Oxygen-independent alkyl radical nanogenerator enhances breast cancer therapy.

The hypoxic microenvironment of breast cancer substantially reduces oxygen-dependent free radical generation. Overexpression of glutathione (GSH) in tumor cells mitigates the impact of free radical generation. In this study, we designed and developed an oxygen-independent alkyl radical nanogenerator (copper monosulfide/2,2'-azabis(2-imidazoline) dihydrochloride@bovine serum albumin; CuS/AIPH@BSA) with spatiotemporally controlled properties and GSH consumption to enhance breast cancer therapy. We encapsulated the alkyl radical initiator, AIPH, in hollow mesoporous CuS nanoparticles with photothermal conversion effect and enveloped them in BSA. AIPH was released and decomposed to generate alkyl radicals in hypoxic breast cancer with the photothermal conversion effect of CuS under near-infrared laser irradiation. CuS consumed high GSH levels in tumor cells because it could form complex with GSH and thereby enhanced free radical treatment. In vivo and in vitro assays demonstrated the anti-tumor efficacy of the rationally designed free-radical nanogenerator in hypoxic microenvironment of breast cancer without showing systemic toxicity.

Neuroinflammation and brain-peripheral interaction in ischemic stroke: A narrative review.

Excessive immune activation within the lesion site can be observed after stroke onset. Such neuroinflammation within the brain parenchyma represents the innate immune response, as well as the result of the additional interactions between peripheral and resident immune cells. Accumulative studies have illustrated that the pathological process of ischemic stroke is associated with resident and peripheral immunity. The infiltration of peripheral immune cells within the brain parenchyma implicitly contributes to secondary brain injuries. Therefore, better understanding of the roles of resident and peripheral immune reactions toward ischemic insult is necessary. In this review, we summarized the interaction between peripheral and resident immunity on systemic immunity and the clinical outcomes after stroke onset and also discussed various potential immunotherapeutic strategies.

Andrographolide Induces Apoptosis in Gastric Cancer Cells through Reactivation of p53 and Inhibition of Mdm-2.

Andrographolide is a labdane diterpenoid isolated from Andrographis paniculata. The plant extract and andrographolide has long been used in traditional medicine practices mainly for gastrointestinal diseases and improving liver function. Andrographolide has shown various pharmacological properties including anti-inflammatory, antioxidant and anticancer activity. This study evaluated the effect of andrographolide on proliferation of human gastric carcinoma cells in relevance to p53 and Mdm-2 pathways. Andrographolide inhibited the proliferation of SGC7901 and AGS cells in a dose-dependent manner with estimated IC50 values 38 and 44 µM respectively. Effect of andrographolide on p53 activity was ascertained by using a p53 activator (RITA) which showed synergistic inhibition of cell proliferation. While andrographolide when used in combination with a p53 inhibitor (pifithrin-α) showed potent restriction over its response. Andrographolide caused decrease in mitochondrial membrane potential as an indicator of apoptotic activity. Andrographolide activated the expression of p53 protein and gene and downregulated the levels of Mdm-2 (negative regulator of p53). Andrographolide inhibited the colony formation abilities in SGC7901 in a p53-dependent manner followed by induction of mitochondrial intrinsic apoptosis through activation of caspases-9 and -3, cleavage of PARP, and inhibition of pro-apoptotic Bcl-2. Andrographolide induced p53 mediated apoptosis in gastric carcinoma cells which adds to a novel approach in anticancer therapies.

Comprehensive analysis of immune-related prognostic genes in the tumour microenvironment of hepatocellular carcinoma.

BACKGROUND: The mortality rate of hepatocellular carcinoma (HCC) remains high worldwide despite surgery and chemotherapy. Immunotherapy is a promising treatment for the rapidly expanding HCC spectrum. Therefore, it is necessary to further explore the immune-related characteristics of the tumour microenvironment (TME), which plays a vital role in tumour initiation and progression. METHODS: In this research, 866 immune-related differentially expressed genes (DEGs) were identified by integrating the DEGs of samples from The Cancer Genome Atlas (TCGA)-HCC dataset and the immune-related genes from databases (InnateDB; ImmPort). Afterwards, 144 candidate prognostic genes were defined through weighted gene co-expression network analysis (WGCNA). RESULTS: Seven immune-related prognostic DEGs were identified using the L1-penalized least absolute shrinkage and selection operator (LASSO) Cox proportional hazards (PH) model, and the ImmuneRiskScore model was constructed on this basis. The prognostic index of the ImmuneRiskScore model was then validated in the relevant dataset. Patients were divided into high- and low-risk groups according to the ImmuneRiskScore. Differences in the immune cell infiltration of patients with different ImmuneRiskScore values were clarified, and the correlation of immune cell infiltration with immunotherapy biomarkers was further explored. CONCLUSION: The ImmuneRiskScore of HCC could be a prognostic marker and can reflect the immune characteristics of the TME. Furthermore, it provides a potential biomarker for predicting the response to immunotherapy in HCC patients.

Protective Effect of D-Carvone against Dextran Sulfate Sodium Induced Ulcerative Colitis in Balb/c Mice and LPS Induced RAW Cells via the Inhibition of COX-2 and TNF-α.

Ulcerative colitis (UC) is an intractable ailment, in which may chronic inflammations/ulcerations may develop in the mucosal lining of the colon with multiple recurrences. Various drugs such as steroids, immunosuppressants, and antibiotics are extensively used to treat UC. The patients suffer from adverse effects of these advanced drugs. So, they need a harmless therapeutic agent from natural sources. The therapeutic D-carvone has an anti-inflammatory action against the investigational colon cancer models. Therefore, we analyzed the effect of D-carvone on dextran sulfate sodium (DSS) provoked colitis model in mice as follows: Group I: noncolitis healthy control mice; Group II: ulcerative colitis mice models; Group III: D-carvone (40 mg/kg) + ulcerative colitis models; Group IV: sulfasalazine (50 mg/kg) + ulcerative colitis models. On the 8th day, the experimental study was terminated and serum samples and colon tissues were processed for further analysis. The effect of D-carvone at different concentration was studied on the LPS challenged RAW 264.7 cell lines. The D-carvone (40 mg/kg) treatment maintained the colon length and decreased disease activity index (DAI) score in UC animals. The increased antioxidant enzymes status and decreased oxidative stress and pro-inflammatory markers were noted in the D-carvone (40 mg/ kg) + UC mice. Histopathological study of colon tissue of D-carvone (40 mg/kg) treated UC mice displayed less mucosal damage and improved crypt integrity and goblet cells compared with DSS only provoked mice. The im-munohistochemical expression of iNOS and COX-2 was drastically diminished in the D-carvone treated UC mice. D-carvone (40 mg/kg) treatment appreciably diminished the LPS provoked NO production and pro-inflammatory modulators in the RAW 264.7 macrophage cell lines. These findings proved that D-carvone has a potential therapeutic effect to prevent LPS induced inflammation in in vitro cells and chemically induced ulcerative colitis in vivo models.

Efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of malignant ascites.

OBJECTIVE: The purpose of this study is to compare the difference of clinical efficacy between conventional intraperitoneal chemotherapy and HIPEC, so as to explore the clinical application value and advantages of HIPEC. DESIGN: A retrospective analysis was conducted on 80 patients with malignant ascites admitted to our hospital from June 2017 to June 2019. The general clinical data and qualitative data of the treatment results of 80 patients with malignant ascites were processed by SPSS19.0 using χ2 test, and quantitative data were processed by t test. P < 0.05, statistical data can be considered statistically significant. RESULTS: 1. There was no significant change in vital signs and temperature in the observation group during the treatment, and the difference was not statistically significant. 2. The short-term total effective rate of patients in the observation group was 91.11%, and the short-term total effective rate of the patients in the control group was 40%. 3. There was no significant difference in the incidence of adverse reactions between the two groups of patients. CONCLUSION: Intraperitoneal hyperthermic chemotherapy combined with intravenous chemotherapy can significantly control malignant ascites and has small adverse reactions, which is worthy of clinical promotion and application.

Kirenol Exhibits the Protective Role against N-Methyl-N-Nitrosourea-Induced Gastric Cancer in Rats via Modulating the Oxidative Stress and Inflammatory Markers.

BACKGROUND: Gastric cancer (GC) may arise in any region of the stomach. Poorly diagnosed GC results in almost one million mortalities annually worldwide. Kirenol is a bioactive compound present in the Sieges beckia sps. OBJECTIVE: In this current, we investigate the anticancer capacity of kirenol against the MNG-stimulated GC in rats via modulating the antioxidants status and inhibition of NF-κB cascade. METHODOLOGY: GC was provoked in the rats via supplementing 100 mg/kg of MNU through the intragastric route for 16 weeks concomitantly with 30 mg/kg of kirenol treatment. The body weight, tumor volume, and incidence of all animals were tabulated every week. The status of gastrin, ALP, LDH, and γ-GT was studied through the ELISA tests. The lipid peroxidation, enzymatic, and nonenzymatic antioxidants were determined via standard procedures. Expression of thioredoxin, glutaredoxin, NF-κB, TNF-α, IL-6, PGE2 was studied through RT-PCR. The gastric mucosa was analyzed microscopically. RESULTS: Kirenol treatment appreciably improved the body weight and diminished the tumor volume and incidences in the MNG-challenged rats. The lipid peroxidation was diminished and the enzymatic and non-enzymatic antioxidants were improved by the kirenol treatment. Kirenol suppressed the status of serum markers of GC and gastrin, ALP, LDH, and γ-GT. The mRNA expression of thioredoxin, glutaredoxin, NF-κB, TNF-α, IL-6, PGE2 was downregulated via the kirenol in the MNG-challenged rats. Histopathological analysis result also confirmed the therapeutic role of kirenol. CONCLUSION: These findings proved that the kirenol appreciably prevented the MNG-triggered GC in rats and it may become a potential drug for the GC treatment in the future.

IFN-ß regulates Th17 differentiation partly through the inhibition of osteopontin in experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) and the corresponding animal model, experimental autoimmune encephalomyelitis (EAE), are chronic neuroinflammatory autoimmune diseases. Increased activation of CD4+T cells, especially the Th1 and Th17 subsets, is thought to play a causal role in this disease. IFN-ß is widely used in the treatment of MS and is found to decrease IL-17 and OPN production in MS patients and EAE mice. However, a definitive molecular mechanism has not yet been fully elucidated. In this study, we investigated the immunomodulatory effect of IFN-ß on the EAE model. We observed disease progression and determined the percentage of Th1/Th17 cells in the peripheral immune organs, brain, and spinal cord of mice. Furthermore, the levels of related cytokines and transcription factors were measured in splenocytes, and the effects of IFN-ß on Th17 differentiation were assessed in vitro. Compared to the control group, IFN-ß treatment significantly reduced the incidence of EAE and the associated pathological damage. Th1 and Th17 cells in IFN-ß-treated mice were significantly reduced, and the levels of cytokines, such as IFN-γ, IL-17, and OPN, were significantly decreased in splenocyte supernatants as well as the levels of corresponding transcription factors. IFN-ß inhibited downstream inflammatory cytokines through the inhibition of PI3K/AKT/NF-κB axis and p38, JNK-MAPK, as well as the regulation of mTOR complexes. Moreover, IFN-ß inhibited Th17 differentiation and neutralizing OPN antibodies offset the inhibitory effect of IFN-ß on Th17 cells. Meanwhile, IFN-ß influenced the acetylation of the Il17a and Opn gene promoters. The findings described herein provide novel evidence for the role of IFN-ß in Th17 differentiation partly through the inhibition of OPN.

NOVA1 acts as an oncogene in osteosarcoma.

Osteosarcoma is one of the most common bone tumors in young patients. NOVA1 (neuro-oncological ventral antigen 1) is a neuron-specific RNA binding-protein and belongs to the Nova family. Previous studies showed that NOVA1 played crucial roles in the development of several tumors. The objective of our study was to study the role of NOVA1 in the osteosarcoma. In our study, we showed that NOVA1 expression was upregulated in osteosarcoma cell lines and tissues. The expression of NOVA1 was upregulated in 22 (22/30; 73%) osteosarcoma cases compared to that in the adjacent tissues. Overexpression of NOVA1 promoted osteosarcoma cell viability, colony formation and invasion. Furthermore, knockdown of NOVA1 suppressed osteosarcoma cell viability, colony formation and invasion. These data suggested that NOVA1 acted as an oncogene in the development of osteosarcoma.

Therapeutic effect of ergotope peptides on CIA by down-regulation of inflammatory and Th1/Th17 responses and induction of regulatory T cells.

Rheumatoid arthritis (RA) is a systemic autoimmune disease that results in a chronic and inflammatory disorder. Dynamic balance of helper T cells (Th)1, Th17 and regulatory T cells (Treg) is broken in RA. Since there is no cure for RA at present, it's necessary to find a truly effective and convenient treatment. Several studies intended to induce ergotopic regulation to treat autoimmune diseases. This study was undertaken to find the potential ergotope peptides and investigate its effect in treating the animal model of RA and their underlying regulatory mechanisms. Firstly, we selected the functional ergotope peptides from 25 overlapping peptides derived from interlukin(IL)-2 receptor (IL-2R) α chain, and then used these peptides to treat collagen-induced arthritis (CIA). The study showed ergotope peptides as immunomodulatory factors with great benefits at the clinical and pathologic levels. This effect was associated with the inhibition of type II collagen (CII)-specific proliferation and autoantibody production as well as the induction of anti-ergotypic immune response, the down-regulation of both Th1 and Th17 cells and their related components, and the emergence of Treg cells that had suppressive actions on autoreactive T cells. We also proved that cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and IL-10 are two important mediators which are critical to Treg suppressive function. The inhibition of Th1 and Th17 in established CIA could be attributed to ergotope induced Treg cells. Our findings reveal that ergotope peptides induce regulatory immune responses and restore immune tolerance, suggesting ergotope peptides treatment appears to be a novel approach to the therapy of RA patients and has a good application prospect with cheap, effective, convenient, wide-spectrum features.

Eriodictyol attenuates cisplatin-induced kidney injury by inhibiting oxidative stress and inflammation.

Eriodictyol, a flavonoid present in citrus fruits, has been reported to have antioxidant and anti-inflammatory effects. In this study, the protective effects of eriodictyol on cisplatin (CP)-induced kidney injury were detected. CP-induced kidney injury model was established by administration of CP (20mg/kg). The results showed that treatment of eriodictyol inhibited the production of blood urea nitrogen (BUN), creatinine, MDA, TBARS, reactive oxygen species (ROS), as well as the production of TNF-α, and IL-1ß in kidney tissues induced by CP. Eriodictyol also up-regulated the activities of SOD, CAT, and GSH-PX decreased by CP. Furthermore, eriodictyol was found to up-regulate the expression of Nrf2/HO-1 and inhibited CP-induced NF-κB activation in kidney tissues. In conclusion, eriodictyol protected against CP-induced kidney injury through activating Nrf2 and inhibiting NF-κB activation.

Berberine ameliorates TNBS induced colitis by inhibiting inflammatory responses and Th1/Th17 differentiation.

Th1 and Th17 cells, and their associated cytokines, have been associated with the pathogenesis of Crohn's disease. Berberine (BBR), a compound long used in traditional Chinese medicines, has been reported to have therapeutic effects in treating experimental colitis. In this study, we show that BBR had a protective effect on mice with TNBS-induced colitis. BBR inhibited levels of IFN-γ, IL-17, IL-6, IL-1ß and TNF-α both in the local colon and sera, and transiently increased levels of IL-22. BBR also markedly increased sIgA expression in the colon. BBR had pronounced effects on macrophage populations. Treatment with BBR adjusted the M2/M1 ratio. In addition, BBR exerted effects on adaptive immunity by suppressing numbers of Th1 and Th17 cells, as well as expression levels of their associated cytokines and transcriptional factors. BBR downregulated STAT3 and STAT1 phosphorylation, and inhibited phosphorylation of NF-kB. In vitro experiments showed that BBR inhibited the differentiation of Th17 and, to a lesser degree, Th1 cells, without affecting regulatory T cells. Therefore, we conclude that BBR plays a regulatory role in modulating the balance of immune responses in TNBS-induced colitis. Our study will help us understand the regulatory mechanisms exerted by BBR in the treatment of IBD.

IFN-ß inhibits T cells accumulation in the central nervous system by reducing the expression and activity of chemokines in experimental autoimmune encephalomyelitis.

Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are chronic neuroinflammatory autoimmune diseases characterized by axonal loss, demyelination and neurodegeneration of the central nervous system (CNS). Overactivation of CD4(+)T cells, especially the Th1 and Th17 subsets, is thought to play a causal role in this disease. In this study, we investigated the immunomodulatory effects of IFN-ß treatment in EAE. IFN-ß significantly inhibits disease severity, and decreases levels of CCR2, CCR4, CCR5, CCR6 and CXCR3 in the CNS. This was associated with fewer Th1/Th17 cells expressing these chemokine receptors. Furthermore, levels of their corresponding ligands CCL2, CCL3, CCL4, CCL5, CCL20, CCL22 and CXCL10 were also reduced, coinciding with reduced CNS inflammation and demyelination. Chemokine expression significantly correlated with disease severity. Furthermore, we demonstrate that IFN-ß reduces CCL2/CCL5 induced-T cell migration by inhibiting p38-MAPK and ERK1/2 activation. Our results reveal that IFN-ß reduces the expression of chemokines and chemokine receptors expressed by encephalitogenic Th1/Th17 cells, thereby decreasing their migration into the CNS.

T cell vaccination inhibits Th1/Th17/Tfh frequencies and production of autoantibodies in collagen-induced arthritis.

The aim of this study is to determine whether the regulatory role of T cell vaccination (TCV) is through inhibition of Th1/Th17/Tfh and production of autoantibodies on collagen-induced arthritis (CIA). First, CIA mice were treated with TCV. After disease onset, the incidence and severity of change in joint histopathology were evaluated. Mice in the TCV-treated group showed less disease severity and less infiltration of inflammatory cells in the joint sections. TCV decreased the frequencies of Th1/Th17/Tfh cells and related cytokines. Reduction of IL-21 may be associated with both Tfh and Th17, which further influence B cell and T cell responses. In addition, inhibition of Th1/Th17/Tfh frequencies led to the reduced expression of T-bet, ROR α , ROR γ t, and Bcl6. Lastly, the proliferation of type-II-collagen-(CII-) specific T cells and the production of anti-CII antibodies were inhibited in the TCV-treated group. The results provide novel evidence that the therapeutic effects of TCV on CIA are associated with the inhibition of Th1/Th17/Tfh frequencies and autoantibodies production.