion were investigated by transwell assay. The expression of MSI1 protein and proliferation, migration-related markers was detected by western blot. The relationship between miR-34c-5p and circ_KIAA1199 or MSI1 was verified by dual-luciferase reporter assay. Animal models were constructed to ascertain the role of circ_KIAA1199 in vivo. The expression of circ_KIAA1199 was elevated in CRC. Circ_KIAA1199 downregulation suppressed CRC cell proliferation, survival, migration and invasion. MiR-34c-5p was a target of circ_KIAA1199. The effects of circ_KIAA1199 downregulation were reversed by miR-34c-5p deficiency. In addition, MSI1 was a target of circ_KIAA1199, and the inhibitory effects of miR-34c-5p restoration on CRC cell proliferation, survival, migration and invasion were reversed by MSI1 overexpression. Circ_KIAA1199 positively regulated MSI1 expression by targeting miR-34c-5p. Moreover, circ_KIAA1199 knockdown blocked tumor growth in animal models. Circ_KIAA1199 functioned as an oncogene to drive the malignant development of CRC by activating MSI1 via competitively targeting miR-34c-5p.

This study explores the potential role of a highly selective caspase-1 inhibitor, VX-765, on extracellular matrix (ECM) accumulation and inflammation in diabetic nephropathy (DN) and the underlying mechanisms.

Novel therapies for the treatment of acute myeloid leukemia (AML) are urgently needed, because current treatments do not cure most patients with AML. We report a domain-focused, kinome-wide CRISPR-Cas9 screening that identified protein kinase targets for the treatment of AML, which led to the identification of Rio-kinase 2 (RIOK2) as a potential novel target. Loss of RIOK2 led to a decrease in protein synthesis and to ribosomal instability followed by apoptosis in leukemic cells, but not in fibroblasts. Moreover, the ATPase function of RIOK2 was necessary for cell survival. When a small-molecule inhibitor was used, pharmacological inhibition of RIOK2 similarly led to loss of protein synthesis and apoptosis and affected leukemic cell growth in vivo. Our results provide proof of concept for targeting RIOK2 as a potential treatment of patients with AML.