Background:
Si-Ni-San (SNS), a commonly used traditional Chinese medicine (TCM) formula, has potency against liver diseases, such as hepatitis and non-alcoholic fatty liver disease (NAFLD). However, ...the therapeutic efficacy and pharmacological mechanisms of action of SNS against liver fibrosis remain largely unclear.
Methods:
A carbon tetrachloride (CCl
4
)-induced liver fibrosis mouse model was adopted for the first time to investigate the beneficial effects of SNS on liver fibrosis. The potential mechanisms of action of SNS were explored using the network pharmacology-based strategy and validated with the aid of diverse assays.
Results:
SNS treatment reduced collagen and ECM deposition, downregulated fibrosis-related factor (hyaluronic acid and laminin) contents in serum, maintained the morphological structure of liver tissue, and improved liver function in the liver fibrosis model. Based on network pharmacology results, apoptosis, inflammation and angiogenesis, together with the associated pathways (including VEGF, TNF, caspase, PPAR-γ and NF-κB), were identified as the mechanisms underlying the effects of SNS on liver fibrosis. Further
in vivo
experiments validated the significant mitigatory effects of SNS on inflammatory infiltration and pro-inflammatory cytokine contents (IFNγ, IL-1β and TGF-β1) in liver tissues of mice with liver fibrosis. SNS suppressed pathologic neovascularization as well as levels of VEGFR1, VEGF and VEGFR2 in liver tissues. SNS treatment additionally inhibited hepatic parenchyma cell apoptosis in liver tissues of mice with liver fibrosis and regulated apoptin expression while protecting L02 cells against apoptosis induced by TNF-α and Act D
in vitro
. Activation of hepatic stellate cells was suppressed and the balance between MMP13 and TIMP1 maintained
in vitro
by SNS. These activities may be associated with SNS-induced NF-κB suppression and PPAR-γ activation.
Conclusion:
SNS effectively impedes liver fibrosis progression through alleviating inflammation, ECM accumulation, aberrant angiogenesis and apoptosis of hepatic parenchymal cells along with inhibiting activation of hepatic stellate cells through effects on multiple targets and may thus serve as a novel therapeutic regimen for this condition.
The thermoelectric (TE) fiber, based on poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS), which possesses good flexibility, a low cost, good environmental stability and ...non-toxicity, has attracted more attention due to its promising applications in energy harvesting. This study presents a self-powered flexible sensor based on the TE properties of the hollow PEDOT:PSS fiber. The hollow structure of the fiber was synthesized using traditional wet spinning. The sensor was applied to an application for finger touch, and showed both long-term stability and good reliability towards external force. The sensor had a high scalability and was simple to develop. When figures touched the sensors, a temperature difference of 6 °C was formed between the figure and the outside environment. The summit output voltages of the sensors with 1 to 5 legs gradually increased from 90.8 μV to 404 μV. The time needed for the output voltage to reach 90% of its peak value is only 2.7 s. Five sensors of legs ranging from 1 to 5 were used to assemble the selector. This study may provide a new proposal to produce a self-powered, long-term and stable skin sensor, which is suitable for wearable devices in personal electronic fields.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background/Aims: Metastasis is the leading cause resulting in high mortality in triple negative breast cancer (TNBC) patients. Cancer cells are skilled at utilizing thioredoxin (Trx) system as an ...efficient antioxidant system to counteract oxidative damage, facilitating the occurrence of metastasis. Here, we identified an organosulfur compound named DATS isolated from garlic, that inhibits the expression of Trx-1 and the enzyme activity of Trx reductase in breast cancer cells. Methods: Tissue microarray of breast cancer patients and immunohistochemical method were used to analyze the role of Trx-1 in breast cancer metastasis. Spotaneous metastasis model and experimental metastasis model combined with HE staining, immunohistochemistry were used to verify in vivo anti-metastatic effect of DATS as well as its regulation on thioredoxin. Western blot, immunofluorescence, redox state assessment and detection of enzyme activity were employed to determine the effect of DATS on thioredoxin system. Trx-1 siRNA interference was used to investigate the conclusive evidence that Trx-1 was the target of DATS. Results: In agreement with reduced Trx-1 nuclear translocation from cytoplasm by DATS, the production of reduced form of Trx-1 was dramatically decreased. Furthermore, in vivo, DATS administration was observed to significantly suppress spontaneous and experimental metastasis in nude mice. Delivery of DATS also resulted in decreased expression of Trx-1 as the direct target, as well as expression of NF-κB and MMP2/9 in primary tumor and lung tissue. Notably, the effects of DATS on the expression of downstream metastasis-associated genes were mediated by Trx-1, as demonstrated by the combination use of DATS and Trx-1 siRNA. Conclusion: Collectively, this present study indicates that targeting Trx system with DATS may provide a promising strategy for treating metastasis of TNBC.
Cancer prevention through intake of biologically active natural products appears to be an accessible way to reduce the risk of cancer. Diallyl disulfide (DADS), a major garlic derivative, has ...exhibited potential role in cancer therapy. The study is aimed to evaluate the prophylactic effect of DADS in chemically induced mouse skin carcinogenesis and investigate the molecular targets mediated by DADS. Two-stage chemically induced carcinogenesis model by cutaneous application of DMBA and subsequent TPA was established to study the prophylactic effect of DADS. As a result, we observed that DADS dose-dependently attenuated skin tumor incidence and multiplicity in the model mice, which was related to the up-regulation of a bunch of antioxidant enzymes activities and the nuclear accumulation of Nrf2. Furthermore, we developed skin carcinogenesis in Nrf2 knockout mice which could reverse the activity of DADS. Finally, we uncovered the underlying mechanism that DADS promoted the endogenous interaction between p21 and Nrf2, which was critical for impairing the Keap1-mediated degradation of Nrf2. Based on the results, we concluded that DADS was a promising cancer chemoprevention agent and suggested a garlic-rich diet might be beneficial to reduce the cancer risk in our daily life.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Quasi-bound states in the continuum (quasi-BIC) are a particular resonant state, which can be regulated by the degree of symmetry breaking in nanostructures. Here, we propose a fourfold rotationally ...symmetric (C 4v ) metasurface supporting the dual quasi-BIC modes. The Fano characteristics have observed in the near-infrared region. The resonant peaks of the dual quasi-BIC modes can be adjusted flexibly and independently with a simple breaking of the structural symmetry. More importantly, the dual quasi-BIC modes demonstrate the extraordinary capability in controlling the optical activity. This work will offer us more freedom for controlling the resonance and optical activity by the quasi-BIC modes, which is promising to engineer the optical device in displaying and optics communications.
Cryptotanshinone (CPT), a fat-soluble phenanthraquinone from Salvia miltiorrhiza Bunge, has been demonstrated to inhibit phosphorylation of p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E ...binding protein 1 (4E-BP1), a couple of direct downstream effectors of the mammalian target of rapamycin complex 1 (mTORC1), resulting in cancer cell arrested in G0 phase and subsequent inhibition of proliferation. However, its concrete molecular mechanism about how CPT inhibits mTORC1 signaling pathway is unclear.
one solution was used to check cell viability and western blotting for determining expression of the indicated proteins. Molecular docking was performed to assess the binding of CPT with mTOR. The co-immunoprecipitation assay was to analyze whether CPT could disrupt the mTORC1 and TSC1/TSC2 complex. Recombinant adenoviral dominant-negative AMPKα was used to downregulate expression of AMPKα and lentiviral AMPK and TSC2 to silence the AMPK and TSC2 in Rh30 cells.
Primarily, Rh30 cells expressing rapamycin-resistant mutant mTOR are also sensitive to CPT, while the molecular docking result for CPT binding to mTOR is negative, suggesting that CPT inhibition of mTORC1 is different from rapamycin. Then the related proteins of PTEN-PI3K pathway was proved not to be affected, but the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) was activated by a concentration- and time- dependent manner, meaning that it may be associated with AMPK. Further results indicated that compound C, inhibitor of AMPK, could clearly reversed CPT inhibitory effect on Rh30 cells, and dominant-negative AMPK in cancer cells conferred resistance to CPT inhibition of 4E-BP1 and phosphorylation of S6K1, as well as sh-AMPK. Furthermore, compared with AMPK-positive MEF cells, AMPK-negative MEF cells are less sensitive to CPT by the findings that 4E-BP1 and phosphorylation of S6K1 express comparatively more. Additionally, phosphorylation of tuberous sclerosis complex 2 (TSC2) was activated under the treatment of CPT, and down-expression of TSC2 by shRNA slightly recovered expression of 4E-BP1 and phosphorylation of S6K1, while co-immunoprecipitation of TSC2 did not alter expression of TSC1 by CPT.
CPT inhibiting mTORC1 pathway was mostly due to activation of AMPK-TSC2 axis rather than specific binding to mTORC1. CPT is a potent anticancer agent targeting AMPK.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Pretreatment with menthol significantly delayed tumor formation and growth.•Menthol could inhibit TPA-induced skin inflammation.•Menthol could inhibit the formation of reactive oxygen species.
This ...diagram summarizes some key menthol-regulated signal transduction pathways implicated in skin cancer. Menthol exerts chemopreventive effects mainly by resisting inflammation and oxidative stress. ROS activation further activates the downstream Ras/Raf signaling pathways, thus activating Erk and p38. NF-κB mediates the regulation of inflammation, the anti-inflammatory ability of which can be inhibited by menthol.
Inflammation and oxidative stress have been implicated in various pathological processes including skin tumorigenesis. Skin cancer is the most common form of cancer responsible for considerable morbidity and mortality, the treatment progress of which remains slow though. Therefore, chemoprevention and other strategies are being considered. Menthol has shown high anticancer activity against various human cancers, but its effect on skin cancer has never been evaluated. We herein investigated the chemopreventive potential of menthol against 9,10-dimethylbenzaanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation, oxidative stress and skin carcinogenesis in female ICR mice. Pretreatment with menthol at various doses significantly suppressed tumor formation and growth, and markedly reduced tumor incidence and volume. Moreover, menthol inhibited TPA-induced skin hyperplasia and inflammation, and significantly suppressed the expression of cyclooxygenase-2 (COX-2). Furthermore, pretreatment with menthol inhibited the formation of reactive oxygen species and affected the activities of a battery of antioxidant enzymes in the skin. The expressions of NF-κB, Erk and p38 were down-regulated by menthol administration. Thus, inflammation and oxidative stress collectively played a crucial role in the chemopreventive efficacy of menthol on the murine skin tumorigenesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Purine adenosine pathway exists widely in the body metabolism, and is involved in regulating various physiological processes. It is one of the important pathways of environmental regulation in human ...body. CD73 is essentially a protease that catalyzes further dephosphorylation of extracellular adenine nucleotides, hydrolyzing extracellular AMP to adenosine and phosphate. CD73 is an important part of the adenosine signaling pathway. Studies have shown that CD73-mediated adenosine pathway can convert the inflammatory ATP into the immunosuppressant adenosine. This paper aims to summarize the relevant effects of CD73 in the occurrence, development and prognosis of liver diseases such as viral hepatitis, highlight the important role of CD73 in liver diseases, especially in viral hepatitis such as HBV and HCV, and explore new clinical ideas for future treatment targets of liver diseases.
Background. Pyroptosis is closely related to the programmed death of cancer cells as well as the tumor immune microenvironment (TIME) via the host-tumor crosstalk. However, the role of ...pyroptosis-related genes as prognosis and TIME-related biomarkers in skin cutaneous melanoma (SKCM) patients remains unknown. Methods. We evaluated the expression profiles, copy number variations, and somatic mutations (CNVs) of 27 genes obtained from MSigDB database regulating pyroptosis among TCGA-SKCM patients. Thereafter, we conducted single-sample gene set enrichment analysis (ssGSEA) for evaluating pyroptosis-associated expression patterns among cases and for exploring the associations with clinicopathological factors and prognostic outcome. In addition, a prognostic pyroptosis-related signature (PPRS) model was constructed by performing Cox regression, weighted gene coexpression network analysis (WGCNA), and least absolute shrinkage and selection operator (LASSO) analysis to score SKCM patients. On the other hand, we plotted the ROC and survival curves for model evaluation and verified the robustness of the model through external test sets (GSE22153, GSE54467, and GSE65904). Meanwhile, we examined the relations of clinical characteristics, oncogene mutations, biological processes (BPs), tumor stemness, immune infiltration degrees, immune checkpoints (ICs), and treatment response with PPRS via multiple methods, including immunophenoscore (IPS) analysis, gene set variation analysis (GSVA), ESTIMATE, and CIBERSORT. Finally, we constructed a nomogram incorporating PPRS and clinical characteristics to improve risk evaluation of SKCM. Results. Many pyroptosis-regulated genes showed abnormal expression within SKCM. TP53, TP63, IL1B, IL18, IRF2, CASP5, CHMP4C, CHMP7, CASP1, and GSDME were detected with somatic mutations, among which, a majority displayed CNVs at high frequencies. Pyroptosis-associated profiles established based on pyroptosis-regulated genes showed markedly negative relation to low stage and superior prognostic outcome. Blue module was found to be highly positively correlated with pyroptosis. Later, this study established PPRS based on the expression of 8 PAGs (namely, GBP2, HPDL, FCGR2A, IFITM1, HAPLN3, CCL8, TRIM34, and GRIPAP1), which was highly associated with OS, oncogene mutations, tumor stemness, immune infiltration degrees, IC levels, treatment responses, and multiple biological processes (including cell cycle and immunoinflammatory response) in training and test set samples. Conclusions. Based on our observations, analyzing modification patterns associated with pyroptosis among diverse cancer samples via PPRS is important, which can provide more insights into TIME infiltration features and facilitate immunotherapeutic development as well as prognosis prediction.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
•JAK/STAT pathway's pivotal role inimmune resistance.•Advancements in combined JAK/STAT and PD-1/PD-L1 therapy.•Review aids tumour treatment and resistance insights.
Programmed cell death protein 1 ...(PD-1) binds to its ligand to help tumours evade the immune system and promote tumour progression. Although anti-PD-1/PD-L1 therapies show powerful effects in some patients, most patients are unable to benefit from this treatment due to treatment resistance. Therefore, it is important to overcome tumour resistance to PD-1/PD-L1 blockade. There is substantial evidence suggesting that the JAK/STAT signalling pathway plays a significant role in PD-1/PD-L1 expression and anti-PD-1/PD-L1 treatment. Herein, we describe the effects of the JAK/STAT signalling pathway on PD-1/PD-L1. Subsequently, the relationship between molecular mutations in the JAK/STAT signalling pathway and immune resistance was analysed. Finally, the latest advancements in drugs targeting the JAK/STAT pathway combined with PD1/PD-L1 inhibitors are summarised.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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