Nifuroxazide suppresses PD-L1 expression and enhances the efficacy of radiotherapy in hepatocellular carcinoma.

Radiation therapy is a primary treatment for hepatocellular carcinoma (HCC), but its effectiveness can be diminished by various factors. The over-expression of PD-L1 has been identified as a critical reason for radiotherapy resistance. Previous studies have demonstrated that nifuroxazide exerts antitumor activity by damaging the Stat3 pathway, but its efficacy against PD-L1 has remained unclear. In this study, we investigated whether nifuroxazide could enhance the efficacy of radiotherapy in HCC by reducing PD-L1 expression. Our results showed that nifuroxazide significantly increased the sensitivity of tumor cells to radiation therapy by inhibiting cell proliferation and migration while increasing apoptosis in vitro. Additionally, nifuroxazide attenuated the up-regulation of PD-L1 expression induced by irradiation, which may be associated with increased degradation of PD-L1 through the ubiquitination-proteasome pathway. Furthermore, nifuroxazide greatly enhanced the efficacy of radiation therapy in H22-bearing mice by inhibiting tumor growth, improving survival, boosting the activation of T lymphocytes, and decelerating the ratios of Treg cells in spleens. Importantly, nifuroxazide limited the increased expression of PD-L1 in tumor tissues induced by radiation therapy. This study confirms, for the first time, that nifuroxazide can augment PD-L1 degradation to improve the efficacy of radiation therapy in HCC-bearing mice.

SiRNA-HIF-1α delivered by attenuated Salmonella enhances the efficacy of Lenvatinib against hepatocellular carcinoma.

The treatment of hepatocellular carcinoma (HCC) remains a major challenge in the medical field. Lenvatinib, a multi-target tyrosine kinase inhibitor, has demonstrated anti-HCC effects by targeting and inhibiting pathways such as vascular endothelial growth factor receptor 1-3 (VEGFR1-3). However, the therapeutic efficacy of Lenvatinib is subject to various influences, with the hypoxic microenvironment of the tumor being a pivotal factor. Consequently, altering the hypoxic milieu of the tumor emerges as a viable strategy to augment the efficacy of Lenvatinib. Hypoxia-inducible factor-1α (HIF-1α), synthesized by tumor cells in response to oxygen-deprived conditions, regulates the expression of resistance genes, promotes tumor angiogenesis and cell proliferation, enhances tumor cell invasion, and confers resistance to radiotherapy and chemotherapy. Thus, we constructed a self-designed siRNA targeting HIF-1α to suppress its expression and improve the efficacy of Lenvatinib in treating HCC. The therapeutic efficacy of siRNA-HIF-1α in combination with Lenvatinib on HCC were evaluated through in vivo and in vitro experiments. The results showed that the recombinant Salmonella delivering siRNA-HIF-1α in combination with Lenvatinib effectively inhibited tumor growth and prolonged the survival of tumor-bearing mice. This treatment approach reduced cell proliferation and angiogenesis in HCC tissues while promoting tumor cell apoptosis. Additionally, this combined therapy significantly increased the infiltration of T lymphocytes and M1 macrophages within the tumor microenvironment, as well as elevated the proportion of immune cells in the spleen, thereby potentiating the host's immune response against the tumor.

Plasmid co-expressing siRNA-PD-1 and Endostatin carried by attenuated Salmonella enhanced the anti-melanoma effect via inhibiting the expression of PD-1 and VEGF on tumor-bearing mice.

Melanoma, the most perilous form of skin cancer, is known for its inherent resistance to chemotherapy. Even with advances in tumor immunotherapy, the survival of patients with advanced or recurrent melanomas remains poor. Over time, melanoma tumor cells may produce excessive angiogenic factors, necessitating the use of combinations of angiogenesis inhibitors, including broad-spectrum options, to combat melanoma. Among these inhibitors, Endostatin is one of the most broad-spectrum and least toxic angiogenesis inhibitors. We found Endostatin significantly increased the infiltration of CD8+ T cells and reduced the infiltration of M2 tumor-associated macrophages (TAMs) in the melanoma tumor microenvironment (TME). Interestingly, we also observed high expression levels of programmed death 1 (PD-1), an essential immune checkpoint molecule associated with tumor immune evasion, within the melanoma tumor microenvironment despite the use of Endostatin. To address this issue, we investigated the effects of a plasmid expressing Endostatin and PD-1 siRNA, wherein Endostatin was overexpressed while RNA interference (RNAi) targeted PD-1. These therapeutic agents were delivered using attenuated Salmonella in melanoma-bearing mice. Our results demonstrate that pEndostatin-siRNA-PD-1 therapy exhibits optimal therapeutic efficacy against melanoma. We found that pEndostatin-siRNA-PD-1 therapy promotes the infiltration of CD8+ T cells and the expression of granzyme B in melanoma tumors. Importantly, combined inhibition of angiogenesis and PD-1 significantly suppresses melanoma tumor progression compared with the inhibition of angiogenesis or PD-1 alone. Based on these findings, our study suggests that combining PD-1 inhibition with angiogenesis inhibitors holds promise as a clinical strategy for the treatment of melanoma.

Synthesis of Asymmetric Urea Derivatives from COS and Amines: Substrate Selection, Scope Studies, and Mechanism Investigation.

A series of asymmetric ureas were synthesized by a one-pot reaction of amines and carbonyl sulfide (COS) under catalyst-free conditions. The highly selective synthesis of asymmetric urea was successfully achieved by the use of weakly nucleophilic aromatic amines and highly nucleophilic secondary aliphatic amines. Moreover, a reaction mechanism was proposed based on the detailed NMR and FTIR study. This efficient synthetic methodology provides a mild and selective method for synthesizing asymmetric urea derivatives.

Attenuated Salmonella carrying siRNA-CD24 improved the effect of oxaliplatin on HCC.

Oxaliplatin is a chemotherapy drug currently utilized in the treatment of advanced cancer patients. However, its tolerability poses a limitation to its clinical application. Studies have demonstrated that the presence of tumor-associated macrophages is positively correlated with poor prognosis in various solid tumors, including hepatocellular carcinoma (HCC), and is a significant factor contributing to oxaliplatin resistance. Therefore, targeting tumor-associated macrophages may be an effective strategy to improve the efficacy of oxaliplatin in the treatment of HCC patients. CD24 is a novel target for tumor therapy that can interact with the inhibitory receptor Siglec-10 on tumor-associated macrophages, transmitting immune inhibitory signals and inhibiting macrophage phagocytosis function. In this study, we utilized RNAi technology to inhibit the expression of CD24 in tumor cells and combined it with oxaliplatin, resulting in reduced tumor invasion, migration, and proliferation, as well as increased cell apoptosis. Furthermore, immunofluorescence and flow cytometry results indicated that both the single treatment group and combination treatment group enhanced the infiltration of immune cells. This study presents a novel approach to identifying combination therapy and targets for the clinical treatment of HCC with oxaliplatin.

Peficitinib ameliorates 5-fluorouracil-induced intestinal damage by inhibiting aging, inflammatory factors and oxidative stress.

5-Fluorouracil (5-FU) is a conventional and effective drug for colorectal cancer patients, and it is an important part of combined chemotherapy and adjuvant chemotherapy. Chemotherapy intestinal mucositis (CIM) is a severe side effect caused by 5-FU that, induces cancer treatment failure and affects patients' quality of life. The mechanism of 5-FU-induced CIM is related to normal cell senescence induced by 5-FU. Peficitinib, a Janus Kinase (JAK) inhibitor, treats inflammatory disorders, including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. However, the therapeutic role and underlying mechanism of peficitinib in CIM remain unclear. The main objective of our research was to investigate the effects of peficitinib on 5-FU-induced senescence and intestinal damage in human umbilical vein endothelial (HUVEC) cells, human intestinal epithelial (HIEC) cells and BABL/C mice. The results showed that 5-FU caused intestinal damage by inducing aging and increasing inflammation and oxidative stress. Peficitinib alleviated aging by reducing senescence-beta-galactosidase (SA-ß-gal) activity and the protein levels of aging indicators (p53, p21, p16). Moreover, peficitinib reversed the changes in senescence-associated secretory phenotype (SASP) expression caused by 5-FU. Besides, 5-FU induced release of inflammatory factors and oxidative stress indicators was reversed by peficitinib. Additionally, the combination of peficitinib and 5-FU reinforced the anticancer curative intent of 5-FU in two colorectal cancer cell lines (HCT116 cells and SW620 cells). In conclusion, peficitinib alleviates mucositis by alleviating aging, reducing inflammatory accumulation and oxidative stress and enhancing the antitumor activity of 5-FU.

Attenuated Salmonella carrying siRNA-PD-L1 and radiation combinatorial therapy induces tumor regression on HCC through T cell-mediated immuno-enhancement.

Hepatocellular carcinoma (HCC), the most prevalent type of aggressive liver cancer, accounts for the majority of liver cancer diagnoses and fatalities. Despite recent advancements in HCC treatment, it remains one of the deadliest cancers. Radiation therapy (RT) is among the locoregional therapy modalities employed to treat unresectable or medically inoperable HCC. However, radioresistance poses a significant challenge. It has been demonstrated that RT induced the upregulation of programmed death ligand 1 (PD-L1) on tumor cells, which may affect response to PD-1-based immunotherapy, providing a rationale for combining PD-1/PD-L1 inhibitors with radiation. Here, we utilized attenuated Salmonella as a carrier to explore whether attenuated Salmonella carrying siRNA-PD-L1 could effectively enhance the antitumor effect of radiotherapy on HCC-bearing mice. Our results showed that a combination of siRNA-PD-L1 and radiotherapy had a synergistic antitumor effect by inhibiting the expression of PD-L1 induced by radiation therapy. Mechanistic insights indicated that the combination treatment significantly suppressed tumor cell proliferation, promoted cell apoptosis, and stimulated immune cell infiltration and activation in tumor tissues. Additionally, the combination treatment increased the ratios of CD4+ T, CD8+ T, and NK cells from the spleen in tumor-bearing mice. This study presents a novel therapeutic strategy for HCC treatment, especially for patients with RT resistance.

Artesunate alleviates 5-fluorouracil-induced intestinal damage by suppressing cellular senescence and enhances its antitumor activity.

BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent diagnosed malignancies and one of the leading causes of cancer-related deaths worldwide. 5-Fluorouracil (5-FU) and its combination regimen are commonly used as primary chemotherapeutic agents for advanced CRC. Intestinal mucositis is one of the most frequent side effects of 5-FU. Artesunate (Arte) is derived from the wormwood plant Artemisia annua. Arte is not only effective against malaria but also diabetes, atherosclerosis, inflammation, and other conditions. The mechanism by which 5-FU damages the intestinal tract is unclear, and there is no standard treatment for diarrhea caused by 5-FU. Therefore, it is critical to discover novel and promising therapeutic drugs for 5-FU side effect treatment. METHODS: The morphology and expression of genes and proteins associated with the aging of HUVECs, HIECs, and intestinal tissues were compared to the those of the control group. The cell lines and tissues were evaluated by SA-ß-Gal staining, Western blotting, and RT‒qPCR. HIEC and HCT116 cell viability was assessed in vitro by a CCK-8 assay and in vivo by a subcutaneous tumor mouse assay. Tumor cell proliferation and apoptosis was evaluated by immunohistochemistry. RESULTS: Here, we report that Arte alleviates the adverse side effects caused by 5-FU in intestinal tissue, and that 5-FU-induced intestinal damage is associated with drug-induced chemical inflammation and an increase in the proportion of senescent cells. Arte decreases the ratio of SA-ß-Gal-positive cells and downregulated the expression of aging-related proteins (p53, p16) and aging-related genes (p53, p21). Mechanistically, Arte relieves intestinal injury by inhibiting mTOR expression, which is associated with the regulation of aging. Moreover, Arte suppresses the p38MAPK and NF-κB signaling pathways, which are related to inflammation regulation. In addition, the combined therapy of Arte plus 5-FU significantly decreases cancer cell viability in vitro. Arte and 5-FU synergistically reduce the growth of colorectal cancer (CRC) xenografts in vivo. CONCLUSIONS: Overall, our findings point to the crucial treatment effect of Arte on inflammation, intestinal cell senescence, and CRC cell proliferation and offer a new option for CRC treatment.

Amonafide Induces HUVEC Senescence by Inhibiting Autophagy.

BACKGROUND: Amonafide (Amo), due to hematotoxicity and digestive tract symptoms, the clinical application of which is limited. Several studies have reported that chemotherapy side effects are closely related to cellular senescence accumulation. Our study aims to examine whether amonafide causes senescence in human umbilical vein endothelial cell (HUVEC) lines and investigate its mechanisms associated with senescence. METHODS: The experiments of expression of genes and proteins associated with aging were carried out with HUVEC cell lines. The experiments were divided into a control group and an amonafide group with different days. The HUVEC senescence cells were detected by SA-ß-Gal staining, Western blotting detected the protein levels of p16, p53, AMPK (Adenosine 5'-Monophosphate (AMP)-Activated Protein Kinase), mTOR (mechanistic Target of Rapamycin), p62, and LC3 (microtubule-associated protein1 light chain 3, MAP1LC3). Fluorescence detected the expression of mRFP (monomeric Red Fluorescent Protein)-GFP (Green Fluorescent Protein)-LC3 and LC3 puncta of HUVEC cells. RT-qPCR (Real-Time Quantitative Polymerase Chain Reaction) tested the expressions of p53, p21, IL (Interleukin)-1ß, IL-6 (Interleukin-6), IL-8 (Interleukin-8), and MCP-1 (Monocyte Chemoattractant Protein-1). CCK-8 (Cell Counting Kit-8) assessed the HUVEC cell viability. RESULTS: Here, we reported that amonafide resulted in an increased proportion of SA-ß-Gal positive cells, high expression of aging-related proteins (p53 p < 0.05; p16 p < 0.05), and aging-related genes (p53 p < 0.05; p21 p < 0.05; IL-1ß p < 0.05; IL-6 p < 0.05; IL-8 p < 0.05; MCP-1 p < 0.05) on the 3rd day. Mechanistically, amonafide could cause an increase in the levels of the mTOR (p < 0.05) on days 1 and 3, and p62 protein (p < 0.05) on day 1, and a decline in LC3II (microtubule-associated protein1 light chain 3Ⅱ)/LC3I levels (p < 0.05) on day 3, which is associated with the regulation of senescence. Additionally, the viability of HUVECs (human umbilical vein endothelial cells) was significantly inhibited by amonafide starting with a concentration of 0.8 µm (p < 0.05). CONCLUSIONS: We first discovered that amonafide caused normal cellular senescence in our experiments. Amonafide-induced cellular aging by inhibiting autophagy and activating the mTOR pathway. The findings may offer new strategies for managing adverse reactions to amonafide.

Atorvastatin calcium alleviates 5-fluorouracil-induced intestinal damage by inhibiting cellular senescence and significantly enhances its antitumor efficacy.

5-Fluorouracil (5-Fu) is the preferred drug in colorectal cancer treatment. Although 5-Fu treatment contributes to the increase in survival rates, long-term use of 5-Fu causes severe intestinal damage, eventually decreasing long-term survival. There is no standardtreatmentfor intestinal damage induced by 5-Fu. Our previous study found that 5-Fu-induced intestinal damage was connected to an increase in senescent cells, and antiaging drugs could relieve some adverse side effects caused by 5-Fu. Hence, it is essential to discover novel, potential antiaging therapeutic drugs for 5-Fu side effect treatment. According to the current study, Atorvastatincalcium (Ator) alleviated cellular senescence in human intestinal epithelial cells (HUVECs) and human umbilical vein endothelial cells (HIECs) caused by oxidative stress and 5-Fu. 5-Fu resulted in an increase in SA-ß-Gal-positive cells, synchronously increased expression of aging-related proteins (p16), aging-related genes (p53, p21), and the senescence-associated secretory phenotype (SASP: IL-1ß, IL-6, TNF-α), while Atorvastatincalcium (Ator) reversed the increase in these indicators. In the BALB/c mouse model, we confirmed that intestinal damage caused by 5-Fu is related to the increase in senescent cells and drug-induced inflammation, with the therapeutic effects of Ator. In addition, Ator increased the sensitivity of 5-Fu to chemotherapy in vitro and in vivo. Combination therapy significantly reduced HCT116 cell viability. Furthermore, Ator and 5-Fu present a cooperative effect on preventing the growth of tumors in CRC xenograft nude mice. In conclusion, our study demonstrates the value of Ator for treating intestinal damage. Moreover, Ator combined with 5-Fu increased the antitumor ability in CRC cells. Additionally, we provide a novel therapeutic protocol for CRC.

IDO2-siRNA Carried by Salmonella Combined with Nifuroxazide Attenuates Melanoma Growth.

BACKGROUND: Melanoma, a highly malignant skin cancer, is a hot topic in oncology treatment research. Nowadays, tumor immunotherapy, especially immunotherapy combined with other therapies, has attracted more and more attention. Indoleamine 2,3-dioxygenase 2 (IDO2), a ratelimiting enzyme of the tryptophan metabolism pathway in the urine of dogs with immunosuppression, is highly expressed in melanoma tissue. Additionally, IDO2 significantly inhibits the anti-tumor immunity of the body and has become a novel target of melanoma treatment. Nifuroxazide, as an intestinal antibacterial agent, was found to be able to inhibit Stat3 expression and exert an anti-tumor effect. Therefore, the present study aimed to examine the therapeutic effect of a self-designed IDO2-small interfering RNA (siRNA) delivered by attenuated Salmonella combined with nifuroxazide on melanoma- bearing mice, as well as determine its underlying mechanism. METHODS: The effect of nifuroxazide on melanoma was detected by flow cytometry, CCK-8 and colony- forming ability assays, respectively, in vitro. The plasmid of siRNA-IDO2 was constructed, and the mice-bearing melanoma model was established. After the treatment, the tumor growth and survival rate were monitored, and the morphological changes of tumor tissue were detected by HE staining. The expression of related proteins was detected by Western blotting, and the expression of CD4 and CD8 positive T cells in tumor tissue was detected by IHC and IF, and the proportion of CD4 and CD8 positive T cells in spleen was detected by flow cytometry. RESULTS: The results demonstrated that the combination therapy effectively inhibited the phosphorylation of Stat3 and the expression level of IDO2 in melanoma cells, which effectively inhibited tumor growth and prolonged the survival time of tumor-bearing mice. The mechanistic study revealed that, compared with control groups and monotherapy groups, the combination treatment group reduced the atypia of tumor cells, increased the apoptotic rate, enhanced the infiltration of T lymphocytes in tumor tissue and increased the CD4+ and CD8+ T lymphocytes in the spleen, suggesting that the mechanism may be associated with the inhibition of tumor cell proliferation, the increase of apoptosis and the enhancement of the cellular immunity. CONCLUSION: In conclusion, IDO2-siRNA combined with nifuroxazide therapy could serve a significant role in the treatment of melanoma-bearing mice, enhance the tumor immunity and provide an experimental basis for identifying a novel combination method for the treatment of melanoma clinically.

End-to-end fatigue driving EEG signal detection model based on improved temporal-graph convolution network.

Fatigue driving is one of the leading causes of traffic accidents, so fatigue driving detection technology plays a crucial role in road safety. The physiological information-based fatigue detection methods have the advantage of objectivity and accuracy. Among many physiological signals, EEG signals are considered to be the most direct and promising ones. Most traditional methods are challenging to train and do not meet real-time requirements. To this end, we propose an end-to-end temporal and graph convolution-based (MATCN-GT) fatigue driving detection algorithm. The MATCN-GT model consists of a multi-scale attentional temporal convolutional neural network block (MATCN block) and a graph convolutional-Transformer block (GT block). Among them, the MATCN block extracts features directly from the original EEG signal without a priori information, and the GT block processes the features of EEG signals between different electrodes. In addition, we design a multi-scale attention module to ensure that valuable information on electrode correlations will not be lost. We add a Transformer module to the graph convolutional network, which can better capture the dependencies between long-distance electrodes. We conduct experiments on the public dataset SEED-VIG, and the accuracy of the MATCN-GT model reached 93.67%, outperforming existing algorithms. Furthermore, compared with the traditional graph convolutional neural network, the GT block has improved the accuracy rate by 3.25%. The accuracy of the MATCN block on different subjects is higher than the existing feature extraction methods.

Anti-inflammation and anti-aging mechanisms of mercaptopurine in vivo and in vitro.

Skin is the biggest organ of the human body, which easily gets irritated by exposure to the sun. Skin photoaging and acute photodamage are caused by intense UV-B radiation. Therefore, it is imperative to find new compounds to prevent skin damage and aging. Mercaptopurine is an immunologic agent commonly used for treating Acute lymphoblastic leukemia and inflammatory bowel disease. The beneficial effects of mercaptopurine on the skin have not been reported, and its intrinsic mechanism of action is unclear. Therefore, this study was to explore mercaptopurine when exposed to UV-B radiation in HacaT cells and C57BL6 mice aging and damage effects. The model of in vivo UV-B-induced skin damage and skin photoaging was established, and the impact of mercaptopurine on cell and animal skin was studied. The study found that mercaptopurine, on the one hand, inhibits cellular and animal senescence. On the other, it inhibits the expression of mitogen-activated protein kinase (MAPK) and the nuclear factor κB (NF-κB), which are important signaling molecules in the early UV-B reaction signaling pathway. In addition, mercaptopurine downregulates matrix metalloproteinase expression, increases collagen fiber content, and facilitates collagen synthesis. Treatment with mercaptopurine also inhibits the expression of inflammatory factors and reduces inflammatory cell infiltration of the skin. In conclusion, our study elucidates mercaptopurine's anti-photoaging and anti-inflammatory activity in cellular and animal models.

Fluvoxamine prompts the antitumor immune effect via inhibiting the PD-L1 expression on mice-burdened colon tumor.

A colon tumor, one of the digestive tract malignant tumors, is harmful to human health. A potential new treatment still deserves attention. The development of a new drug needs more resources, including time and expense. Therefore, the old drug with new targets has become a current research hotspot. Fluvoxamine, as an antidepressant, could play an effect on inhibiting 5-hydroxytryptamine reuptake. In the present research, the antitumor effects and possible mechanisms of fluvoxamine are validated. The results showed that fluvoxamine significantly suppressed the migration and proliferation of tumor cells, and increased the apoptosis in vitro. Additionally, fluvoxamine significantly delays tumor development, and prompts the apoptosis in tumor tissues of mice-burdened colon tumors in vivo. The tumor suppression might be related with that fluvoxamine inhibits the expression of phosphorylated signal transducer and activator of transcription 3, matrix metalloproteinase 2, and cleaved-caspase 3. Importantly, fluvoxamine significantly reduces the expression level of programmed cell death ligand 1. This could be a possible reason that treatment with fluvoxamine drives the infiltration of T lymphocytes and M1-type macrophages in tumor tissues. Taken together, this research suggests that fluvoxamine might be a promising drug to treat colon cancer by inhibiting the proliferation and migration, inducing apoptosis, and even increasing the immune response of antitumor.

Belinostat (PXD101) resists UVB irradiation-induced cellular senescence and skin photoaging.

Belinostat (PXD101), a new histone deacetylase inhibitor, has shown good performance in various cancer treatments and has been approved by the FDA for the treatment of recurrent or refractory peripheral T-cell lymphoma (PTCL) in patients with drugs. PXD101 is considered to have certain anti-allergic and anti-inflammatory properties, but its beneficial effects in UVB-induced skin photoaging have not been reported. In a recent study, HacaT cells and C57BL6 mice were used to study the impact of PXD101 on UVB-induced cellular senescence and skin photoaging and to explore their potential mechanisms of action. Studies have shown that PXD101 inhibits UVB-induced HacaT cell senescence, which appears to be achieved by inhibiting activation of the UVB-induced NF-κB/p65 signaling pathway. At the same time, PXD101 inhibits the expression of MMPs. In addition, PXD101 alleviated skin damage on the dorsal skin of mice, reduced skin aging and inflammation, increased collagen fiber synthesis, and restored UVB-induced epidermal thickening. In short, we believe that PXD101 effectively inhibits cellular senescence and skin photoaging caused by UVB exposure, a potential method for developing clinical prevention and treatment of skin aging.

siRNA targeting PD-L1 delivered with attenuated Salmonella enhanced the anti-tumor effect of lenvatinib on mice bearing Hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a primary liver cancer representing serious harm to human health. The effective treatment of HCC is challenging. Lenvatinib is an inhibitor of polytyrosine kinase that exerts an effect against HCC by blocking the VEGF signaling pathway. However, its efficacy in most patients remains unsatisfactory. The factors influencing tumorigenesis are diverse; thus, combined treatment is an important strategy against tumors. Programmed death ligand-1 (PD-L1), which binds to programmed death-1 (PD-1), significantly compromises the anti-tumor effect of T cells. Therefore, we designed a siRNA-PD-L1 and delivered it using attenuated Salmonella, and its synergistic effects with Lenvatinib against HCC were evaluated. The results showed that the combination of Lenvatinib and siRNA-PD-L1 inhibited tumor growth in H22 tumor-bearing mice, arrested cell proliferation, and increased cell apoptosis in the tumor. The combination treatment synergistically inhibited the expression of VEGF and PD-L1 and contributed to the increase in T-cell infiltration in the tumor tissues and the ratio of T cells in the spleen. Furthermore, the combination treatment increased the number of granzyme B+ T cells, indicating a significantly improved anti-tumor immunity in mice. Therefore, this combination might be a potential novel strategy for HCC treatment.

Marimastat alleviates oxidative stress induced cellular senescence by activating autophagy.

Marimastat is one of the potent inhibitors of MMP (MMPIs) with few side effects. The impact of marimastat on cellular senescence remains unexplored. Our study evaluated the marimastate effect on oxidative stress-induced cell senescence using NIH3T3 cells. Marimastate administration was found to suppress senescence-ß-galactosidase (SA-ß-gal) activity and development linked with aging. Furthermore, we observed that this effect of marimastat was closely linked with the recovery of autophagy dysfunction and mTOR suppression in H2O2-treated cells. Notably, this study demonstrated the marimastat effect on senescence inhibition for the first time.

Nifuroxazide in combination with CpG ODN exerts greater efficacy against hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common malignant tumour in China that remains a major challenge to the medical community, and effective treatment is urgently needed. Due to complex tumorigenesis, monotherapy shows poor therapeutic effects, and combined treatment becomes a necessary option. YW002, a CpG ODN-containing sequence, has been proven to enhance antitumor effects in tumour-bearing mouse models. Moreover, as a broad-spectrum antimicrobial drug, nifuroxazide exhibited an anti-HCC effect through activation of p-Stat3. Here, we tested the effect of nifuroxazide on HCC in vitro and then explored the therapeutic effect of combined nifuroxazide and CpG ODN on HCC in vivo. Nifuroxazide inhibited proliferation, induced apoptosis and suppressed migration and invasion in HepG2 cells in vitro. The combination therapy using nifuroxazide and CpG ODN significantly suppressed the growth of tumours in tumour-bearing mice with few side effects and achieved better therapeutic effects on HCC than monotherapy. Moreover, combined nifuroxazide and CpG ODN therapy significantly induced apoptosis, enhanced the infiltration of CD4+ and CD8+ T lymphocytes and macrophages in tumour tissue, and increased the ratio of CD4+ and CD8+ T lymphocytes in the spleens of tumour-bearing mice. The introduction of this combination therapy combining nifuroxazide and CpG ODN provided a new strategy for HCC treatment.

Taraxasterol prompted the anti-tumor effect in mice burden hepatocellular carcinoma by regulating T lymphocytes.

Hepatocellular carcinoma (HCC) is a common digestive malignant tumor with high morbidity and mortality worldwide, however, the treatment of HCC and prognosis of patients are not optimistic, finding more effective treatments are imperative. Taraxacum officinale (L.) Weber ex F.H.Wigg is a perennial herb of compositae, and our study has demonstrated that Taraxacum officinale polysaccharide has certain anti-tumor effect on HCC cells. Taraxasterol (TS) is a natural product extracted from Taraxacum officinale with strong physiological, pharmacological and biological activities, but the effect of TS on HCC is yet to be determined. Therefore, the aim of this study is to explore the effect of dandelion sterol on HCC in vivo and in vitro. The results showed that TS significantly inhibited the proliferation, induced apoptosis and blocked cell cycle in HCC cell lines HepG2 and Huh7 cells in vitro. TS inhibited the tumor growth of H22 bearing mice and the expression of Ki67 in vivo. More importantly, TS regulated the immunity of H22 bearing mice by elevating the ratio of CD4+ T cells in spleen, and increasing the number of T cell infiltration in tumor tissue. Except immunomodulation, the mechanism of tumor growth inhibition may be related to the regulation of apoptosis related proteins and IL-6/STAT3 pathway. TS significantly inhibited the growth of HCC cells both in vitro and in vivo. The study would provide a theoretical basis for the new application of TS and the adjuvant treatment of malignant tumor with traditional Chinese medicine.