Effect of lithium on chemotherapy-induced neutropenia in Egyptian breast cancer patients; a prospective clinical study.

PURPOSE: Myelosuppressive chemotherapy-induced neutropenia (CIN) remains a major limitation of cancer treatment efficacy, necessitating very expensive supportive care. Lithium carbonate, an inexpensive drug, can increase the number of neutrophils, possibly providing an efficacious and cost-effective alternative for treating CIN. The aim of this study was to determine whether lithium therapy can attenuate chemotherapy-induced neutropenia and leukopenia in breast cancer patients. METHODS: A total of 50 breast cancer patients were enrolled in this prospective, interventional, randomized, controlled, and single-blind study. The patients were divided into two groups: a control group (group 1, N = 25 patients) and a lithium-treated (treatment) group (group 2, N = 25 patients). Group 1 patients were further subclassified into a non-neutropenic control group (N = 16) and a neutropenic control (N = 9) based on the subsequent development of severe neutropenia, or not. The control group received 4 cycles of doxorubicin or epirubicin plus cyclophosphamide followed by 2 cycles of paclitaxel. The treatment group received the same regimen as the control group as well as oral lithium carbonate throughout the chemotherapy cycles. RESULTS: The results showed that the absolute neutrophil count (ANC) was increased in the lithium-treated group, while it was markedly reduced in both the non-neutropenic and neutropenic control groups (by 55.56% and 65.42% post-4 chemotherapy cycles, and by 19.57% and 39.90% post-6 cycles, respectively). The same pattern of alterations was observed for the total white blood cell count in both the control and treatment groups. In addition, the incidence and period prevalence were greatly reduced in the lithium-treated group compared to non-neutropenic and neutropenic control groups. CONCLUSION: Lithium therapy ameliorated chemotherapy-induced leukopenia and neutropenia in breast cancer patients. This may provide a new strategy for cost-effective treatment of CIN, particularly in Egyptian cancer patients.

Association between genetic polymorphism, severity, and treatment response among COVID-19 infected Egyptian patients.

Background: The world has been suffering from the Coronavirus Disease-2019 (COVID-19) pandemic since the end of 2019. The COVID-19-infected patients differ in the severity of the infection and the treatment response. Several studies have been conducted to explore the factors that affect the severity of COVID-19 infection. One of these factors is the polymorphism of the angiotensin converting enzyme 2 (ACE-2) and the type 2 transmembrane serine protease (TMPRSS2) genes since these two proteins have a role in the entry of the virus into the cell. Also, the ACE-1 regulates the ACE-2 expression, so it is speculated to influence the COVID-19 severity. Objective: This study investigates the relationship between the ACE-1, ACE-2, and TMPRSS2 genes single nucleotide polymorphism (SNPs) and the COVID-19 disease severity, treatment response, need for hospitalization, and ICU admission in Egyptian patients. Patients and Methods: The current study is an observational prospective, cohort study, in which 109 total COVID-19 patients and 20 healthy volunteers were enrolled. Of those 109 patients, 51 patients were infected with the non-severe disease and were treated in an outpatient setting, and 58 suffered from severe disease and required hospitalization and were admitted to the ICU. All 109 COVID-19 patients received the treatment according to the Egyptian treatment protocol. Results: Genotypes and allele frequencies among severe and non-severe patients were determined for ACE-1 rs4343, TMPRSS2 rs12329760, and ACE-2 rs908004. The GG genotype and the wild allele of the ACE-2 rs908004 and the mutant allele of the ACE-1 rs4343 were significantly more predominant in severe patients. In contrast, no significant association existed between the TMPRSS2 rs12329760 genotypes or alleles and the disease severity. Conclusion: The results of this study show that the ACE-1 and ACE-2 SNPs can be used as severity predictors for COVID-19 infection since also they have an effect on length of hospitalization.

Crosstalk among apoptosis, inflammation, and autophagy in relation to melatonin protective effect against contrast-induced nephropathy in rats.

Contrast medium (CM) is a chemical substance that is used for imaging anatomical boundaries and to explore normal and abnormal physiological findings; the use of CM was associated with kidney injury and acute renal failure. Melatonin (M) possesses antioxidant, anti-inflammatory, and antiapoptotic effects in addition to autophagy modulation. This study aimed to investigate the protective effect of M against contrast-induced nephropathy (CIN) and its impact on the crosstalk between inflammasome, apoptosis, and autophagy in CIN. Male albino rats received M (10, 20, and 40 mg/kg/day, intraperitoneally) for 3 days. One hour after the last administration, rats were subjected to CIN induction (10 mg/kg indomethacin, double doses of l-NAME 10 mg/kg, i.v., and meglumine diatrizoate 60% 6 mL/kg, i.v.). CIN-induced kidney damage was evidenced through elevated kidney function biomarkers and induced renal histopathological changes. Pretreatment with M caused a significant decrease in nephrotoxicity biomarkers and histopathological alterations. Moreover, CIN-induced oxidative stress, NLRP3 inflammasome, and apoptosis were attenuated by M. Furthermore, M modulates autophagy in CIN rats. M inhibits CIN-induced NLRP3-inflammasome activation and apoptosis as well as enhances autophagy.

Role of cytoglobin in cigarette smoke constituent-induced loss of nitric oxide bioavailability in vascular smooth muscle cells.

Cytoglobin (Cygb) has been identified as the major nitric oxide (NO) metabolizing protein in vascular smooth muscle cells (VSMCs) and is crucial for the regulation of vascular tone. In the presence of its requisite cytochrome B5a (B5)/B5 reductase-isoform-3 (B5R) reducing system, Cygb controls NO metabolism through the oxygen-dependent process of NO dioxygenation. Tobacco cigarette smoking (TCS) induces vascular dysfunction; however, the role of Cygb in the pathophysiology of TCS-induced cardiovascular disease has not been previously investigated. While TCS impairs NO biosynthesis, its effect on NO metabolism remains unclear. Therefore, we performed studies in aortic VSMCs with tobacco smoke extract (TSE) exposure to investigate the effects of cigarette smoke constituents on the rates of NO decay, with focus on the alterations that occur in the process of Cygb-mediated NO metabolism. TSE greatly enhanced the rates of NO metabolism by VSMCs. An initial increase in superoxide-mediated NO degradation was seen at 4 h of exposure. This was followed by much larger progressive increases at 24 and 48 h, accompanied by parallel increases in the expression of Cygb and B5/B5R. siRNA-mediated Cygb knockdown greatly decreased these TSE-induced elevations in NO decay rates. Therefore, upregulation of the levels of Cygb and its reducing system accounted for the large increase in NO metabolism rate seen after 24 h of TSE exposure. Thus, increased Cygb-mediated NO degradation would contribute to TCS-induced vascular dysfunction and partial inhibition of Cygb expression or its NO dioxygenase function could be a promising therapeutic target to prevent secondary cardiovascular disease.

PEG-SOD attenuates the mitogenic ERK1/2 signaling cascade induced by cyclosporin A in the liver and kidney of albino mice.

The calcineurin inhibitor, cyclosporin A (CsA) is one of the most common immunosuppressive agents used in organ transplantation. However, its clinical use is often limited by several unwanted effects including nephrotoxicity and hepatotoxicity. By using immunohistochemical and ELISA techniques, it was found that CsA administration causes a rapid activation of a disintegrin and metalloproteases-17 (ADAM-17), epidermal growth factor receptor (EGFR) and subsequent ERK1/2 phosphorylation in the liver and kidney of albino mice. Furthermore, this study presents mechanistic relevance of this signaling cascade involving reactive oxygen species (ROS)-mediated ADAM-17/EGFR/ERK1/2 activation as indicated by a clear reduction in ADAM-17 and EGFR activities as well as ERK1/2 phosphorylation when the animals pretreated with Polyethylene glycol-superoxide dismutase (PEG-SOD) before CsA administration. Collectively, our findings demonstrate that CsA has the ability to activate ADAM-17-mediated EGFR/ERK1/2 phosphorylation in the liver and kidney of albino mice in ROS-dependent manner. Finally, these data may support the concept of using antioxidant therapy as a valuable approach for the prevention of CsA-induced nephrotoxicity and hepatotoxicity.

Contrast media (meglumine diatrizoate) aggravates renal inflammation, oxidative DNA damage and apoptosis in diabetic rats which is restored by sulforaphane through Nrf2/HO-1 reactivation.

Diabetes mellitus is an independent risk factor for renal impairment in patients exposed to contrast media. It doubles the risk and decreases survival rate of contrast induced nephropathy (CIN). Sulforaphane has antioxidant properties via Nrf2 activation. The interaction of diabetes and/or sulforaphane with contrast media on Nrf2 regulation is not yet understood. Herein, diabetes was induced by a single intra-peritoneal injection of streptozotocin. Animals were then divided into five groups; control non-diabetic group; diabetic group; diabetic/sulforaphane group; diabetic/CIN group; diabetic/CIN/sulforaphane group. Animals were assessed 24 h after CIN induction. Sulforaphane improved the impaired nephrotoxicity parameters, histopathological features, and oxidative stress markers induced by contrast media (meglumine diatrizoate) in diabetic rats. Immunofluorescence detection revealed increased Nrf2 expression in kidney sections after sulforaphane pretreatment. Moreover, gene expression of Nrf2 and HO-1 were up-regulated, while IL-6 and caspase3 were down-regulated in kidney tissues of animals pretreated with sulforaphane. In NRK-52E cells, sulforaphane pretreatment significantly ameliorated the cytotoxicity of meglumine diatrizoate. However, silencing Nrf2 using small interfering RNA (siRNA) abolished the cytoprotective effects of sulforaphane. Collectively, the results of this study suggest that Nrf2/HO-1 pathway has a protective role against CIN and support the clinical implication of Nrf2 activators, such as sulforaphane, in CIN particularly in diabetic patients.

Lansoprazole halts contrast induced nephropathy through activation of Nrf2 pathway in rats.

Contrast-induced nephropathy (CIN) is an important cause of acute kidney injury characterized by significant mortality and morbidity. To date, there is no successful protective regimen for CIN especially in poor kidney function patients. Lansoprazole has been shown to exert antioxidant action through induction of nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway. The aim of the present study is to investigate the potential of lansoprazole to activate Nrf2 pathway in the kidney and consequently to protect against oxidative stress induced by iodinated contrast media. Lansoprazole, at a dose of 100 mg/kg, showed a significant induction of Nrf2 mRNA after 3 h. Administration of contrast media induced significant increase in serum creatinine and blood urea nitrogen, histological deterioration, and reduction in total antioxidant capacity. Moreover, it instigated the defensive Nrf2 gene expression and immunoreactivity. In addition, there were overexpression of HO-1, caspase 3, p53 and IL6 genes and downregulation of Bcl2 gene. Pre-treatment with lansoprazole (100 mg/kg) ameliorated the nephrotoxicity parameters and oxidative stress, improved histological lesions, and hijacked apoptotic and inflammatory markers that were provoked by contrast media. In conclusion, lansoprazole attenuates experimental CIN which might be due to activation of Nrf2 antioxidant defence pathway. These findings highlight the potential benefit of incorporating lansoprazole in the protective regimen against CIN especially for susceptible patients.

Imbalance between the anti- and pro-inflammatory milieu in blood leukocytes of autistic children.

Accumulating evidence suggests an association between immune dysfunction and autism disorders in a significant subset of children. In addition, an imbalance between pro- and anti-inflammatory pathways has been proposed to play an important role in the pathogenesis of several neurodevelopmental disorders including autism; however, the role of anti-inflammatory molecules IL-27 and CTLA-4 and pro-inflammatory cytokines IL-21 and IL-22 has not previously been explored in autistic children. In the current study, we investigated the expression of IL-21, IL-22, IL-27, and CD152 (CTLA-4) following an in-vitro immunological challenge of peripheral blood mononuclear cells (PBMCs) from children with autism (AU) or typically-developing children (TD) with phorbol-12-myristate 13-acetate (PMA) and ionomycin. In our study, cells from children with AU had increased IL-21 and IL-22 and decreased CTLA-4 expression on CD4+ T cells as compared with cells from the TD control. Similarly, AU cells showed decreased IL-27 production by CD14+ cells compared to that of TD control cells. These results were confirmed by real-time PCR and western blot analyses. Our study shows dysregulation of the immune balance in cells from autistic children as depicted by enhanced pro-inflammatory cytokines, 'IL-21/IL-22' and decreased anti-inflammatory molecules, 'IL-27/CTLA-4'. Thus, further study of this immune imbalance in autistic children is warranted in order to facilitate development of biomarkers and therapeutics.

IQGAP1 gene silencing induces apoptosis and decreases the invasive capacity of human hepatocellular carcinoma cells.

IQ motif-containing GTPase-activating proteins (IQGAPs) belong to a conserved family, and they are involved in various intracellular processes. IQGAP1 is expressed in all cells, while IQGAP2 and IQGAP3 are mainly expressed in hepatic cells. IQGAP1 has been suggested to be an oncogene, while IQGAP2 is considered a tumor-suppressor gene. However, the relationship between RAS family genes and IQGAP genes remains unclear. We recently demonstrated this interaction in a chemically induced mouse liver cancer. In this study, IQGAP1 expression was partially silenced in human hepatocellular carcinoma (HepG2) cells. We investigated the impact of IQGAP1 silencing on the interactions of IQGAP and RAS with several apoptotic proteins, including caspase-3 (CASP3), BCL2-associated X protein (BAX), and B-cell leukemia/lymphoma 2 (BCL2). Additionally, we investigated the effects of the interactions of these genes on cell viability, proliferation, apoptosis, and invasive capacity. IQGAP1 siRNA-treated HepG2 cells showed lower invasive capacity than the control cells, and this reduction was time- and vector concentration-dependent. In addition, IQGAP1 silencing resulted in significantly lower IQGAP1 level and subsequently higher IQGAP2 and IQGAP3 expression in HepG2 cells than in the control. Flow cytometry analyses indicated that the silencing of IQGAP1 can induce early and late apoptosis in HepG2 cells. Additionally, IQGAP2, IQGAP3, CASP3, and BAX were upregulated whereas IQGAP1 and BCL2 were downregulated in the siRNA-treated cells. Furthermore, we observed that the mRNA levels of HRAS, KRAS, NRAS, and MRAS decreased upon IQGAP1 silencing. These findings indicate that IQGAP1 potentially regulates the expression of IQGAP and RAS gene families and demonstrate its regulatory role in the apoptotic network. Taken together, our findings suggest that IQGAP1 silencing plays crucial roles in the apoptosis of HepG2 cells and lowers their proliferative and invasive capacities.

Thymoquinone inhibits growth of human medulloblastoma cells by inducing oxidative stress and caspase-dependent apoptosis while suppressing NF-κB signaling and IL-8 expression.

Medulloblastoma (MB) is the most common malignant brain tumor of childhood. The transcription factor NF-κB is overexpressed in human MB and is a critical factor for MB tumor growth. NF-κB is known to regulate the expression of interleukin-8 (IL-8), the chemokine that enhances cancer cell growth and resistance to chemotherapy. We have recently shown that thymoquinone (TQ) suppresses growth of hepatocellular carcinoma cells in part by inhibiting NF-κB signaling. Here we sought to extend these studies in MB cells and show that TQ suppresses growth of MB cells in a dose- and time-dependent manner, causes G2M cell cycle arrest, and induces apoptosis. TQ significantly increased generation of reactive oxygen species (ROS), while pretreatment of MB cells with the ROS scavenger N-acetylcysteine (NAC) abrogated TQ-induced cell death and apoptosis, suggesting that TQ-induced cell death and apoptosis are oxidative stress-mediated. TQ inhibitory effects were associated with inhibition of NF-κB and altered expression of its downstream effectors IL-8 and its receptors, the anti-apoptotic Bcl-2, Bcl-xL, X-IAP, and FLIP, as well as the pro-apoptotic TRAIL-R1, caspase-8, caspase-9, Bcl-xS, and cytochrome c. TQ-triggered apoptosis was substantiated by up-regulation of the executioner caspase-3 and caspase-7, as well as cleavage of the death substrate poly(ADP-ribose)polymerase. Interestingly, pretreatment of MB cells with NAC or the pan-caspase inhibitor zVAD-fmk abrogated TQ-induced apoptosis, loss of cyclin B1 and NF-κB activity, suggesting that these TQ-mediated effects are oxidative stress- and caspase-dependent. These findings reveal that TQ induces both extrinsic and intrinsic pathways of apoptosis in MB cells, and suggest its potential usefulness in the treatment of MB.

Gene expression of IQGAPs and Ras families in an experimental mouse model for hepatocellular carcinoma: a mechanistic study of cancer progression.

IQGAPs genes play critical role in either induction or suppression of cancer and its progression, however the relationship between Ras genes and these genes are still unclear. In this study, we tried to understand the mechanistic action of IQGAPs genes and its correlation with Ras genes in mouse hepatic cancer model. The genetic expressions of IQGAP1, IQGAP2, IQGAP3, Hras, Kras, Nras, Mras, Caspase3, and BAX were followed in both hepatocellular carcinoma and normal liver cells of Balbc mice. Genotoxic agent diethylnitrosamine (DEN)-induced hepatic cancer model was induced in male mice and recorded the occurrence of hepatocellular carcinoma by morphological and histological changes in the liver. It was observed that mRNA expressions of IQGAP1, Hras, Kras, Nras, Mras, Caspase3, and BAX genes were highly elevated in hepatocellular carcinoma cells when compared with normal liver cells, additionally their expressions increased by concentrating the dose of DEN. While, the expressions of IQGAP2 and IQGAP3 were significantly decreased in hepatocellular carcinoma cells when compared with normal liver cells, as well as their expressions decreased more with increasing the dose of DEN. It was concluded from this study that IQGAP1 has a strong signaling relationship with Ras genes in induction of cancer and it is considered as a key gene for induction or suppression of the hepatocellular carcinoma.

Naringin attenuates the development of carrageenan-induced acute lung inflammation through inhibition of NF-κb, STAT3 and pro-inflammatory mediators and enhancement of IκBα and anti-inflammatory cytokines.

Naringin has been reported to possess diverse pharmacological properties, including anti-arthritic and anti-inflammatory activities. The aim of the present study was to determine the potential anti-inflammatory effect of naringin in a mouse model of carrageenan-induced pleurisy. A single dose of naringin (40 and 80 mg/kg) was administered per oral (p.o.) 1 h before carrageenan (Cg) administration. Pro- and anti-inflammatory cytokines were analysed in pleural fluid. We also assessed the effects of naringin on the expression levels of iNOS, inducible cyclooxygenase isoform (COX-2), ICAM-1, MIP-2, PGE2, STAT3, TGF-ß1, nuclear factor kappa B (NF-κB) and inhibitor of kappa B (IκBα) in lung tissue. The histological examinations revealed anti-inflammatory effect of naringin while Cg group deteriorated. Naringin downregulated Th1 and upregulated Th2 cytokines. Western blot analyses revealed increased protein expression of NF-κB, STAT3 and COX-2 and decreased IκBα in response to Cg treatment, which were reversed by the treatment with naringin. In the Cg group, mRNA expression levels of pro-inflammatory mediators upregulated and anti-inflammatory mediators downregulated. Naringin reversed these actions.

Amelioration of autoimmune arthritis by naringin through modulation of T regulatory cells and Th1/Th2 cytokines.

Naringin, a well-known flavanone glycoside found in grapefruit and other citrus fruits, was determined to be an effective anti-inflammatory compound. We investigated the effect of naringin on the key mediators of arthritic inflammation, namely T cell subsets, CD4(+)GITR(+) expressing cells, CD4(+)CD25(+)Foxp3(+) (Treg), Th1/Th2 cytokines and inflammatory mediators. We treated Balb/c mice (p.o.) with naringin (20, 40 and 80 mg/kg) for 14 days. Compared with the vehicle-treated and arthritic-control mice, the naringin treatment demonstrated a considerable decrease in the level of T cells, CD4(+)GITR(+), Th1 cytokine and inflammatory mediator expressions. In contrast, naringin treatment resulted in significantly up-regulated Treg and Th2 cytokine levels. Therefore, the naringin-induced inhibition of the T cells, various pro-inflammatory cytokines and inflammatory mediators that facilitate cellular infiltration into the joints might have contributed to its anti-arthritic activity. Our data suggest that naringin diminished the AIA in mice and it could be a potential alternative/adjunct treatment for RA.

Role of a histamine 4 receptor as an anti-inflammatory target in carrageenan-induced pleurisy in mice.

The histamine 4 receptor (H4R) is expressed primarily on cells involved in inflammation and immune responses. Despite much research into inflammatory diseases, no drugs with favourable safety profiles are yet available for their treatment. The aim of the present study was to determine the potential anti-inflammatory effect of 4-methylhistamine (4-MeH) or JNJ77777120 (JNJ) and to explore the role of H4R in a mouse model of carrageenan (Cg) -induced pleurisy. A single dose of 4-MeH or JNJ (30 mg/kg) was administered intraperitoneally 1 hr before Cg administration. The results illustrate that both the numbers of CD4(+) , CD25(+) , CD4(+)  CD25(+) , GITR(+) , GITR(+)  IL-17A(+) -expressing T cells and the levels of T helper type 1 (Th1)/Th17 cytokines were markedly increased in both the Cg-treated and 4-MeH-treated groups, whereas the cytokines produced by Th2 cells were significantly decreased in the same groups. However, JNJ treatment significantly decreased both the number of T-cell subsets and GITR(+) , GITR(+)  IL-17A(+) -expressing T cells, and the production of Th1/Th17 cytokines. Further, JNJ up-regulated the expression of the Th2 cytokines. RT-PCR analysis revealed an increased expression of interleukin-1ß, tumour necrosis factor-α, monocyte chemoattractant protein-1 and intercellular adhesion molecule-1 in the Cg-treated and 4-MeH-treated groups, which was reduced by treatment with JNJ in lung tissues. Moreover, histological examinations revealed anti-inflammatory effects of JNJ, whereas 4-MeH worsened Cg-induced inflammation. In conclusion, the results of the present work clearly indicate that JNJ possesses important anti-inflammatory properties that are increased in 4-MeH-treated mice, suggesting that H4R are involved in pleurisy and that JNJ has an anti-inflammatory effect in associated disease conditions.

Anti-inflammatory effect of Euphorbia hirta in an adjuvant-induced arthritic murine model.

Despite extensive research into inflammatory diseases to date, no drugs with favourable safety profiles are available for treatment. Euphorbia hirta (E. hirta) is a tree that is locally used as a traditional medicine in Africa and Australia to treat numerous diseases such as hypertension, antipyretic and anti-inflammatory activities. The aim of the present study was to determine the potential anti-arthritic effects of E. hirta in mouse models of adjuvant induced arthritis (AIA). We treated BALB/c mice with (p.o.) E. hirta (25, 50, 100, and 200 mg/kg) daily (13 days) beginning at the onset of AIA. We examined the effect of E. hirta on key mediators of arthritic-inflammation, including pro-inflammatory (IL-2, IFN-γ, and TNF-α) and anti-inflammatory (IL-4 and IL-5) cytokines, T-cell activation markers (CD25/CD69), and co-stimulatory molecules (CD80/CD86). We also examined the inflammatory mediators (PGE2 and LTB4) response. E. hirta-treated mice showed a substantial reduction in the levels of pro-inflammatory cytokines, down regulated cell activation markers and co-stimulatory molecules, and up regulated anti-inflammatory cytokines. E. hirta decreased the levels of inflammatory-mediators in AIA animals. Supplementation with an E. hirta extract may be a promising treatment for arthritic and inflammatory diseases.

Thymoquinone suppression of the human hepatocellular carcinoma cell growth involves inhibition of IL-8 expression, elevated levels of TRAIL receptors, oxidative stress and apoptosis.

Hepatocellular carcinoma (HCC) is the fourth most common solid tumor worldwide. The chemokine interleukin-8 (IL-8) is overexpressed in HCC and is a potential target for therapy. Although the transcription factor NF-κB regulates IL-8 expression, and while thymoquinone (TQ; the most bioactive constituent of black seed oil) inhibits NF-κB activity, the precise mechanisms by which TQ regulates IL-8 and cancer cell growth remain to be clarified. Here, we report that TQ inhibited growth of HCC cells in a dose- and time-dependent manner, caused G2M cell cycle arrest, and stimulated apoptosis. Apoptosis was substantiated by activation of caspase-3 and -9, as well as cleavage of poly(ADP-ribose)polymerase. TQ treatments inhibited expression of NF-κB and suppressed IL-8 and its receptors. TQ treatments caused increased levels of reactive oxygen species (ROS) and mRNAs of oxidative stress-related genes, NQO1 and HO-1. Pretreatment of HepG2 cells with N-acetylcysteine, a scavenger of ROS, prevented TQ-induced cell death. TQ treatment stimulated mRNA expression of pro-apoptotic Bcl-xS and TRAIL death receptors, and inhibited expression of the anti-apoptotic gene Bcl-2. TQ enhanced TRAIL-induced death of HepG2 cells, in part by up-regulating TRAIL death receptors, inhibiting NF-κB and IL-8 and stimulating apoptosis. Altogether, these findings provide insights into the pleiotropic molecular mechanisms of TQ-dependent suppression of HCC cell growth and underscore potential of this compound as anti-HCC drug.

Involvement of histamine 4 receptor in the pathogenesis and progression of rheumatoid arthritis.

Rheumatoid arthritis (RA) is one of the major autoimmune diseases with a global prevalence. Despite significant research into this disease, no drugs with acceptable safety profiles are yet available for its treatment. We investigated the possible anti-arthritic effects of the 4-methylhistamine (4-MeH) histamine 4 receptor (H4R) agonist and the JNJ77777120 (JNJ) H4R antagonist to explore the role of H4R in a mouse model of collagen antibody-induced arthritis (CAIA). Arthritis was induced via intravenous (tail vein) injection of Balb/c mice with a 5-clone cocktail of mAbs against collagen type II, followed by LPS, and the effects of treatment with 4-MeH or JNJ (30 mg kg(-1), i.p, twice daily) for 7 days (prophylactic or therapeutic regimens) were assessed. The results revealed increased paw edema, arthritic scores, joint histological inflammatory damage and matrix metalloproteinase-3 levels and high levels of Th1 pro-inflammatory cytokine mRNA and serum proteins in CAIA mice or following H4R activation via 4-MeH. Additionally, 4-MeH efficiently increased expression levels of NF-κB p65. JNJ-treated mice showed a substantial reduction in all the previously mentioned effects, with a similar trend being observed under prophylactic and therapeutic treatment regimens. The results of the present work indicate that JNJ exhibits significant anti-inflammatory and anti-arthritic activities, demonstrating the clear involvement of H4R antagonism in the pathogenesis and progression of RA.

Grape seed proanthocyanidin extract protects against carrageenan-induced lung inflammation in mice through reduction of pro-inflammatory markers and chemokine expressions.

Proanthocyanidins are the most abundant phenolic compounds and have been reported to exert anti-inflammatory actions. The aim of this study was to investigate the effects of grape seed proanthocyanidin extract (GSPE) in a mouse model of carrageenan-induced pleurisy. Following the induction of pleurisy using λ-carrageenan (Cg, 1 %), GSPE (25, 50 and 100 mg/kg) was administered per-oral (p.o.), and the glucocorticoid-induced tumour necrosis factor receptor (GITR), IL-17A expressing cells and other markers, such as cytokines (Th1/Th2 and Th17), were studied. We evaluate the effects of GSPE on the mRNA expression of pro-inflammatory and anti-inflammatory mediators. The results illustrated that the cell numbers of IL-17A and GITR expressing cells and the cytokine levels in Th1/Th17 cells were markedly increased in the Cg-group, whereas the cytokines produced by Th2 cells were significantly decreased in the same group. Treatment with GSPE reversed these effects. Histological examinations revealed anti-inflammatory effects of GSPE.

CARP-1 functional mimetics: a novel class of small molecule inhibitors of medulloblastoma cell growth.

Medulloblastomas (MBs) constitute an aggressive class of intracranial pediatric tumors. Current multimodality treatments for MBs include surgery, ionizing radiation, and chemotherapy. Toxic side effects of therapies coupled with high incidence of recurrence and the metastatic spread warrant development of more effective, less toxic therapies for this disease. CARP-1/CCAR1 is a peri-nuclear phospho-protein that is a co-activator of the cell cycle regulatory anaphase promoting complex/cyclosome (APC/C) E3 ligase. CARP-1 functional mimetics (CFMs) are a novel class of small molecule compounds that interfere with CARP-1 binding with APC/C subunit APC-2, and suppress growth of a variety of cancer cells in part by promoting apoptosis. Here we investigated MB growth inhibitory potential of the CFMs and found that CFM-4 inhibits growth of MB cells in part by inducing CARP-1 expression, promoting PARP cleavage, activating pro-apoptotic stress-activated protein kinases (SAPK) p38 and JNK, and apoptosis. Gene-array-based analysis of the CFM-4-treated Daoy MB cells indicated down-regulation of a number of key cell growth and metastasis-promoting genes including cell motility regulating small GTP binding protein p21Rac1, and extracellular matrix metallopeptidase (MMP)-10. Moreover, CFM-4 treatment stimulated expression of a number of molecules such as neurotrophin (NTF)3, and NF-κB signaling inhibitors ABIN1 and 2 proteins. Overexpression of NTF3 resulted in reduced MB cell viability while knock-down of NTF3 interfered with CFM-4-dependent loss of viability. CFMs also attenuated biological properties of the MB cells by blocking their abilities to migrate, form colonies in suspension, and invade through the matrix-coated membranes. Together our data support anti-MB properties of CFM-4, and provide a proof-of-concept basis for further development of CFMs as potential anti-cancer agents for MBs.

Effect of long-term human exposure to environmental heavy metals on the expression of detoxification and DNA repair genes.

The present study was designed to evaluate the influence of long-term environmental human exposure to three heavy metals, lead (Pb), cadmium (Cd), and mercury (Hg), on the expression of detoxifying, xenobiotic metabolizing, and DNA repair genes in Mahd Ad-Dahab city. The study groups consisted of 40 healthy male residents (heavy metal-exposed) and 20 healthy male from Riyadh city, 700 km away, and served as control group. The heavy metal-exposed group with high exposure to Pb, Cd, or Hg was divided into three subgroups Pb-, Cd-, and Hg-exposed groups, respectively. The mRNA expression levels of detoxifying, NQO1, HO-1, GSTA1, MT-1, and HSP70, were significantly decreased in all heavy metal-exposed group as compared to control group. This was accompanied with a proportional decrease in the expression of xenobiotic metabolizing gene, cytochrome P4501A1. On the other hand, the DNA repair gene OGG1 and the 8-OHdG level were dramatically inhibited in Cd-exposed group only.