DMH Treatment Research Articles

Evaluation of Various Support Intensities of Digital Mental Health Treatment for Reducing Anxiety and Depression in Adults: Protocol for a Mixed Methods, Adaptive, Randomized Clinical Trial.

Anxiety and depression are leading causes of disease worldwide, requiring timely access to evidence-based treatment. Digital mental health (dMH) interventions increase accessibility to evidence-based psychological services delivered in a variety of web-based formats (eg, self-help and therapist-assisted interventions). Robust and rigorous studies of adaptive web-based intervention designs are scarce. No identified randomized clinical trial has investigated the efficacy of a 2-stage adaptive design, whereby the program-only condition or no support dMH treatment program is augmented by either low or high therapist assistance, if a participant does not improve or engage in the program-only condition. The primary objective is to assess whether low or high therapist-assisted support delivered via video chat is more effective in reducing anxiety and depressive symptoms compared with a dMH program-only condition. The secondary objective is to evaluate the role of motivation; self-efficacy; and preferences in participant engagement, adherence, and clinical outcomes (anxiety and depression symptoms) among the 3 treatment conditions (program only, low-intensity therapist assistance, and high-intensity therapist assistance). A mixed methods analysis of factors affecting participant attrition, participant reasons for nonengagement and withdrawal, and therapist training and implementation of dMH interventions will be completed. Qualitative data regarding participant and therapist experiences and satisfaction with video chat assessment and treatment will also be analyzed. Australian adults (N=137) with symptoms or a diagnosis of anxiety or depression will be screened for eligibility and given access to the 8-module Life Flex dMH treatment program. On day 15, participants who meet the augmentation criteria will be stepped up via block randomization to receive therapist assistance delivered via video chat for either 10 minutes (low intensity) or 50 minutes (high intensity) per week. This adaptive trial will implement a mixed methods design, with outcomes assessed before the intervention (week 0), during the intervention (weeks 3 and 6), after the intervention (week 9), and at the 3-month follow-up (week 21). The primary outcome measures are for anxiety (Generalized Anxiety Disorder-7) and depression severity (Patient Health Questionnaire-9). Measures of working alliance, health status, health resources, preferences, self-efficacy, and motivation will be used for secondary outcomes. Qualitative methods will be used to explore participant and therapist experiences of video chat assessment and treatment, participant reasons for withdrawal and nonengagement, and therapist training and implementation experiences. Data collection commenced in November 2020 and was completed at the end of March 2022. This is the first mixed methods adaptive trial to explore the comparative efficacy of different intensity levels of self-help and a therapist-assisted dMH intervention program delivered via video chat for adults with anxiety or depression. Anticipated results may have implications for the implementation of dMH interventions. Australian and New Zealand Clinical Trials Registry 12620000422921; https://tinyurl.com/t9cyu372. RR1-10.2196/45040.

An Integrative Approach to Characterize the Early Phases of Dimethylhydrazine-Induced Colorectal Carcinogenesis in the Rat.

This study aimed to characterize an animal model of colorectal cancer (CRC) in the early stages of disease development. Twenty-nine male Wistar rats were divided into two control groups (CTRL1 and CTRL2), receiving EDTA–saline injections and two induced groups (CRC1 and CRC2), receiving 1,2-dimethylhydrazine (DMH) injections for seven consecutive weeks. CRC1 and CTRL1 were euthanized at the 11th week, while CRC2 and CTRL2 were euthanized at the 17th week. DMH treatment decreased microhematocrit values and IL-6, ghrelin, and myostatin serum levels. Histopathological analysis of intestinal sections showed that DMH-treated rats were characterized by moderate to severe epithelial dysplasia. An adenoma was observed in one animal (CRC2 group), and the presence of inflammatory infiltrate at the intestinal level was primarily observed in DMH-treated animals. DMH also induced Ki-67 immunoexpression. The gut microbiota analysis showed a higher abundance of Firmicutes, Clostridia, Clostridiales, Peptostreptococcaceae, Blautia, Romboutsia, and Clostridium sensu stricto in CRC than CTRL rats, whereas Prevotellaceae, Prevotella, Akkermansia, and Lactobacillus levels were more prevalent in CTRL animals. Our results suggest that this model could be helpful to investigate chemoprevention in the early stages of CRC.

Piclamilast mitigates 1,2-dimethylhydrazine induced colon cancer in rats through modulation of Ras/PI3K/Akt/mTOR and NF-κβ signaling

Colorectal cancer (CRC) is the third leading type of adult cancer in both genders with high morbidity and mortality worldwide. Even though the discovery of many antineoplastic drugs for CRC, the current therapy is not adequately efficient.This study was designed to investigate the effect and mechanism of Piclamilast (PIC), a selective PDE4 inhibitor, on a DMH-induced colorectal cancer (CRC) rat model. The rats were grouped (n = 10) into group 1 (control), group 2 (PIC 3 mg/kg, p.o.), groups 3–5 received DMH (20 mg/kg/week, S.C.), and groups 4 and 5 received PIC (1 and 3 mg/kg/day, p.o.) for 15 weeks. The DMH treatment increased aberrant crypt foci (ACF), Proliferating cell nuclear antigen (PCNA), and TBARS levels, along with decreased antioxidant defenses (GSH, GSH-Px, and catalase). Increased NF-κβ expression and inflammatory cytokines were also evident. PIC dose-dependently reduced ACF and restored oxidative stress and inflammatory markers favorably. Moreover, PIC in its large, tested dose only significantly increased the intracellular level of cAMP and suppressed the activation of Ras and PI3K and its downstream Akt/mTOR signaling. Furthermore, PIC promoted CRC apoptosis, and increased the gene expression of the apoptotic factors, caspase-3 and Bax, and decreased the anti-apoptotic factor Bcl-2. The results of this study show that PIC may be a promising therapeutic agent for the treatment of CRC. PIC might inhibit the proliferation of CRC cells and induce apoptosis via multiple mechanisms that involve its antioxidant effect and inhibition of NF-κβ and Ras/PI3K/Akt/mTOR signaling.

Lactobacillus rhamnosus confers protection against colorectal cancer in rats

Purpose: To investigate the protective effect and mechanism of action of Lactobacillus rhamnosus against colorectal cancer (CRC).
 Methods: A total of 40 healthy female Sprague Dawley rats weighing 100 – 140 g (mean weight = 120 ± 20 g) were used for this study. The rats were randomly assigned to four groups of 10 rats each: normal control group, L. rhamnosus group; 1, 2-dimethylhydrazine (DMH) group and treatment group. Rats in L. rhamnosus group were inoculated with L. rhamnosus (1 x 108 CFU/mL) orally for 20 weeks, while rats in DMH group received 35 mg DMH/kg /week intraperitoneally for 10 weeks for induction of CRC. Treatment group rats received 35 mg DMH/kg bwt intraperitoneally for 10 weeks for induction of CRC, and were treated with L. rhamnosus (1 x 108 CFU/mL) orally for 20 weeks. After 20 weeks, the rats were euthanized using ether anesthesia. Expressions of inflammatory, angiogenesis and proapoptotic genes were determined using Western blotting and real-time quantitative polymerase chain reaction (qRT-PCR).
 Results: Treatment with L. rhamnosus significantly reduced the incidence of CRC in the rats (p < 0.05). The incidence of multiple tumors in the treatment group was also significantly reduced, when compared to DMH group (p < 0.05). The protein expressions of inducible nitric oxide synthase (iNOS), tumor necrosis factor α (TNF-α), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), cyclooxygenase-2 (COX-2), bcl-2 and vascular endothelial growth factor α (VEGF-α) were significantly upregulated in DMH group, when compared with normal control group (p < 0.05). However, treatment with L. rhamnosus significantly down-regulated the expressions of these proteins (p < 0.05). DMH treatment also significantly upregulated the expressions of iNOS, TNF-α, VEGF-α, NF-kB, β-catenin and bax genes (p < 0.05). However, L. rhamnosus significantly reversed the effects of DMH on the expression levels of these genes (p < 0.05).
 Conclusion: These results show that L. rhamnosus prevents CRC via suppression of expressions of inflammatory and angiogenesis genes, and upregulation of apoptotic gene expression.

Effects of Dietary Ethanol Extracts from Sake Rice and Sake Lees on Intestinal Impairment in Mice.

Glucosylceramide (GlcCer), a major sphingolipid in plants and fungi, is known to have food functions, such as preventing intestinal impairment and enhancing the moisture content of skin. This study investigated the influence of fermentation on the composition and function of lipophilic components containing GlcCer in plant-based foods; we compared the effects of ethanol extracts from sake rice (SR) and sake lees (SL) on colon impairment in mice. GlcCer and ceramide (Cer) levels in SL were much higher than those in SR, and GlcCer in SL contained 9-methyl-trans-4,trans-8-sphingadienine as a fungi-specific sphingoid base. 1,2-dimethylhydrazine (DMH) treatment markedly increased the formation of aberrant crypt foci (ACF) and the levels of TNF-α and lipid oxidation in mice colons. However, dietary SR or SL significantly suppressed these DMH-induced changes, and SR demonstrated stronger effects than SL. In addition, dietary SR or SL suppressed the expression of apoptotic and anti-apoptotic proteins induced by DMH treatment. This study suggests that SR or SL intake could reduce colon ACF formation via the suppression of inflammation and oxidation-induced cell cycle disturbances. When compared to SR, the weaked effects of SL rich in GlcCer may be the result of the changes in sphingolipid composition (sphingoid base and Cer) and differences in the concentration of other bioactive compounds produced or digested during fermentation.

Synbiotic Combination of Djulis (Chenopodium formosanum) and Lactobacillus acidophilus Inhibits Colon Carcinogenesis in Rats.

Djulis is a functional grain containing prebiotic dietary fiber, which has an anti-cancer potential. This study examined the preventive effect of djulis alone or in combination with Lactobacillus acidophilus on colon carcinogenesis induced by 1,2-dimethylhydrazine (DMH) and dextran sulfate sodium (DSS). Rats were divided into five groups and fed B (AIN-93G, blank), C (AIN-93G, control), D (10% djulis), DLA (10% djulis plus 5 × 106 cfu L. acidophilus/g), and DHA (10% djulis plus 5 × 107 cfu L. acidophilus/g) diets, respectively. All rats except for those in group B received three doses of DMH (40 mg/kg) by intraperitoneal injection and 3% DSS in drinking water. After 10 weeks of feeding, the colon was analyzed for precancerous lesions and biomarkers. DMH and DSS treatment induced aberrant crypt foci (ACF), especially in the distal colon. D, DLA, and DHA significantly reduced the numbers of total ACF, sialomucin-producing ACF (SIM-ACF), and mucin-depleted foci (MDF) in the distal colon compared to C. Additionally, DLA and DHA further downregulated the expressions of proliferating cell nuclear antigen (PCNA) and cyclooxygenase-2 (COX-2) and regulated apoptosis-related proteins. These results suggest that synbiotic combination of djulis and L. acidophilus shows the best inhibitory effect on colon carcinogenesis via regulation of proliferative, inflammatory, and apoptotic pathways.

Immunomodulatory Effect of Lactobacillus casei in a Murine Model of Colon Carcinogenesis.

We previously reported beneficial effects of the probiotic strain Lactobacillus casei 393 in hindering colon carcinogenesis in a 1,2-dimethylhydrazine (DMH)-induced BALB/c mouse model of colon cancer. In the present study, we investigated the effect of preventive administration of L. casei 393 on the levels of selected pro- and anti-inflammatory circulating cytokines, as well as subpopulations of splenic T cells. The resulting experimental data on IFNγ, TNFα, IL-10, and colon histological features demonstrated that administration of L. casei 2 weeks before DMH treatment impaired the pro-inflammatory effect of DMH, while maintaining the levels of the three cytokines as well as colon histology; it also modulated splenic CD4+, CD8+, and NK T cell subpopulations. The preventive administration of L. casei to DMH-treated mice increased IL-17A synthesis and Treg percentages, further indicating a tumor-protecting role. Together, the results suggest that the colon-cancer-protective properties of L. casei 393 involve the dampening of inflammation through cytokine homeostasis and the maintenance of a healthy T cell subpopulation dynamic. For these reasons, probiotics such as L. casei may contribute to the health of the host as they promote optimal control of the immune response. Further, they may be used as prophylactic agents in combination with standard therapies against colon cancer.

Inhibitory Effect of Dietary Curcumin on 1, 2-Dimethylhydrazine-Induced Colon Preneoplasia in Irradiated Rats

Introduction: Prevention of cancer remains a primary need and new chemopreventive agents must be developed for this purpose. It is well known that the radiotherapy is associated with severe side effects and offers no firm expectation for a cure. Thus, there is a constant need for the investigation of other potentially useful options. One of the widely sought approaches is cancer chemoprevention that uses natural agents. Curcumin, a natural plant product, has been shown to have anti-inflammatory and antioxidant properties and which, thus, may be a potential anticancer drug. Material and Methods: The inhibitory effects of dietary curcumin (0.6 % in diet) on colonic precancerous lesions in rats treated with 1,2-dimethylhydrazine, (DMH, 20 mg/kg, s.c. once weekly for 6 weeks) or exposed to γ-radiation (6.5 Gy) alone or in combination were evaluated histologically and histochemically. Results: The results showed clear features of colonic dysplasia with DMH treatment. The dysplastic crypts exhibited marked hyperchromatism, loss of polarity besides nuclear and cellular stratification. Whereas, γ-irradiation revealed marked crypt dilatation accompanied by disorganized crypt structure and alteration of surface epithelium. The results also demonstrate an apparent synergy between the radiation and the chemical carcinogen in the induction of augmentation of mucosal abnormalities accompanied with increased total DNA content and cell proliferation. Consistent with these observations, changes in the type of mucous secretion with predominance of sialomucins were observed in the areas of mild to moderate dysplasia whilst the surrounding normal epithelium produced sulphated material. Mucus depletion was a common feature in areas of severe dysplasia. Addition of curcumin to the diet remarkably reduced the amount and severity of dysplastic lesions with DMH-induced colon preneoplasia without appreciable toxicity. Moreover, curcumin could prevent or improve the disruption of colonic architecture caused by γ- irradiation. Such improvement was also investigated but to a lesser extent with the combined radiation and DMH. Conclusion: These results indicated that curcumin is potent in inhibiting the preneoplastic lesions and other cellular events relevant to colon and was, therefore, of value as a safe chemotherapeutic agent.

Chemopreventive efficacy zingerone (4-[4-hydroxy-3-methylphenyl] butan-2-one) in experimental colon carcinogenesis in Wistar rats.

Colorectal cancer is one of the most common cancers worldwide. Development of naturally occurring inexpensive and safe alternatives can be effective in suppressing colon related proliferations. Zingerone (4-[4-hydroxy-3-methylphenyl] butan-2-one), a polyphenolic alkanone of ginger, has massive pharmacological properties and thus can be used as promising candidate against various ailments. In the current study, we aimed at demonstrating the protective effect of zingerone against experimental colon carcinogenesis and elucidating its possible mechanism by studying inflammatory and Nrf-2 signaling cascade. Four groups of animals (I-IV) were made with six animals each. Group I (control) was given normal saline orally. Group II was given 1,2-dimethylhydrazine (DMH) at the dose rate of 20 mg/kg body weight. Group III and IV were treated with DMH at the dose rate of 20 mg/kg body weight and also received oral treatment of zingerone at a dose rate of 50 and 100 mg/kg body weight, respectively, for first 5 weeks and animals were euthanized after 16 weeks. Our results reveal that DMH treated rats exhibited elevated ROS and MDA levels, increased activity of cytochrome P450 2E1 and serum marker enzyme carcinoembreyonic antigen (CEA), increased no of aberrant crypts of foci (ACF), and elevated expression of inflammatory and proliferative proteins. Nrf-2 was downregulated by DMH treatment. Treatment with zingerone to DMH treated rats, resulted in alterations in the activity of the cytochrome P450 2E1 and CEA. In addition, immunostaining of NF-kB-p65, COX-2, iNOS, and PCNA, Ki-67 was suppressed by zingerone. Furthermore, zingerone administration also attenuated the level of IL-6 and TNF-α and it also helps in preserving mucous layer. Thus, zingerone could be considered as a good chemopreventive agent in experimental model of colon carcinogenesis. Further studies are required to study other pathways involved in colon carcinogenesis and their modulation buy zingerone.

Extraction of Lipophilic Fraction from Polished Rice Improves Its Ameliorative Effect on Intestinal Impairment

Glucosylceramide (GlcCer), a major sphingolipid in plants and fungi, is known to have food functions such as preventing intestinal impairment and enhancing the moisture content of skin. However, there is little information about functions of GlcCer in food sources as most of the studies on GlcCer functions are done using purified GlcCer. This study was performed to investigate the effects of GlcCer contained in food on intestinal impairment; polished rice flour (RF) and this ethanol extract (RE) were used as sources of GlcCer, and these were evaluated by studying the formation of aberrant crypt foci (ACF) in 1,2-dimethylhydrazine (DMH)-treated mice, which is a model of colon cancer. Mice were fed with either a control diet, a RF diet where RF replaces cornstarch (150 g/kg), or a plus RE diet (0.5 g/kg; RE was extracted from the same amount of RF present in the RF diet). The amount of GlcCer was similar in both the RF and RE diets (3.0 and 2.7 mg/kg, respectively). DMH treatment induced the formation of ACF and the production of inflammation-related cytokines. Both dietary RF and RE suppressed ACF formation and RE, in particular, showed a significant suppressive effect. Dietary RE inhibited the production of almost all of the inflammation-related cytokines studied, while RF suppressed only a few of these cytokines. The present study suggests that the lipophilic fraction including GlcCer, present in polished rice has protective effects against intestinal impairment, but it requires extraction since digestion alone is not enough to elicit its complete protective action.

Pectin-encrusted gold nanocomposites containing phytic acid and jacalin: 1,2-dimethylhydrazine-induced colon carcinogenesis in Wistar rats, PI3K/Akt, COX-2, and serum metabolomics as potential targets.

Phytic acid (PA) has momentous chemotherapeutic potential. Due to the chelate formation and rapid elimination, it is not popular in cancer treatment. The present work was inquested to develop a surface-modified nanoformulation of PA which prevents its speedy elimination and maximizes chemotherapeutic action. Chloroauric acid was reduced with pectin to produce pectin-gold nanoparticles (PGNPs). PGNPs were incubated with PA and jacalin for drug loading and surface modifications, respectively, to form PA-loaded jacalin-pectin-gold nanoparticles (PA-J-PGNPs). Formulation(s) were assessed for various pharmaceutical/pharmacological parameters. To validate the efficacy against colon carcinogenesis, formulation(s) were assessed in 1,2-dimethylhydrazine (DMH)-treated Wistar rats. DMH treatment distorted colonic architecture, oxidative, and hemodynamic parameters, which were favorably restored by PA-J-PGNP administration. To further confirm our deliberations, formulation(s) were also examined against DMH-altered metabolic changes and expression of markers pertaining to cellular proliferation, which was reinstated by PA-J-PGNPs. Our findings establish PA formulation(s) as a promising approach for suppression of colon carcinogenesis.

Chemopreventive role of olive oil in colon carcinogenesis by targeting noncoding RNAs and methylation machinery.

Epigenetic therapy induced by dietary components has become a strong interest in the field of cancer prevention. Olive oil, a potent dietary chemopreventive agent, control colon cancer, however, its role in epigenetic therapy remains unclear. Thus, we aimed to investigate the effect of olive oil in a preclinical model of colon cancer by targeting genetic and epigenetic mechanisms. DMH was used to induce colon cancer in rats; while olive oil was given to separate group of rats along with DMH treatment. Tumor burden and incidence in DMH and DMH + olive oil-treated rats was observed by macroscopic examination and histoarchitectural studies. Potent anti-inflammatory, anti-angiogenic and pro-apoptotic activity of olive oil was explored by gene expression and immunohistochemical studies. The effect of olive oil on epigenetic alterations was examined by detecting promoter methylation with MS-HRM and dysregulation of miRNA by TaqMan MicroRNA Assay. We observed that olive oil administration lowered tumor incidence and inhibited the development of tumors in DMH-treated rats. Olive oil markedly decreased the expression of inflammatory and angiogenic markers and restored the expression of pro-apoptotic markers in DMH-treated rats. Furthermore, the inverse relationship between gene expression and DNA methylation, deviant miRNA pattern and miRNA silencing mediated by aberrant DNA methylation was also seen in DMH-treated rats, which was potentially reversible upon olive oil treatment. Our study concludes that olive oil may play a role in the epigenetic therapy by altering NF-κB and apoptotic pathways via targeting noncoding RNAs and methylation machinery that affecting epigenome to prevent colon carcinogenesis.

Ellagic acid ameliorates cisplatin toxicity in chemically induced colon carcinogenesis

Cis-diamminedichloroplatinum(II) (cisplatin) (CP) is an important chemotherapeutic agent used in the treatment of several cancers. However, it has several side effects including nephrotoxicity gonadotoxicity, hepatotoxicity, and ototoxicity. In in vitro experiments, antioxidants or reactive oxygen species scavengers have a cytoprotective effect on cells exposed to cisplatin (CP). Ellagic acid (EA) is one such bioactive polyphenol that is abundant in some fruits, nuts, and seeds. Various authors have reported that EA has strong antioxidant and antitumor potential. The present study was, therefore, carried out to explore the protective potential of EA on CP-induced gonadotoxicity and nephrotoxicity in colon tumor-bearing mice. Animals were divided into five groups: Group I: normal control, Group II: DMH treated. After 20weeks of DMH treatment, the animals were divided into four subgroups, viz., Group III: no treatment, Group IV: EA, Group V: CP, and Group VI: CP + EA. Administration of EA significantly ameliorated the toxicity caused by CP as indicated by improved kidney function tests and reproductive function tests. EA treatment to CP-abused mice also led to a marked reduction in the extent of peroxidative damage to tissue as was evident from the improvement in the histopathological changes in kidney and testis. Blood counts were also improved on administration of EA to CP-treated mice. This article provides the evidence that antioxidant efficacy of EA has beneficial effects on CP-induced nephrotoxicity and gonadotoxicity and contributes to understanding the role of oxidative stress, and suggests several points as part of the mechanism of CP toxicity.

Chemoprevention by Probiotics During 1,2-Dimethylhydrazine-Induced Colon Carcinogenesis in Rats.

Probiotics are believed to have properties that lower the risk of colon cancer. However, the mechanisms by which they exert their beneficial effects are relatively unknown. To assess the impact of probiotics in preventing induction of colon carcinogenesis in rats. The rats were divided into six groups viz., normal control, Lactobacillus plantarum (AdF10)-treated, Lactobacillus rhamnosus GG (LGG)-treated, 1,2-dimethylhydrazine (DMH)-treated, L. plantarum (AdF10)+DMH-treated and L. rhamnosus GG (LGG)+DMH-treated. Both the probiotics were supplemented daily at a dose of 2×1010 cells per day. DMH at a dose of 30mg/kg body weight was administered subcutaneously twice a week for the first 4weeks and then once every week for a duration of 16weeks. Glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and catalase as protein expression of genes involved in apoptosis were assessed during DMH-induced colon carcinogenesis in rats. DMH treatment decreased the activity of GSH, GPx, GST, SOD and catalase. However, AdF10 and LGG supplementation to DMH-treated rats significantly increased the activity of these enzymes. Further, DMH treatment revealed alterations in the protein expressions of various genes involved in the p53-mediated apoptotic pathway such as p53, p21, Bcl-2, Bax, caspase-9 and caspase-3, which, however, were shifted towards normal control levels upon simultaneous supplementation with probiotics. The present study suggests that probiotics can provide protection against oxidative stress and apoptotic-related protein disregulation during experimentally induced colon carcinogenesis.

Arsenic trioxide exposure accelerates colon preneoplasic aberrant crypt foci induction regionally through mitochondrial dysfunction.

Arsenic poisoning is a worldwide problem. Thus, we studied the effects of arsenic trioxide (ATO) administration on a 1,2-dimethylhydrazine (DMH)-induced preneoplasic colon carcinogenesis model. Mice were separated into four study groups; the control group received only vehicles. The ATO group received daily a 2.5 mg kg-1 dose for 4 weeks. The DMH group received DMH (20 mg kg-1) twice in two weeks. The third group (D-ATO) had the same as the DMH group with ATO administration starting at week 10. At the end of 14 weeks, colons from sacrificed mice were taken, segmented into distal and proximal and subjected to aberrant crypt foci (ACF), aberrant crypt (AC) counting, alcian blue, H&E and Hoechst histological study and lastly oxidative stress marker analysis as well as mitochondrial swelling assessment. Data showed a significant increase in ACF and AC after DMH treatment, which was further increased after ATO addition. A perturbed histological structure was observed and loss of mucin producing cells in the colon tissue was observed. An important impact on the distal colon compared to the proximal one was noticed. The oxidative stress balance showed a similar pattern with an increase in MPO, NO/l-ornithine balance and MDA, while a decrease was observed in the antioxidant enzymes (CAT, SOD and GSH). In all parameters analyzed, the distal colons showed higher values than proximal. Furthermore, histological cell death analysis in combination with mitochondrial permeability pore opening suggested ATO contribution in the pathological effect. Our study has shown that ATO administration accelerated colon cancer development suggesting the heaviness of such treatments and the need to explore combinations and cycle type formulas.

Effect of carcinogen 1,2-dimethylhydrazine treatment on fiber types in skeletal muscles of male Wistar rats.

The cancerogen 1,2-dimethylhydrazine (DMH), widely used in the experimental animal model of carcinogenesis, affects various organs, but its effect on muscle fibers is unknown. To evaluate the effect of 15-week DMH treatment on the fiber size and myosin heavy chain (MyHC) isoforms, which substantially determine fiber types and their contractile characteristics, pure and hybrid fiber types were immunohistochemically determined according to the MyHC isoform expression in soleus, extensor digitorum longus, gastrocnemius medialis and lateralis muscles of DMH-treated and control male Wistar rats. Whereas the size of fibers was mostly unaffected, the MyHC isoform expression was partially affected in both gastrocnemius samples, but not in the soleus and extensor digitorum longus of DMH-treated rats. The lower proportions of hybrid fiber types and especially that of type 1/2x in most gastrocnemius samples of DMH-treated rats resulted in a shift towards a single MyHC isoform expression, but the extent and pattern of the MyHC isoform shift varied across the different gastrocnemius samples. Such variable response to DMH treatment across muscles indicates that each muscle possesses its own adaptive range. These findings are essential for an accurate evaluation of skeletal muscle characteristics in DMH animal model.

Metformin prevents hormonal and metabolic disturbances and 1,2-dimethylhydrazine-induced colon carcinogenesis in non-diabetic rats.

Effects of two doses of the anti-diabetic drug, metformin (MF), on hormonal and metabolic levels of serum of non-diabetic male Wistar rats with 1,2-dimethylhydrazine (DMH)-induced colon tumor adenocarcinomas were studied. Carcinogenesis in the animals was also observed. Rats with DMH-induced colon adenocarcinomas had elevated levels of serum glucose, insulin, insulin-like growth factor-1, total cholesterol, triglycerides, catalase, malonic dialdehyde, glycated hemoglobin, aspartate aminotransferase, and alanine aminotransferase and decreased hemoglobin. Treatment with two doses of MF normalized majority of these changes in DMH-treated rats, whereas the drug was ineffective in rats without DMH treatment. The only exception was the decreased triglyceride levels in MF-treated rats. A 100 mg/kg dose of MF increased DMH-induced exophytic colon carcinomas and decreased endophytic tumors compared with untreated rats. Moreover, both MF doses increased DMH-induced and highly differentiated tumors and decreased the invasiveness of colon carcinomas compared with rats provided with DMH and water. Therefore, effects of MF on metabolic homeostasis are critical for preventing colon cancer.

Coffee arabica complies Chemo-preventive Activity against DMH-induced Colorectal Cancer in Experimental Rat Model

The aim of this study was to evaluate chemopreventive potential of Coffee arabica in DMH-induced colorectal carcinogenesis in the rat model. Totally, 35 female wistar rats were divided into seven equal groups. Groups I-VII except group VI were given freshly prepared neutral DMH in normal saline, once a week for 5 weeks. Group VI received normal saline alone. Groups II and III received oral dose of coffee every time when they are given DMH. Groups IV and V received coffee after 5 months of DMH treatment. Group VII was treated with aspirin. Multiple plaque lesions, aberrant crypts and aberrant crypt foci were observed in colorectal walls of the DMH alone treated rat groups. The numbers of preneoplastic features were significantly reduced in coffee or aspirin treated groups. Histologically, different degree of dysplasia and hyperplasia was observed in DMH alone group. The above features were significantly reduced in coffee or aspirin treated groups. Serum biomarkers and body weight of DMH-induced colorectal cancer were appreciably maintained in coffee and aspirin treated groups. Taken together, the results of this study revealed that Coffee arabica has significant effect on reducing the number of preneoplastic lesions and polyps, considerably suppressing tumor progression and invasion.

Effects of Dietary Plant-origin Glucosylceramide on Colon Cytokine Contents in DMH-treated Mice.

In this study, the effects of dietary plant-origin glucosylceramide (GlcCer) on colon cytokine contents were investigated in 1,2-dimethylhydrazine (DMH)-treated mice, a model of colon cancer. DMH treatment induced the formation of aberrant crypt foci (ACF) and the production of inflammatory cytokines and chemokaines. Dietary GlcCer suppressed ACF formation and cytokine production in these mice. In particular, chemokine production was suppressed by dietary GlcCer. These GlcCer-related trends of suppression were similar to those observed in our previous study on dextran sulfate sodium salt (DSS)-treated mice. These results provide further evidence for the suppression of DMH-induced inflammation by dietary GlcCer.

Cellular immune response in rats with 1,2-dimethylhydrazine-induced colon cancer after transplantation of placenta-derived multipotent cells

We describe the state of the immune system at the late stage of 1,2-dimethylhydrazine (DMH)-induced colon cancer and after administration of placenta-derived multipotent cells (PDMCs). The spleen and thymus indices did not differ among the groups of intact and DMH-treated rats and were not affected by the administration of placenta-derived multipotent cells following the DMH treatment. Moreover, no difference in spontaneous or stimulated phagocytic activity of peritoneal macrophages was observed between healthy rats or the animals with DMH-induced colon cancer (with or without the administration of PDMCs). However, the proliferation of the T cells in the spleen was lower in rats with colon cancer regardless of the administration of PDMCs. Similarly, no changes were observed in the cell cycle distribution of proliferating spleen cells after stimulation by lipopolysaccharide.Conclusion. Our data demonstrate the absence of the active reaction by peritoneal macrophages and spleen cells to a colon cancer at mid/late stage. Additionally, the administration of PDMCs does not result in a measurable anti-tumor immune response.