M2 Macrophage Prominently Distributed in the Rat's Colon of DMH-Induced Inflammation Associated Colorectal Cancer.

OBJECTIVE: The aim of this study is to examine the M1 and M2 macrophages distribution in the rat's colon of DMH-induced inflammation associated colorectal cancer. METHODS: Colon tissue of three groups of 4 rats that induced using 1,2 dimethylhydrazine (DMH) at 30 mg/kg bw every week for 9, 11, and 13 weeks were used. The M1 and M2 distribution was examined by using antibody anti iNOS for M1 and anti-CD163 for M2 with immunohistochemistry method. The data was presents in figure and table in the form of percentage. RESULT: M1 macrophage was found in all groups in the low distribution level (25% - 50%), while M2 macrophage was observed in all groups with 100% distribution. In the longer period of DMH induction, M2 macrophages was distributed more abundant. CONCLUSION: All of the rat's colon showing chronic inflammation that led to the tumorigenesis.

Antineoplastic Activity Evaluation of Brazilian Brown Propolis and Artepillin C in Colorectal Area of Wistar Rats.

OBJECTIVE: The study's aim was to evaluate Brazilian Brown Propolis (BBP) and Artepillin C (ARC) chemopreventive action in Wistar rats' colons. METHODS: Fifty male Wistar rats were divided into ten experimental groups, including control groups, groups with and without 1,2-dimethylhydrazine (DMH) induction, and BBP, ARC, and ARC enriched fraction (EFR) treatments, for sixteen weeks. Aberrant crypt foci (ACF) were classified as hyperplastic or dysplastic, and proliferating cell nuclear antigen (PCNA) expression was quantified. RESULT: ACF amounts in experimental groups (induced or not) decreased in both colon portions, while the isolated Aberrant Crypt (AC) number increased. Experimental groups of animals showed higher hyperplasia and dysplasia amounts compared with control groups. The ACF dysplastic amount present in groups induced and treated, in both colon portions, had similar values to IDMH (DMH induction group without treatment). In addition, DMH was effective in ACF inducing and there was positive staining for PCNA in basal and upper dysplastic foci portions in all experimental groups, in the mitotic index (MI) evaluation. To conclude, considering all the experimental groups, the one treated with EFR (fraction enriched with ARC) had the lowest rates of cell proliferation. CONCLUSION: BBP and its derivatives prevented crypt cell clonal expansion.

Caffeic acid 3,4-dihydroxyphenethyl ester prevents colorectal cancer through inhibition of multiple cancer-promoting signal pathways in 1,2-Dimethylhydrazine/dextran sodium sulphate mouse model.

OBJECTIVE: To elucidate the potential feature and mechanism of the caffeic acid 3,4-dihydroxyphenethyl ester (CADPE) molecule, which can prevent colorectal cancer (CRC) in the 1,2-Dimethylhydrazine (DMH)/dextran sodium sulphate (DSS)-induced mouse model. METHODS: Institute of cancer research (ICR) male mice were injected with 20 mg/kg DMH for a week. After that, 2% DSS was administered in the drinking water for another 7 d. The CADPE treatment was given to the DMH/DSS induced male mice at three different periods until their sacrifice. Histopathological examination was used for observing the CRC development at colonic mucosa. Immunohistochemistry (IHC), blood cells smearing and crypt damage scoring methods were used for investigating the anti-inflammation feature of CADPE related to CRC. The reversing targets searching method was applied with artificial intelligence (AI), computer-aided drug designing (CADD) and Ingenuity Pathway Analysis (IPA) techniques for predicting the potential targets and mechanism of CADPE highly related to CRC. RESULTS: The data indicated that CADPE inhibited CRC tumor development in the colitis-associated DMH/DSS induced mouse model after giving the early treatment. CADPE also impeded the acute inflammation by decreasing the infiltration of neutrophils significantly during the initial stage of CRC development. Finally, our data showed that CADPE prevented CRC by blocking active sites of three pivotal protein targets including epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) in two major cancer development pathways. CONCLUSIONS: CADPE effectively prevented CRC at early stage of tumor germination in the DMH/DSS mouse model highly likely due to its anti-acute inflammation characteristic and the ability of blocking EGFR, ERK and mTOR activities in two highly related CRC developing pathways.

Effects of probiotic supplementation on chronic inflammatory process modulation in colorectal carcinogenesis.

The current study investigated the potential effects of probiotic supplementation on colorectal carcinogenesis chemically induced with 1,2-dimethylhydrazine (DMH) and treated with 5-fluorouracil (5FU)-based chemotherapy in mice. Animals were randomly allocated in five different groups: Control: which not receive any treatment throughout the experimental course; Colitis model group (DMH): treated with DMH; DMH+ 5FU: animals received I.P. (intraperitoneal) dose of chemotherapy on a weekly basis; DMH+PROB: animals received daily administrations (via gavage) of probiotics (Lactobacillus: acidophilus and paracasei, Bifidobacterium lactis and bifidum); and DMH+ PROB+ 5FU: animals received the same treatment as the previous groups. After ten-week treatment, mice's large intestine was collected and subjected to colon length, histopathological, periodic acid-schiff (PAS) staining and immunohistochemistry (TLR2, MyD88, NF-κB, IL-6, TLR4, TRIF, IRF-3, IFN-γ, Ki-67, KRAS, p53, IL-10, and TGF-ß) analyzes. Variance (ANOVA) and Kruskal-Wallis tests were used for statistical analysis, at significance level p 0.05. Probiotics' supplementation has increased the production of Ki-67 cell-proliferation marker, reduced body weight, and colon shortening, as well as modulated the chronic inflammatory process in colorectal carcinogenesis by inhibiting NF-κB expression and mitigating mucin depletion. Thus, these findings lay a basis for guide future studies focused on probiotics' action mechanisms in tumor microenvironment which might have implications in clinical practice.

Anonna crassiflora suppresses colonic carcinogenesis through its antioxidant effects, bioactive amines, and phenol content in rats.

Marolo (Annona crassiflora) is an underutilized Brazilian Cerrado fruit with few reports in the literature about its bioactive compounds and functional properties. In this context, the chemoprevention against the carcinogen 1,2-dimethylhydrazine (DMH)-induced pre-neoplastic lesions in Wistar rat colon was investigated and correlated with marolo's antioxidant activity and the contents of phenolic compounds and bioactive amines. Total phenolic compounds (TPC) and total flavonoids compounds (TFC) were determined in the marolo pulp extract by spectrophotometric and Ultra-Performance Liquid Chromatography and diode array detection (UPLC-DAD) analysis. Free bioactive amines were determined by High Performance Liquid Chromatography and fluorescence detection (HPLC-FLD) after post column derivatization with o-phthalaldehyde. In addition, the in vitro antioxidant activity was determined by DPPH, and ABTS. Wistar rats were treated orally with marolo pulp at 0.7, 1.4 and 2.8 g/kg body weight (bw)/day added to a standard ration. Four subcutaneous injections of DMH (40 mg/kg bw) were used to induce a pre-neoplastic lesion that was assessed by the aberrant crypt foci (ACF) assay. The marolo pulp (fresh weigh) showed high content of total phenolic compounds (9.16 mg GAE/g), with predominance of chlorogenic acid (1.86 µg/g) and epicatechin (0.99 µg/g), and total flavonoids (7.26 mg CE/g), ∼85 % of the TPC. The marolo pulp had significant contents of tyramine (31.97 mg/kg), putrescine (20.65 mg/kg), and spermidine (6.32 mg/kg). The marolo pulp inhibited (p < 0.05) pre-neoplastic lesions induced by DMH administration at the all concentrations tested. These findings indicate that marolo pulp has a colon carcinogenesis chemopreventive effect, which could be due to, at least in parts, its antioxidant action associated with its phenolics and flavonoids content as well of spermidine.

NANOPARTICLES AND COLORECTAL CANCER: CAN THE USE OF METAL NANOPARTICLE COMPOSITIONS AFFECT OXIDATIVE STRESS MARKERS AND COLON HISTOLOGICAL CHANGES UNDER DMH-INDUCED CARCINOGENESIS.

Colorectal cancer (CRC) - a significant global health challenge. Exploring biological markers of oxidative stress is crucial, as they can play an essential role in initiating the transition from an organ's "healthy state" to a "malignant injury." There is substantial promise in investigating the level of 8-isoprostane (8-isoPGF2α) as a novel and dependable marker of oxidative stress. This paper presents that 8-isoprostane levels have been linked to the development of severe structural changes in the colon wall, accompanied by endogenic intoxication syndrome. The obtained results prove the strong connection between oxidative stress and carcinogenesis progression. Our research further illustrates the favorable and potentially beneficial impact of the Au/Ag/Fe NPs composition, which can find utility in a diverse range of contemporary applications.

Synergistic Antigenotoxic and Antioxidant Action of Gum Arabic and Eugenol in Rat Liver Following Induction of Colorectal Carcinogenesis.

OBJECTIVE: Much research has been conducted to identify natural antioxidant and antimutagenic compounds capable of preventing, reverting or treating conditions caused by oxidative stress and genotoxicity. In this study we evaluated the effects of 10% gum arabic (GA) and eugenol (EUG) on hepatic oxidative stress and genotoxicity induced by dimethylhydrazine (DMH) in rats. METHODS: The prevention arm of the study included 4 control groups and 4 experimental groups. Once a week for 20 weeks, the controls received saline s.c. while the experimental groups received DMH at 20 mg/kg s.c. During the same period and for an additional 9 weeks, the animals received either water, 10% GA , EUG or 10% GA + EUG  by gavage. The treatment arm of the study included 4 control groups and 4 experimental groups. Once a week for 20 weeks, the controls received saline s.c. while the experimental groups received DMH at 20 mg/kg s.c. During the subsequent 9 weeks, the animals received either water, 10% GA, EUG or 10% GA + EUG  by gavage. Finally, the livers were harvested for histopathological study with HE, measurement of genotoxicity and oxidative stress. RESULT: Genotoxicity and oxidative stress were found to be significantly lower in Group XII (animals treated concomitantly with GA and EUG). This is the first study to observe the synergistic action of GA and EUG administered concomitantly in this scenario. CONCLUSION: Indicating a synergistic antigenotoxic and antioxidant effect on liver cells in rats with DMH-induced colorectal carcinogenesis.

Panx1 knockout promotes preneoplastic aberrant crypt foci development in a chemically induced model of mouse colon carcinogenesis.

Colorectal cancer, which is the third leading cause of cancer-related deaths worldwide, is a multistep disease, featuring preneoplastic aberrant crypt foci (ACF) as the early morphological manifestation. The roles of hemichannel-forming transmembrane Pannexin 1 (Panx1) protein have not been investigated in the context of colon carcinogenesis yet, although it has contrasting roles in other cancer types. Thus, this study was conducted to examine the effects of Panx1 knockout (Panx1-/- ) on the early events of chemically induced colon carcinogenesis in mouse. Wild type (WT) and Panx1-/- female C57BL6J mice were submitted to a chemically induced model of colon carcinogenesis by receiving six intraperitoneal administrations of 1,2-dimethylhydrazine (DMH) carcinogen. Animals were euthanized 8 h (week 7) or 30 weeks (week 37) after the last DMH administration in order to evaluate sub-acute colon toxicity outcomes or the burden of ACF, respectively. At week 7, Panx1 genetic ablation increased DMH-induced genotoxicity in peripheral blood cells, malondialdehyde levels in the colon, and apoptosis (cleaved caspase-3) in colonic crypts. Of note, at week 37, Panx1-/- animals showed an increase in aberrant crypts (AC), ACF mean number, and ACF multiplicity (AC per ACF) by 56%, 57% and 20%, respectively. In essence, our findings indicate that Panx1 genetic ablation promotes preneoplastic ACF development during chemically induced mouse colon carcinogenesis, and a protective role of Panx1 is postulated.

2,4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone from Cleistocalyx nervosum var. paniala seeds attenuated the early stage of diethylnitrosamine and 1,2-dimethylhydrazine-induced colorectal carcinogenesis.

BACKGROUND: Dichloromethane extract of Cleistocalyx nervosum var. paniala seeds exhibited an anticarcinogenicity against chemically-induced the early stages of carcinogenesis in rats. This study aimed to identify anticarcinogenic compounds from C. nervosum seed extract (CSE). METHODS: Salmonella mutation assay was performed to determine mutagenicity and antimutagenicity of partially purified and purified compounds of CSE. The anticarcinogenic enzyme-inducing activity was measured in Hepa1c1c7. Moreover, the anticancer potency was examined on various human cancer cell lines. The anticarcinogenicity of DMC was investigated using dual-organ carcinogenicity model. The number of preneoplastic lesions was evaluated in the liver and colon. The inhibitory mechanisms of DMC on liver- and colorectal carcinogenesis were investigated. RESULTS: Six partially purified fractions (MK1 - MK6) and purified compounds, including 2,4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) and hariganetin, were obtained from CSE. Among these fractions, MK4 and DMC presented the greatest antimutagenicity against indirect mutagens in bacterial model. Moreover, MK5 possessed an effective anticarcinogenic enzyme inducer in Hepa1c1c7. The MK4, DMC and CSE showed greater anticancer activity on all cell lines and exhibited the most effective toxicity on colon cancer cells. Furthermore, DMC inhibited the formation of colonic preneoplastic lesions in carcinogens-treated rats. It reduced PCNA-positive cells and frequency of BCAC in rat colon. DMC also enhanced the detoxifying enzyme, GST, in rat livers. CONCLUSIONS: DMC obtained from CSE may be a promising cancer chemopreventive compound of colorectal cancer process in rats. It could increase detoxifying enzymes and suppress the cell proliferation process resulting in prevention of post-initiation stage of colorectal carcinogenesis.

Raptinal ameliorates 1,2-dimethylhydrazine-induced colon cancer through p53/Bcl2/Bax/caspase-3-mediated apoptotic events in vitro and in vivo.

OBJECTIVES: Colon carcinoma stands as the most familiar malignancy throughout across the globe. Raptinal induce apoptosis through the alteration of cellular events. Thus, in the present investigation, the anticancer activity of raptinal counter to 1,2-dimethylhydrazine (DMH) persuaded colon carcinoma has been evaluated through both in vivo and in vitro systems. MATERIALS AND METHODS: The pharmacophore analysis demonstrated the binding efficacy of raptinal with the apoptotic proteins. The chemotherapeutic activity of raptinal was examined through HT-29 human colorectal cancer (CRC) cell line as well as DMH persuaded CRC in the rat model. The cytotoxicity analysis, flow cytometry, and DAPI analysis have been carried out on HT-29 cell line through in vitro assessment. The colon carcinoma has been induced through DMH administration and subsequently Dextran sulfate sodium treatment in male Wistar rats. After 18 weeks of raptinal treatment, the colon tissues have been investigated for aberrant crypt foci (ACF) count, antioxidant status, histology, immunohistochemical assessment, and apoptotic analysis. RESULTS: The raptinal therapy on HT-29 cells demonstrated a substantial % of early apoptosis followed by G0 and G1 phase arrest, which subsequently led to apoptosis. Furthermore, it inhibits ACF development with improved colonic abrasions and structural integrity of colonic mucosa with increased levels of antioxidants, proapoptotic biomarkers including p53, caspase-3, Bax and downstream effects of Bcl-2, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 mutation. CONCLUSIONS: These findings indicate the raptinal effectively reduces colon cancer by inducing apoptosis through p53/Bcl2/Bax/caspase-3 pathway and suppressing IL-6, TNF-mediated chronic inflammation in the colon cancer microenvironment.

Combination of vitamin D and probiotics inhibits chemically induced colorectal carcinogenesis in Wistar rats.

The modulation of inflammatory elements, cell differentiation and proliferation by vitamin D and the role of probiotics in the intestinal microbiota and immunogenic response have sparked interest in the application of both in chemotherapeutics and chemoprevention of colorectal tumors. AIMS: The present study aimed to investigate the effects of isolated and/or combined treatment of vitamin D3 and probiotics on colorectal carcinogenesis. MAIN METHODS: Pre-neoplastic lesions were induced with 1,2-dimethylhydrazine in the colon of Wistar rats, which were treated with probiotics and/or vitamin D in three different approaches (simultaneous, pre-, and post-treatment). We investigated the frequency of aberrant crypt foci (ACF) and aberrant crypt (AC) in the distal colon, fecal microbiome composition, gene and protein expression through immunohistochemical and RT-PCR assays, and general toxicity through water consumption and weight gain monitoring. KEY FINDINGS: Results confirm the systemic safety of treatments, and show a protective effect of vitamin D and probiotics in all approaches studied, as well as in combined treatments, with predominance of different bacterial phyla compared to controls. Treated groups show different levels of Nrf2, GST, COX2, iNOS, ß-catenin and PCNA expression. SIGNIFICANCE: These experimental conditions explore the combination of vitamin D and probiotics supplementation at low doses over pathways involved in distinct stages of colorectal carcinogenesis, with results supporting its application in prevention and long-term strategies.

The Potential Chemopreventive Effect of Andrographis paniculata on 1,2-Dimethylhydrazine and High-Fat-Diet-Induced Colorectal Cancer in Sprague Dawley Rats.

Colorectal cancer (CRC) is responsible for a notable rise in the overall mortality rate. Obesity is found to be one of the main factors behind CRC development. Andrographis paniculata is a herbaceous plant famous for its medicinal properties, particularly in Southeast Asia for its anti-cancer properties. This study examines the chemopreventive impact of A. paniculata ethanolic extract (APEE) against a high-fat diet and 1,2-dimethylhydrazine-induced colon cancer in Sprague Dawley rats. Sprague Dawley rats were administered 1,2-dimethylhydrazine (40 mg/kg, i.p. once a week for 10 weeks) and a high-fat diet (HFD) for 20 weeks to induce colorectal cancer. APEE was administered at 125 mg/kg, 250 mg/kg, and 500 mg/kg for 20 weeks. At the end of the experiment, blood serum and organs were collected. DMH/HFD-induced rats had abnormal crypts and more aberrant crypt foci (ACF). APEE at a dose of 500 mg/kg improved the dysplastic state of the colon tissue and caused a 32% reduction in the total ACF. HFD increased adipocyte cell size, while 500 mg/kg APEE reduced it. HFD and DMH/HFD rats had elevated serum insulin and leptin levels. Moreover, UHPLC-QTOF-MS analysis revealed that APEE was rich in anti-cancer phytochemicals. This finding suggests that APEE has anti-cancer potential against HFD/DMH-induced CRC and anti-adipogenic and anti-obesity properties.

Jaboticaba (Myrciaria cauliflora) Fruit Extract Suppressed Aberrant Crypt Formation in 1,2-Dimetylhydrazine-Induced Rats.

Early intervention can significantly improve the colorectal cancer survival rate. Foods rich in phenolic compounds, such as jaboticaba (Myrciaria cauliflora), may prevent tumorigenesis. We investigated the effectivity of jaboticaba whole fruit ethanolic extract (FEX) in suppressing aberrant crypt foci (ACF), the earliest lesion of colorectal cancer (CRC), in 1,2-dimethylhydrazine (DMH)-induced rats and the underlying mechanisms related to the gut microbiota composition and short chain fatty acid (SCFA). This study was approved by the Institutional Animal Care and Use Committee (IACUC) of Providence University (Trial Registration Number 20180419A01, registration date: 22 December 2018). The FEX contains gallic acid and an especially high ellagic acid concentration of 54.41 ± 1.80 and 209.79 ± 2.49 mg/100 g FEX. The highest total ACF number (150.00 ± 43.86) was recorded in the DMH control (D) group. After 56 days of oral FEX treatment, the total ACF number in the low FEX dosage (DL) group was significantly lower compared to the D group (p < 0.05). The large-sized ACF (> 5 foci), which has a higher probability of progressing to later stage, was significantly decreased in the high FEX dosage (DH) group. The 16s rDNA metagenomic sequencing of the cecal material revealed that the CRC biomarker Lachnoclostridium was significantly suppressed in the DH group (p < 0.05), whereas some SCFA-producing taxa and the cecal butyrate concentration were significantly elevated in the DL and DH groups (p < 0.05). This study demonstrated the potential of jaboticaba whole fruit in CRC prevention, especially in the initial stage, by shifting gut microbiota composition and improving cecal butyrate level.

Long-term 1,2-dimethylhydrazine triggers pathological remodeling of colon mucosa through repression of sestrin2, nuclear factor (erythroid-derived 2)-like 2, and sirtuin4 stimulating mitochondrial stress and metabolic reprogramming.

1,2-Dimethylhydrazine (DMH) is a plant toxicant that enters the food web through the diet. It is biotransformed into azoxymethane, a colon carcinogen, during the first hepatic passage. In mice, this study assessed the role of glutamate dehydrogenase (GDH), a key glutaminolysis enzyme in DMH-induced colorectal cancer (CRC). Colon samples were taken from mice given 6 or 15 weekly doses of 20 mg/kg DMH and serially sacrificed. Repeated DMH doses induced early aberrant crypt foci that evolved into irreversible adenocarcinomas over 24 weeks, along with an increase in GDH and lactate dehydrogenase activities (+ 122%, + 238%, P < 0.001), indicating a switch to aerobic glycolysis and glutaminolysis. Transcriptional downregulation of the endogenous GDH inhibitor, sirtuin4, and two redox regulators, mitochondrial sestrin2 and nuclear factor (erythroid derivative 2)-like 2 (- 26% and - 22%, P < 0, 05; and - 30%, P < 0.01), exacerbated mitochondrial stress by boosting mitochondrial superoxide dismutase activity (+ 240% (P < 0.001) while depressing catalase activity and GSH levels (- 57% and - 60%, P < 0.001). In vitro, allosteric GDH inhibition by 50 µM epigallocatechin gallate decreased human carcinoma (HCT-116) cells' viability, clonogenicity, and migration (- 43% and - 57%, P < 0.001, 41%, P < 0.05), while stimulating ROS release (+ 57%, P < 0.001). Dimethylfumarate (DMF), a linear electrophile and mitochondrial fumarate analog, rebalanced ROS levels (- 34%, P < 0.05) and improved GDH activity, cell viability, and tumorogenic capacity (+ 20%, 20%, P < 0.001; and 33%, P < 0.05). Thus, the pathological remodeling of colon mucosa is supported by metabolic reprogramming bypassing uncoupled mitochondria. DMF highlights the critical role of electrophile response elements in modulating redox mithormesis and redox homeostasis during CRC.

Therapeutic role of biogenic silver and gold nanoparticles against a DMH-induced colon cancer model.

Colorectal cancer (CRC) ranks third among fatal diseases afflicting mankind globally due to the shortage of primary detection methods and appropriate choice of drugs. Moreover, current treatments such as chemo drugs and radiotherapies create adverse effects and lead to drug resistance. In this context, recent advances in nanomedicine offer novel clinical solutions for colon cancer therapy. The current study denotes the therapeutic roles of biogenic Abutilon indicum silver and gold nanoparticles (AIAgNPs and AIAuNPs) against a 1, 2-dimethyl hydrazine (DMH)-induced CRC in Wistar rats. Following treatment of nanoparticles (NPs), the CRC rats showed great localization of AIAgNPs and AIAuNPs in colon tumors shown by ICP-OES, indicating their bioavailability. The AIAgNPs and AIAuNPs significantly enhanced cellular antioxidant enzyme levels including catalase, SOD, GSH, GPx and reduced lipid peroxidation (LPO) compared to the standard drug paclitaxel. AIAgNPs and AIAuNPs revealed significant protection against metastasis compared to paclitaxel shown in the histopathological study. The important CRC signaling molecules of the Wnt pathway, the ß-catenin and Tcf-4 levels were significantly downregulated in AIAgNPs and AIAuNPs treated CRC rats compared to paclitaxel. Furthermore, the expression levels of cleaved apoptotic caspase-9, -8, and - 3 and lamins were significantly upregulated in AIAgNPs and AIAuNPs treated CRC rats compared to paclitaxel. This preclinical study provides substantial insights into the anti-colon cancer roles of biogenic NPs and gives an idea for targeting different cancers.

Arthrospira (Spirulina) platensis feeding reduces the early stage of chemically induced rat colon carcinogenesis.

Colorectal cancer is the third most diagnosed cancer worldwide and linked to dietary/lifestyle factors. Arthrospira (Spirulina) platensis (AP) contains bioactive compounds with beneficial effects in vivo/in vitro. We evaluated the effects of AP feeding against 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis. Male Sprague Dawley rats were given subcutaneous injections of DMH (4 × 40 mg/kg body weight) (G1-G3) or vehicle (G4-G5) twice a week (weeks 3-4). During weeks 1-4, animals were fed a diet containing 1 % (G2) or 2 % (G3-G4) AP powder (w/w). After this period, all groups received a balanced diet until week 12. Some animals were euthanised after the last DMH injection (week 4) for histological, immunohistochemical (Ki-67, γ-H2AX and caspase-3) and molecular analyses (real time-PCR for 91 genes), while other animals were euthanised at week 12 for preneoplastic aberrant crypt foci (ACF) analysis. Both AP treatments (G2-G3) significantly decreased the DMH-induced increase in γ-H2AX (DNA damage) and caspase 3 (DNA damage-induced cell death) in colonic crypts at week 4. In addition, Cyp2e1 (Drug metabolism), Notch1, Notch2 and Jag1 genes (Notch pathway) and Atm, Wee1, Chek2, Mgmt, Ogg1 and Xrcc6 genes (DNA repair) were also down-regulated by 2 % AP feeding (G3) at week 4. A significant reduction in ACF development was observed in both AP-treated groups (G2-G3) at week 12. In conclusion, findings indicate that AP feeding reduced acute colonic damage after DMH, resulting in fewer preneoplastic lesions. Our study provided mechanistic insights on dietary AP-preventive effects against early colon carcinogenesis.

Social determinants of mental health and adolescent anxiety and depression: Findings from the 2018 to 2019 National Survey of Children's Health.

BACKGROUND: There is a current crisis in children's mental health. Defining social determinants of mental health (SDMH) facilitates investigations of social impact on mental health. AIMS: To examine associations between nine SDMH and adolescent depression and anxiety in a U.S. nationally representative sample. METHODS: Poor access to health care, caregiver underemployment, food insecurity, poorly built environment, housing insecurity, household dysfunction adverse childhood experiences (ACEs), racism, caregiver poor education, and poverty/income inequality were assessed from the 2018 to 2019 National Survey of Children's Health (NSCH) (N = 24,817). RESULTS: The likelihood of reporting adolescent depression and/or anxiety was assessed for each SDMH using multinomial logistic regressions. All SDMH, besides caregiver underemployment, were associated with increased odds of reporting adolescent anxiety, depression, or anxiety and depression. Only household dysfunction ACEs and racism had statistically significant associations for all three mental health outcomes. CONCLUSIONS: Interventions targeting ACEs and racism may be more impactful in mitigating mental health challenges associated with SDMH during adolescence. The NSCH may provide an important public health tool to investigate SDMH in children.

EFFECT OF DRY EXTRACT FROM REISHI MUSHROOMS ON THE STATE OF ANTIOXIDANT SYSTEM IN RATS WITH DMH-INDUCED COLON CARCINOGENESIS.

OBJECTIVE: The aim: To study pro- and antioxidant systems indicators in rats with chemically induced colon carcinogenesis on the background of the reishi mushrooms dry extract use. PATIENTS AND METHODS: Materials and methods: The study was performed on 120 white male rats. Chronic oncogenic intoxication was modeled by administering 1,2-dimethyl¬hydrazine (DMH) hydrochloride for 30 weeks (1 time per week). A dry extract from the reishi mushrooms was administered intragastrically daily at a dose of 100 mg/kg of the animal's body weight. Blood and liver samples were taken for research monthly. The state of the pro- and antioxidant systems was studied by the content of oxidative modification of proteins products, superoxide dismutase and catalase activity, contents of reduced glutathione and ceruloplasmin. RESULTS: Results: An increase in the activity of free radical oxidation processes after DMH-induced colon carcinogenesis in rats is evidenced by a decrease in the super-oxide dismutase activity, catalase activity, content of reduced glutathione, an increase in the content of ceruloplasmin and products of oxidative modification of proteins in the blood serum and liver of animals. The effectiveness of the dry extract of reishi mushrooms and its positive effect on the state of pro- and antioxidant systems was experimentally proved. CONCLUSION: Conclusions: The use of the dry extract of reishi mushrooms under conditions of DMH-induced colon carcinogenesis in rats led to normalization of the anti¬oxidant protection system state and the reduction of oxidative stress.

Antioxidant and Anticancer Potentials of the Olive and Sesame Mixture against Dimethylhydrazine-Induced Colorectal Cancer in Wistar Rats.

Cancer is one of the leading causes of death worldwide, and natural agents have shown some promise in fighting it. Thus, the present study tried to evaluate the healing potential of an equal combination of olive and sesame extract (MOS) against the colorectal cancerous lesions that were induced by dimethylhydrazine (DMH) in male rats and also compare the anticarcinogenic potential of the MOS and vitamin E with each other. Therefore, the mixture of equal olive and sesame extract (MOS) was used as the main treatment, alongside vitamin E as a parallel treatment. This study examined the red blood cell (RBC) and white blood cell (WBC) levels, biochemical indices, lactate dehydrogenase (LDH), C-reactive protein (CRP), total protein (TP), creatine kinase (CPK), albumin, and the colon tissue pathology, as well as the level of protein expression of the adenomatous polyposis coli (APC), proliferating cell nuclear antigen (PCNA), carcinoembryonic antigen (CEA), and platelet-derived growth factor (PDGF). Also, the tissue stress markers including total antioxidant capacity (TAC), malondialdehyde (MDA), and superoxide dismutase (SOD) were analyzed. Overall, the results represented a significant reduction in the congestion, mitotic index, inflammation, and cell destruction in the MOS group compared to the DMH group. In terms of the oxidative stress level, a significant increase was observed in the DMH group in comparison with the DMH-MOS group (P < 0.05), and the MOS significantly increased TAC level (P < 0.05). Furthermore, the DMH+MOS-exposed group exhibited a significantly lower expression of the PCNA, CEA, and PDGF proteins than those of the DMH group. Overall, the MOS showed that it can effectively prevent DMH-induced colon lesions. This mixture, as a strong antioxidant agent, can be clinically applied for preventing and treating colorectal cancer, the effectiveness of which is higher than that of vitamin E.

Ficus dubia latex extract prevent DMH-induced rat early colorectal carcinogenesis through the regulation of xenobiotic metabolism, inflammation, cell proliferation and apoptosis.

Ficus dubia latex is recognized as a remedy in Asian traditional medicine with various therapeutic effects. The present study aimed to determine the preventive action of Ficus dubia latex extract (FDLE) on 1,2-dimethylhydrazine (DMH)-induced rat colorectal carcinogenesis and its mechanisms. The experiment included an initiation model in which rats were orally administered with FDLE daily for 1 week before DMH injection until the end of the experiment, while only after DMH injection until the end in the post-initiation model. The results firstly indicated that FDLE treatment could reduce the level of methylazoxymethanol (MAM) in rat colonic lumen by inhibition of the activities of both phase I xenobiotic metabolizing enzymes in the liver and ß-glucuronidase in the colon, leading to reduced DNA methylation in colonic mucosal cells, related to the number of ACF in the initiation stage. Besides, FDLE modulated the inflammation which could suppress the growth and induce apoptosis of aberrant colonic mucosal cells, leading to retardation of ACF multiplicity. Therefore, FDLE showed the ability to suppress the DMH-induced rat ACF formation and inflammation promoted growth of ACF. In conclusion, FDLE had the potential to prevent carcinogens-induced rat colorectal carcinogenesis in the initiation stage.