Analysis of Correlation Between LncRNA TDRG1 Expression and its Prognosis in Cervical Carcinoma Tissues.

To explore and analyze the correlation between LncRNA TDRG1 expression degree and the prognosis of cervical carcinoma tissues. The cervical cancer tissues and para-carcinoma tissues of 106 patients with cervical carcinoma surgically removed in our hospital were chosen as specimens. LncRNA TDRG1 expression in cervical carcinoma tissues and para-carcinoma tissues was inspected by real-time fluorescence quantitative PCR, and the correlation between LncRNA TDRG1 and the clinicopathological parameters and disease prognosis was analyzed. The relative expression of LncRNA TDRG1 in cervical carcinoma tissues was critically gone up (P < 0.05) compared to para-carcinoma tissues. The relative expression of LncRNA TDRG1 in cervical carcinoma was correlated with FIGO staging, lymph node metastasis, infiltrating depth of cervical basal, and the differentiation of cancer cells (P < 0.05). According to the results of the Kaplan-Meier curve and Log-rank test, the overall survival conditions of subjects with low-lncRNA TDRG1 were superior to that of those with high-lncRNA TDRG1 expression (P < 0.05). The expression of LncRNA TDRG1 in cervical carcinoma tissues and the clinicopathological features in predicting the overall survival (OS) in sufferers with cervical carcinoma were investigated by the Cox regression model. LncRNA TDRG1 expression in cervical carcinoma tissues is tightly associated with the progression and prognosis of cervical carcinoma, which may be a latent biological indicator for clinical diagnosis and prognosis of cervical carcinoma.

Cutaneous leishmaniasis in Tabuk, Saudi Arabia: epidemiological trends from 2006 to 2021.

Introduction: cutaneous leishmaniasis (CL) is a vector-borne protozoan skin disease that affects all human ages and can pose extreme social and psychological impacts. This study aimed to reveal the epidemiological trends of CL in the Tabuk region, the Kingdom of Saudi Arabia (KSA), during the period from 2006 to 2021. Methods: patients with CL, who were detected and registered at the regional Vector-borne Diseases Control Unit of the Tabuk province, between January 2006 and December 2021, were analyzed in this retrospective study. The patients´ data included their nationality, gender, and age, and their annual and month-by-month recorded patterns. Results: a total of 1575 CL patients were reported during the said period. They were 53.1% Saudis and 46.9% non-Saudi expatriates with a ratio around 1.1: 1.0; and they were re-categorized as 83.17% males and 16.83% females with a ratio of 4.9: 1.0 (p <0.5). Additionally, the majority (1002/1575; 63.6%) of these CL patients were in age group of 15-45 years (p <0.5), and the lowest number was in age group of <5 years. Most importantly, there was a continuous annual and month-by-month record of these patients; reflecting CL endemicity in the Tabuk region of KSA. Conclusion: the present findings imply that CL is endemic in the Tabuk region of KSA. As there is a recent increase in human immigration to this region, sustainable monitoring of CL and improving its control measures is warranted.

Seroprevalence of Toxoplasma gondii infection among babies in Jeddah Province, Saudi Arabia: a retrospective study.

Introduction: toxoplasmosis is an opportunistic protozoan disease caused by Toxoplasma gondii (T. gondii) infection. It affects all human ages, including children, and can pose serious health problems, particularly in developing countries. Nevertheless, the epidemiological status of neonatal and childhood toxoplasmosis remains largely unknown in Saudi Arabia. The present study aimed to determine the seroprevalence of T. gondii infection among Saudi babies residing in Jeddah Region of Saudi Arabia. Methods: this hospital-based retrospective study was conducted between January 2019 and March 2021 at three governmental hospitals in Jeddah Region: King Fahad, King Abdulaziz, and East Jeddah Hospital. It included 502 babies (269 boys and 233 girls; 0-4 years old), who were screened by enzyme linked immunosorbent assay (ELISA) for the detection of anti-T. gondii immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies in their serum. Results: among the 502 studied babies, the overall seropositivity rate of T. gondii infection was 18.53% (93/502) subscribed as 90 babies (17.9%) with IgG seropositive and 3 babies (0.60%) with IgM seropositivity. The all IgG seropositive babies were IgM seronegative and vice versa. Additionally, the highest proportion of IgG seropositivity was detected in 0-6 month old babies (7.17%); followed by 5.38% and 4.98% in 7-12 and 13-18 months old babies, respectively, while the 3 babies with IgM seropositivity were 13-18 months old. Conclusion: the present findings highlighted the seroprevalence situation of toxoplasma infection among babies in some Saudi communities and raise the importance to increase the screening programs and preventative implements against toxoplasmosis in Saudi Arabia.

Antioxidant, Antidiabetic, and Antibacterial Potentials and Chemical Composition of Salvia officinalis and Mentha suaveolens Grown Wild in Morocco.

This work evaluated in vitro antioxidant, antidiabetic, and antibacterial properties of Salvia officinalis (S. officinalis) and Mentha suaveolens (M. suaveolens) essential oils (EO). The EOs were extracted, and their chemical composition was determined using GC-MS analysis. The in vitro antioxidant, antidiabetic, and antibacterial activities of S. officinalis and M. suaveolens EO were shown to be remarkable. Furthermore, S. officinalis EO demonstrated better antioxidant findings (using DPPH, ABTS, and FRAP test) than M. suaveolens EO (p < 0.5). There were no significant differences in the inhibitory effects of the EOs on α-amylase and α-glucosidase activities in the antidiabetic assays. All of the examined bacterial strains (10 different strains), with the exception of P. aeruginosa, demonstrated significant sensitivity to the tested EOs, with M. suaveolens EO exhibiting better activity than S. officinalis EO. Thus, the research indicated that EO from these two medicinal plants has considerable potential for application in the formulation of antibacterial, antioxidant, and antidiabetic pharmaceuticals. However, more research studies are required to interpret the pharmacologic action of the studied EOs and their principal constituents and to confirm their safety.

LncRNA NEAT2 Modulates Pyroptosis of Renal Tubular Cells Induced by High Glucose in Diabetic Nephropathy (DN) by via miR-206 Regulation.

Patients suffering from terminal-stage diabetic nephropathy (DN) are commonly diagnosed with kidney failure. The condition of DN patients gets generally improved by long-chain noncoding RNA (LncRNA) since it regulates microRNA (miR). The current study analyzes the role played by NEAT2/miR-206 upon cell death of renal tubular epithelial cells (RTECs), high glucose (HG)-induced inflammation and oxidative stress in diabetic nephropathy (DN). The researcher used high glucose (HG) to treat HK-2 cells in in vitro conditions to establish the DN cell model. qRT-PCR was used to confirm the transfection effect whereas the researcher also tested NEAT2, nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing (NLRP3), caspase-1, interleukin IL-1ß, gasdermin D (GSMDD)-N, and miR-206. To analyze the proteins in caspase-1, IL-1ß, GSMDD-N, and NLRP3, Western blot technique was performed. The technique is also used to observe the pyroptosis. To identify TNF-α, IL-6, MCP-9, NEAT2, miR-206, and NLRP3, dual-luciferase reporter assay was conducted through ELISA kit to emphasize the correlation that exists among the above-mentioned factors. NEAT2 has been confirmed to have bound with miR-206 through double luciferase report experiments as well as RNA immunoprecipitation (RIP). NEAT2, present in HK-2 cells, was induced by HG. So, if NEAT2 is knocked down, it would mitigate TNF-α, IL-6, and MCP-9 as well. Among the HK-2 cells intervened with HG, the overexpressed miR-206 that was transfected into cells was in alignment with the modifications introduced in inflammatory factors and cytokines after NEAT2 is knocked down. The current study concludes that if NEAT2 is upregulated, it has the potential to retreat the inhibition of miR-206 on inflammatory response as well pyroptosis. Further, by targeting miR-206, NEAT2 has the potential to enhance HG-induced HK-2 pyroptosis. This miR-206 is predicted to be a latent target in the clinical treatment of DN.

Ethnopharmacological Survey and Comparative Study of the Healing Activity of Moroccan Thyme Honey and Its Mixture with Selected Essential Oils on Two Types of Wounds on Albino Rabbits.

Wound healing consists of several continuous phases involving various cells and chemical intermediates. As a rich source of nutrition elements, honey has proved to have potential benefits in the treatment of various diseases. The present study was designed to investigate the healing effect of a honey mixture with selected essential oils on chemical and thermal wound models in rabbits. Dressing mixtures of Thymus vulgaris honey with three essential oils (Origanum vulgare, Rosmarinus officinalis, and Thymus vulgaris) were prepared and applied daily in the treatment groups. These essential oils were rich in phytochemicals and had significant antibacterial activity against four selected ATCC bacterial strains. Madecasol ointment was used as a standard control. The healing effect of the mixtures was evaluated by measuring wound surface area and comparing healing time. The results showed that the healing rate in the treatment groups was significantly higher than that of the untreated group and standard group. The best healing effect for burns was seen in the mixture of honey and Thymus vulgaris essential oil, which had wound closure rates of 85.21% and 82.14% in thermal- and chemical-induced burns, respectively, and showed the shortest healing time (14 days) in comparison to other groups. Therefore, it can be concluded that honey mixtures have significant beneficial effects on skin wound healing and, thus, they may be used as a healing agent in different types of wounds in humans after specific clinical trials.

Defining a murine ovarian cancer model for the evaluation of conditionally-replicative adenovirus (CRAd) virotherapy agents.

BACKGROUND: Virotherapy represents a promising approach for ovarian cancer. In this regard, conditionally replicative adenovirus (CRAd) has been translated to the context of human clinical trials. Advanced design of CRAds has sought to exploit their capacity to induce anti-tumor immunization by configuring immunoregulatory molecule within the CRAd genome. Unfortunately, employed murine xenograft models do not allow full analysis of the immunologic activity linked to CRAd replication. RESULTS: We developed CRAds based on the Ad5/3-Delta24 design encoding cytokines. Whereas the encoded cytokines did not impact adversely CRAd-induced oncolysis in vitro, no gain in anti-tumor activity was noted in immune-incompetent murine models with human ovarian cancer xenografts. On this basis, we explored the potential utility of the murine syngeneic immunocompetent ID8 ovarian cancer model. Of note, the ID8 murine ovarian cancer cell lines exhibited CRAd-mediated cytolysis. The use of this model now enables the rational design of oncolytic agents to achieve anti-tumor immunotherapy. CONCLUSIONS: Limits of widely employed murine xenograft models of ovarian cancer limit their utility for design and study of armed CRAd virotherapy agents. The ID8 model exhibited CRAd-induced oncolysis. This feature predicate its potential utility for the study of CRAd-based virotherapy agents.

Pharmacotherapy with Thymoquinone Improved Pancreatic ß-Cell Integrity and Functional Activity, Enhanced Islets Revascularization, and Alleviated Metabolic and Hepato-Renal Disturbances in Streptozotocin-Induced Diabetes in Rats.

AIMS: This study is aimed at evaluating the antidiabetic effects of thymoquinone (TQ) on streptozotocin (STZ)-induced diabetes in rats, and exploring the possible underlying mechanisms. METHODS: Diabetes was induced in adult male Wistar rats by intraperitoneal injection of freshly prepared STZ (65 mg/kg). After disease induction, 42 rats were equally assigned to: controls, STZ-diabetic group, and STZ-diabetic group treated with oral TQ (35 mg/kg/day) for 5 weeks. Fasting blood glucose levels were determined weekly, and the animals were euthanized at day 38 post-STZ injection. Blood samples were assessed for glucose-insulin homeostasis parameters (plasma glucose, glycated hemoglobin, serum insulin, homeostatic model assessment of insulin resistance, and insulin sensitivity index) and lipid profile. Resected pancreases were subjected to histological examination and immunohistochemical or enzyme-linked immunosorbent assay assessment to determine the pancreatic expression of insulin sensitizing ß-cells, anti-apoptotic protein "survivin," apoptosis-inducer "caspase-3," prototypic angiogenic factors (vascular endothelial growth factor [VEGF] and endothelial cluster of differentiation 31 [CD31]), pro- and anti-inflammatory cytokines (interleukin-1beta [IL-1ß] and interleukin-10 [IL-10], respectively), thiobarbituric acid reactive substances (TBARS), total glutathione (GSH), and superoxide dismutase (SOD). The hepato-renal statuses were assessed biochemically and histologically. RESULTS: Therapy with TQ markedly improved the integrity of pancreatic islets, glucose-insulin homeostasis-related parameters, lipid profile parameters, and hepato-renal functional and histomorphological statuses that collectively were severely deteriorated in untreated diabetic group. Mechanistically, TQ therapy efficiently increased insulin producing ß-cells, upregulated survivin, VEGF, CD31, IL-10, GSH and SOD, and downregulated caspase-3, IL-1ß, and TBARSs in the pancreatic tissues of STZ-diabetic rats. CONCLUSIONS: These findings prove the anti-diabetic potential of TQ and its efficacy in regenerating pancreatic ß-cells and ameliorating pancreatic inflammation and oxidative stress, and highlight its novelty in repressing apoptosis of ß-cells and enhancing islet revascularization in STZ-diabetic rats. Further studies are required to support these findings and realize their possible clinical significance.

Seroprevalence of Asymptomatic Dengue Virus Infection and Its Antibodies Among Healthy/Eligible Saudi Blood Donors: Findings From Holy Makkah City.

BACKGROUND: Threat to blood transfusion-transmitted dengue virus (DENV) and its antibodies has recently emerged worldwide. Dengue fever is an endemic disease in Saudi Arabia, particularly in its Western region. The aim of this study was to estimate the seroprevalence of asymptomatic DENV infection and its antibodies among eligible Saudi blood donors. METHODS: Serum samples from 910 healthy/eligible adult male Saudi blood donors, who reside in Holy Makkah City of Saudi Arabia, were collected between March 2015 and August 2016 and screened for the detection of DENV nonstructural protein 1 (NS1) antigen and anti-DENV IgM and IgG antibodies using commercial enzyme-linked immunosorbent assay kits (Panbio, Brisbane, QLD, Australia). RESULTS: Among the tested donors, 48 (5.3%) were seropositive for DENV-NS1 antigen, whereas 50 (5.5%) and 354 (38.9%) were seropositive for anti-DENV IgM and IgG antibodies, respectively. Seropositivity for DENV-NS1 antigen and/or anti-DENV IgM antibody among the tested donors reflects their ongoing asymptomatic viremic infectious stage with DENV during their donation time, whereas high prevalence of anti-DENV IgG seropositivity reflects the high endemicity of dengue disease in this region of Saudi Arabia. CONCLUSIONS: These results show high prevalence of asymptomatic DENV infection and its antibodies among Saudi blood donors, raising the importance of establishing blood screening for dengue disease at different blood donation services and units in Saudi Arabia to improve the guarantee of blood transfusions and to control DENV dissemination.

Thymoquinone potentiates chemoprotective effect of Vitamin D3 against colon cancer: a pre-clinical finding.

Prevention of colon cancer among high-risk group has been long lasting research goal. Emerging data have evidenced the anticancer activities of Vitamin D3 (Vit.D) and Thymoquinone (TQ). The aim of the current study was to evaluate the synergistic potential of Thymoquinone and Vitamin D3 in the control of colon cancer progression using azoxymethane-induced rat model. Vit.D and TQ were given individually or in combination 4 week prior to induction and continued for a total of 20 week. At the end of the study, all animals were euthanized and their resected colons were examined macroscopically and microscopically for tumor growth. Colonic tissue preparations were used for measuring gene expression and/or protein levels of selected pro and anti-tumor biomarkers using quantitative RT-PCR, ELISA and immunohistochemistry. Compared with their individual supplementation, combined Vit.D/TQ showed prominent anti-tumor effect manifested by significant reduction (P < 0.05) of the numbers of grown tumors and large aberrant crypts foci. Mechanistically, gene expression and/or protein quantification studies revealed that combined Vit.D/TQ supplementation induced significant reduction (P < 0.01 and P < 0.05) of pro-cancerous molecules (Wnt, ß-catenin, NF-κB, COX-2, iNOS, VEGF and HSP-90) as well as significant increase (P < 0.01 and P < 0.05, respectively) of anti-tumorigenesis biomarkers (DKK-1, CDNK-1A, TGF-ß1, TGF-ß/RII and smad4) as compared to un-supplemented or individually supplemented groups, respectively. In conclusion, TQ augmented the chemopreventive effect of Vit.D during the initiation phase of colon cancer in rat model, with the potential to suppress progression of pre-neoplastic lesions in colon carcinogenesis.

Activins and their related proteins in colon carcinogenesis: insights from early and advanced azoxymethane rat models of colon cancer.

BACKGROUND: Activin-A may exert pro- or anti-tumorigenic activities depending on cellular context. However, little is known about its role, or the other mature activin proteins, in colorectal carcinoma (CRC). This study measured the expression of activin ßA- & ßB-subunits, activin type IIA & IIB receptors, smads 2/3/4/6/7 and follistatin in CRC induced by azoxymethane (AOM) in rats. The results were compared with controls and disseminated according to the characteristics of histopathological lesions. METHODS: Eighty male Wistar rats were allocated into 20 controls and the remaining were equally divided between short 'S-AOM' (15 weeks) and long 'L-AOM' (35 weeks) groups following injecting AOM for 2 weeks. Subsequent to gross and histopathological examinations and digital image analysis, the expression of all molecules was measured by immunohistochemistry and quantitative RT-PCR. Activin-A, activin-B, activin-AB and follistatin were measured by ELISA in serum and colon tissue homogenates. RESULTS: Colonic pre-neoplastic and cancerous lesions were identified in both AOM groups and their numbers and sizes were significantly (P < 0.05) greater in the L-AOM group. All the molecules were expressed in normal colonic epithelial cells. There was a significantly (P < 0.05) greater expression of ßA-subunit, IIB receptor and follistatin in both pre-neoplastic and cancerous tissues. Oppositely, a significant (P < 0.05) decrease in the remaining molecules was detected in both AOM groups. Metastatic lesions were only observed within the L-AOM group and were associated with the most significant alterations of all molecules. Significantly higher concentrations of activin-A and follistatin and lower activin-AB were also detected in both groups of AOM. Tissue and serum concentrations of activin-A and follistatin correlated positively, while tissue activin-AB inversely, and significantly with the numbers and sizes of colonic lesions. CONCLUSIONS: Normal rat colon epithelial cells are capable of synthesising, controlling as well as responding to activins in a paracrine/autocrine manner. Colonic activin systems are pathologically altered during tumorigenesis and appear to be time and lesion-dependent. Activins could also be potential sensitive markers and/or molecular targets for the diagnosis and/or treatment of CRC. Further studies are required to illustrate the clinical value of activins and their related proteins in colon cancer.

Thymoquinone subdues tumor growth and potentiates the chemopreventive effect of 5-fluorouracil on the early stages of colorectal carcinogenesis in rats.

Colorectal cancer (CRC) is one of the most prevalent cancers and has a high mortality rate. Insensitivity and the limited therapeutic efficacy of its standard chemotherapeutic drug, 5-fluorouracil (5-FU), represents an important challenge in CRC treatment. The robust antitumor properties of thymoquinone (TQ), the main bioactive constituent of Nigella sativa, have recently been demonstrated on different cancers. We investigated whether TQ could potentiate the chemopreventive effect of 5-FU to eradicate the early stages of CRC and elucidated its underlying mechanisms. An intermediate-term (15 weeks) model of colorectal tumorigenesis was induced in male Wistar rats by azoxymethane (AOM), and the animals were randomly and equally divided into five groups: control, AOM, AOM/5-FU, AOM/TQ, and AOM/5-FU/TQ. TQ (35 mg/kg/d; 3 d/wk) was given during the seventh and 15th weeks post-AOM injection, while 5-FU was given during the ninth and tenth weeks (12 mg/kg/d for 4 days; then 6 mg/kg every other day for another four doses). At week 15, the resected colons were subjected to macroscopic, histopathological, molecular, and immunohistochemical examinations. Interestingly, 5-FU/TQ combination therapy resulted in a more significant reduction on AOM-induced colorectal tumors and large aberrant crypts foci than treatment with the individual drugs. Mechanistically, 5-FU and TQ remarkably cooperated to repress the expression of procancerous Wnt, ß-catenin, NF-κB, COX-2, iNOS, VEGF, and TBRAS and upregulate the expression of anti-tumorigenesis DKK-1, CDNK-1A, TGF-ß1, TGF-ßRII, Smad4, and GPx. Overall, our findings present the first report describing the in vivo enhancement effect of combined TQ and 5-FU against early stages of CRC; however, further studies are required to determine the value of this combination therapy in an advanced long-term model of CRC and also to realize its clinical potential.

Combinatorial strategies based on CRAd-IL24 and CRAd-ING4 virotherapy with anti-angiogenesis treatment for ovarian cancer.

BACKGROUND: A major hurdle incurrent to the human clinical application of conditionally replicative adenovirus (CRAd)-based virotherapy agents is their limited therapeutic efficacy. In this study we evaluated whether arming our previously reported Ad5/3Δ24 CRAd vector containing a 24-base pair deletion in the E1A conserved region 2, which allows selective replication within Rb-p16-deficient tumor cells, to express therapeutic genes could improve oncolytic virus potency in ovarian cancer cells. We choose to assess the therapeutic benefits achieved by virus-mediated expression of interleukin 24 (IL-24), a cytokine-like protein of the IL-10 family, and the inhibitor of growth 4 (ING4) tumor suppressor protein. RESULTS: The generated CRAd-IL24 and CRAd-ING4 vectors were tested in ovarian cancer cell lines in vitro to compare their replication, yield, and cytotoxic effects with control CRAd Ad5/3∆24 lacking the therapeutic gene. These studies showed that CRAd-IL24 infection resulted in significantly increased yield of infectious particles, which translated to a marked enhancement of virus-induced cytotoxic effects as compared to CRAd-ING4 and non-armed CRAd. Testing CRAd-IL24 and CRAd-ING4 vectors combined together did not revealed synergistic effects exceeding oncolytic potency of single CRAD-IL24 vector. Both CRAds were also tested along with anti-VEGF monoclonal antibody Avastin and showed no significant augmentation of viral cytolysis by anti-angiogenesis treatment in vitro. CONCLUSIONS: Our studies validated that arming with these key immunomodulatory genes was not deleterious to virus-mediated oncolysis. These findings thus, warrant further preclinical studies of CRAd-IL24 tumoricidal efficacy in murine ovarian cancer models to establish its potential utility for the virotherapy of primary and advanced neoplastic diseases.

Combined therapy with oncolytic adenoviruses encoding TRAIL and IL-12 genes markedly suppressed human hepatocellular carcinoma both in vitro and in an orthotopic transplanted mouse model.

BACKGROUND: Gene-based virotherapy mediated by oncolytic viruses is currently experiencing a renaissance in cancer therapy. However, relatively little attention has been given to the potentiality of dual gene virotherapy strategy as a novel therapeutic approach to mediate triplex anticancer combination effects, particularly if the two suitable genes are well chosen. Both tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and interleukin-12 (IL-12) have been emerged as promising pharmacological candidates in cancer therapy; however, the combined efficacy of TRAIL and IL-12 genes for treatment of human hepatocellular carcinoma (HCC) remains to be determined. METHODS: Herein, we investigated the therapeutic efficacy of concurrent therapy with two armed oncolytic adenoviruses encoding human TRAIL gene (Ad-ΔB/TRAIL) and IL-12 gene (Ad-ΔB/IL-12), respectively, on preclinical models of human HCC, and also elucidated the possible underlying mechanisms. The effects of Ad-ΔB/TRAIL+Ad-ΔB/IL-12 combination therapy were assessed both in vitro on Hep3B and HuH7 human HCC cell lines and in vivo on HCC-orthotopic model established in the livers of athymic nude mice by intrahepatic implantation of human Hep3B cells. RESULTS: Compared to therapy with non-armed control Ad-ΔB, combined therapy with Ad-ΔB/TRAIL+Ad-ΔB/IL-12 elicited profound anti-HCC killing effects on Hep3B and HuH7 cells and on the transplanted Hep3B-orthotopic model. Efficient viral replication and TRAIL and IL-12 expression were also confirmed in HCC cells and the harvested tumor tissues treated with this combination therapy. Mechanistically, co-therapy with Ad-ΔB/TRAIL+Ad-ΔB/IL-12 exhibited an enhanced effect on apoptosis promotion, activation of caspase-3 and-8, generation of anti-tumor immune response evidenced by upregulation of interferon gamma (IFN-γ) production and infiltration of natural killer-and antigen presenting cells, and remarkable repression of intratumor vascular endothelial growth factor (VEGF) and cluster of differentiation 31 (CD31) expression and tumor microvessel density. CONCLUSIONS: Overall, our data showed a favorable therapeutic effect of Ad-ΔB/TRAIL+Ad-ΔB/IL-12 combination therapy against human HCC, and may therefore constitute a promising and effective therapeutic strategy for treating human HCC. However, further studies are warranted for its reliable clinical translation.

Paricalcitol Enhances the Chemopreventive Efficacy of 5-Fluorouracil on an Intermediate-Term Model of Azoxymethane-Induced Colorectal Tumors in Rats.

Colorectal cancer is a common cancer with high mortality rate. Despite being the standard anti-colorectal cancer drug, 5-fluorouracil (5-FU) exhibits only limited therapeutic benefits. Herein, we investigated whether paricalcitol, a synthetic vitamin D analogue with potential antitumor properties, would enhance the chemopreventive efficacy of 5-FU on an intermediate-term (15 weeks) model of colorectal tumors induced by azoxymethane (AOM) in rats. After AOM injection, 5-FU was administered during the 9th and 10th weeks (12 mg/kg/day for 4 days, then 6 mg/kg every other day for another 4 doses), whereas paricalcitol (2.5 µg/kg/day; 3 days/week) was given from the 7th to the 15th week. At week 15, the animals were euthanized and their resected colons were examined macroscopically and microscopically. Quantitative RT-PCR was used to measure the transcription activities of Wnt, ß-catenin, DKK-1, CDNK-1A, NF-κB, and COX-2 genes, and ELISA was used to quantify the protein levels of ß-catenin, COX-2, HSP90, and VEGF. IHC was additionally used to measure ß-catenin, HSP90, and inducible nitric oxide synthase (iNOS). Compared with their individual therapy, combination of 5-FU and paricalcitol showed more significant reducing effect on numbers of grown tumors and large aberrant crypts foci. Mechanistically, paricalcitol and 5-FU had cooperated together to repress the expression of procancerous Wnt, ß-catenin, NF-κB, COX-2, iNOS, VEGF, and HSP-90 more, and to upregulate the expression of antitumorigenesis DKK-1 and CDNK-1A, compared with their monotherapies. Our findings suggest that combined use of paricalcitol with 5-FU exhibits an augmenting chemopreventive effect against colorectal tumors, and might potentially be useful for chemoprevention in colorectal cancer patients. Cancer Prev Res; 9(6); 491-501. ©2016 AACR.

Vitamin D and chronic hepatitis C: effects on success rate and prevention of side effects associated with pegylated interferon-α and ribavirin.

Chronic hepatitis C (CHC) is one of the most common causes of liver diseases worldwide, affecting 3% of the world population and 3 to 4 million people acquire new infection annually. Despite the recent introduction of novel antiviral drugs for the treatment of CHC, these drugs are expensive and the access to them is not an option for many patients. Hence, the traditional therapy by pegylated interferon-α (Peg-IFN-α) and ribavirin may still have a role in the clinical management of CHC especially in developing countries. However, this standard therapy is associated with several severe extra-hepatic side effects and the most common adverse events are hematological abnormalities and thyroid disorders and they could result in dose reduction and/or termination of therapy. Vitamin D has been shown to be a key regulatory element of the immune system, and its serum concentrations correlate with the severity of liver damage and the development of liver fibrosis/cirrhosis. Furthermore, supplementation with vitamin D with Peg-IFN-α based therapy for the treatment of CHC could be beneficial in increase the response rate to Peg-INF-α based therapy. Vitamin D has also been shown to regulate the thyroid functions and the process of erythropoiesis. This review appraises the data to date researching the role of vitamin D during the treatment of CHC and the potential role of vitamin D in preventing/treating Peg-IFN-α induced thyroiditis and anemia during the course of treatment.

Pegylated Interferon-α Modulates Liver Concentrations of Activin-A and Its Related Proteins in Normal Wistar Rat.

AIMS: To measure the expression of activin ßA-subunit, activin IIA and IIB receptors, Smad4, Smad7, and follistatin in the liver and the liver and serum concentrations of mature activin-A and follistatin in normal rat following treatment with pegylated interferon-α (Peg-INF-α) and ribavirin (RBV). MATERIALS AND METHODS: 40 male Wistar rats were divided equally into 4 groups: "control," "Peg-only" receiving 4 injections of Peg-INF-α (6 µg/rat/week), "RBV-only" receiving ribavirin (4 mg/rat/day) orally, and "Peg & RBV" group receiving both drugs. The expression of candidate molecules in liver was measured by immunohistochemistry and quantitative PCR. The concentrations of mature proteins in serum and liver homogenate samples were measured using ELISA. RESULTS: Peg-INF-α ± RBV altered the expression of all candidate molecules in the liver at the gene and protein levels (P < 0.05) and decreased activin-A and increased follistatin in serum and liver homogenates compared with the other groups (P < 0.05). There were also significant correlations between serum and liver activin-A and follistatin. CONCLUSION: Peg-INF-α modulates the hepatic production of activin-A and follistatin, which can be detected in serum. Further studies are needed to explore the role of Peg-INF-α on the production of activins and follistatin by the liver and immune cells.

Vitamin D3 enhances the tumouricidal effects of 5-Fluorouracil through multipathway mechanisms in azoxymethane rat model of colon cancer.

BACKGROUND: Vitamin D3 and its analogues have recently been shown to enhance the anti-tumour effects of 5- Fluorouracil (5-FU) both in vitro and in xenograft mouse model of colon cancer. This study measured the potential mechanism(s) by which vitamin D3 could synergise the tumouricidal activities of 5-FU in azoxymethane (AOM) rat model of colon cancer. METHODS: Seventy-five male Wistar rats were divided equally into 5 groups: Control, AOM, AOM-treated by 5-FU (5-FU), AOM-treated by vitamin D3 (VitD3), and AOM-treated by 5-FU + vitamin D3 (5-FU/D). The study duration was 15 weeks. AOM was injected subcutaneously for 2 weeks (15 mg/kg/week). 5-FU was injected intraperitoneally in the 9th and 10th weeks post AOM (8 total injections were given: 12 mg/kg/day for 4 successive days, then 6 mg/kg every other day for another 4 doses) and oral vitamin D3 (500 IU/rat/day; 3 days/week) was given from week 7 post AOM till the last week of the study. The colons were collected following euthanasia for gross and histopathological examination. The expression of ß-catenin, transforming growth factor-ß1 (TGF-ß1), TGF-ß type 2 receptor (TGF-ßR2), smad4, inducible nitric oxide synthase (iNOS), and heat shock protein-90 (HSP-90) proteins was measured by immunohistochemistry. In colonic tissue homogenates, quantitative RT-PCR was used to measure the mRNA expression of Wnt, ß-catenin, Dickkopf-1 (DKK-1) and cyclooxygenase-2 (COX-2) genes, while ELISA was used to measure the concentrations of TGF-ß1, HSP-90 and COX-2 proteins. RESULTS: Monotherapy with 5-FU or vitamin D3 significantly decreased the number of grown tumours induced by AOM (P < 0.05); however, their combination resulted in more significant tumouricidal effects (P < 0.05) compared with monotherapy groups. Mechanistically, vitamin D3/5-FU co-therapy significantly decreased the expression of Wnt, ß-catenin, iNOS, COX-2 and HSP-90 and significantly increased the expression of DKK-1, TGF-ß1, TGF-ßR2, smad4 (P < 0.05), in comparison with their corresponding monotherapy groups. CONCLUSIONS: Vitamin D3 and 5-FU synergise together and exhibit better anticancer effects by modulating Wnt/ß-catenin pathway, TGF-ß1 signals, iNOS, COX-2 and HSP-90. Further studies are required to illustrate the clinical value of vitamin D supplementation during the treatment of colon cancer with 5-FU in human patients.

The effects of pegylated interferon-α and ribavirin on liver and serum concentrations of activin-A and follistatin in normal Wistar rat: a preliminary report.

BACKGROUND: Activin-A and follistatin regulate the liver and the immune system. AIMS: To measure the effects of treatment with pegylated-interferon-α (Peg-IFN-α) and ribavirin on the concentrations of mature activin-A and follistatin in serum and liver tissue homogenates in rats. METHODS: A total of 28 male Wistar rats were divided equally into four groups as follow: 'Control group' (n = 7), 'PEG only group' consisted of those that only received a weekly injection of Peg-IFN-α (6 µg/rat) for 4 weeks, 'RBV only group' received ribavirin only (4 mg/rat/day) orally for 35 days and the last group received both Peg-IFN-α and ribavirin 'PEG & RBV group'. The concentrations of candidate proteins in serum and liver samples were measured using ELISA. RESULTS: Pegylated-interferon-α decreased activin-A and increased follistatin significantly in serum and liver of 'PEG only' and 'PEG & RBV' groups compared with the 'Control' and 'RBV only' groups (P < 0.05). There was no significant difference between the 'RBV only' and 'Control' groups (P > 0.05) in the concentrations of candidate proteins. A significant positive correlations between serum and liver activin-A (r = 0.727; P = 0.02 × 10(-3)) and follistatin (r = 0.540; P = 0.01) was also detected. CONCLUSION: Pegylated-interferon-α modulates the production of activin-A and follistatin by the liver, which is reflected and can be detected at the serum level. Further studies are needed to explore the role of Peg-IFN-α based therapy on the production of activins and follistatin by the liver and immune cells.