Crimean-Congo hemorrhagic fever virus prevalence in livestock of Jabalpur, Madhya Pradesh, Central India and its implications for public health.

The rise of Crimean-Congo Hemorrhagic Fever (CCHF), poses a significant global health challenge, urging immediate action and continuous surveillance. With no available vaccines, monitoring pathogen presence is critical to identify at-risk areas promptly. A study was designed to assess the incidence of CCHF virus in goats and cattle using commercial ELISA IgG kits in tribal-dominated regions. Overall, 16% of the samples (n = 63/393) were positive for CCHF virus-specific IgG antibodies, whereas sero-prevalence detected in cattle 11.6% [95% CI:7-17.7] and in goats 18.9% [95% CI: 13.76-24.01], respectively. Statistically, Animal gender and age didn't significantly affect prevalence (p-value >0.05). Our finding indicates unnoticed CCHF virus circulation. Notably, lack of public awareness about zoonotic diseases in the study region was recorded. To combat this emerging tick-borne disease effectively, it's crucial to screen individuals with hemorrhagic manifestations in healthcare settings and active surveillance of ticks to prevent unwarranted public health outbreaks and design preventive interventions.

Prioritization of Physio-Biochemical Selection Indices and Yield-Attributing Traits toward the Acquisition of Drought Tolerance in Chickpea (Cicer arietinum L.).

Chickpea is widely grown in rainfed areas of developing countries because of its nutritional abundance and adaptability. To overcome the environmental effect of drought on yield, a characteristic-linked selection strategy is proved as well-thought-out and advantageous for the development of drought-tolerant cultivars. To precisely understand the contribution of various physio-biochemical and yield-attributing traits toward drought tolerance in chickpea (Cicer arietinum L.), forty chickpea genotypes were evaluated in the years 2020-2021 and 2021-2022 under normal irrigated as well as drought-stressed conditions. Among the studied genotypes, genotype ICC4958 retained the highest chl content (0.55 mg g-1 FW), minimal electrolyte leakage, and superoxide dismutase (1.48 U/mg FW) and peroxidase (2.21 µmol/min/g FW) activities while cultivar JG11 maintained the maximum relative water content and proline accumulation. The principal-component-based biplots prioritized the physio-biochemical and yield-accrediting characteristics based on their association significance and contribution to terminal drought tolerance. Under drought stress, grain yield per plant was depicted to have a strongly positive association with canopy temperature depression, catalase, superoxide dismutase, and peroxidase activities as well as total soluble sugar, proline, and chlorophyll content, along with the numbers of pods and biological yield per plant. These identified physio-biochemical and yield-attributing traits can be further deployed to select drought-tolerant chickpea genotypes for the breeding of climate-smart chickpea genotypes.

Molecular Advances to Combat Different Biotic and Abiotic Stresses in Linseed (Linum usitatissimum L.): A Comprehensive Review.

Flax, or linseed, is considered a "superfood", which means that it is a food with diverse health benefits and potentially useful bioactive ingredients. It is a multi-purpose crop that is prized for its seed oil, fibre, nutraceutical, and probiotic qualities. It is suited to various habitats and agro-ecological conditions. Numerous abiotic and biotic stressors that can either have a direct or indirect impact on plant health are experienced by flax plants as a result of changing environmental circumstances. Research on the impact of various stresses and their possible ameliorators is prompted by such expectations. By inducing the loss of specific alleles and using a limited number of selected varieties, modern breeding techniques have decreased the overall genetic variability required for climate-smart agriculture. However, gene banks have well-managed collectionns of landraces, wild linseed accessions, and auxiliary Linum species that serve as an important source of novel alleles. In the past, flax-breeding techniques were prioritised, preserving high yield with other essential traits. Applications of molecular markers in modern breeding have made it easy to identify quantitative trait loci (QTLs) for various agronomic characteristics. The genetic diversity of linseed species and the evaluation of their tolerance to abiotic stresses, including drought, salinity, heavy metal tolerance, and temperature, as well as resistance to biotic stress factors, viz., rust, wilt, powdery mildew, and alternaria blight, despite addressing various morphotypes and the value of linseed as a supplement, are the primary topics of this review.

Genome Editing and Improvement of Abiotic Stress Tolerance in Crop Plants.

Genome editing aims to revolutionise plant breeding and could assist in safeguarding the global food supply. The inclusion of a 12-40 bp recognition site makes mega nucleases the first tools utilized for genome editing and first generation gene-editing tools. Zinc finger nucleases (ZFNs) are the second gene-editing technique, and because they create double-stranded breaks, they are more dependable and effective. ZFNs were the original designed nuclease-based approach of genome editing. The Cys2-His2 zinc finger domain's discovery made this technique possible. Clustered regularly interspaced short palindromic repeats (CRISPR) are utilized to improve genetics, boost biomass production, increase nutrient usage efficiency, and develop disease resistance. Plant genomes can be effectively modified using genome-editing technologies to enhance characteristics without introducing foreign DNA into the genome. Next-generation plant breeding will soon be defined by these exact breeding methods. There is abroad promise that genome-edited crops will be essential in the years to come for improving the sustainability and climate-change resilience of food systems. This method also has great potential for enhancing crops' resistance to various abiotic stressors. In this review paper, we summarize the most recent findings about the mechanism of abiotic stress response in crop plants and the use of the CRISPR/Cas mediated gene-editing systems to improve tolerance to stresses including drought, salinity, cold, heat, and heavy metals.

Screening and Selection of Drought-Tolerant High-Yielding Chickpea Genotypes Based on Physio-Biochemical Selection Indices and Yield Trials.

Chickpea production is seriously hampered by drought stress, which could be a great threat in the future for food security in developing countries. The present investigation aimed to screen the drought-tolerant response of forty desi chickpea genotypes against drought stress through various physio-biochemical selection indices and yield-attributing traits. Principle component-based biplot analysis recognized PG205, JG2016-44, JG63, and JG24 as tolerant genotypes based on physiological selection indices. These genotypes retained higher relative water content, stomatal conductance, internal CO2 concentration, and photosynthetic rate. ICC4958, JG11, JAKI9218, JG16, JG63, and PG205 were selected as tolerant genotypes based on biochemical selection indices. These genotypes sustained higher chlorophyll, sugar and proline content with enhanced antioxidant enzyme activities. With respect to yield trials, JAKI9218, JG11, JG16, and ICC4958 had higher seed yield per plant, numbers of pods, and biological yield per plant. Finally, JG11, JAKI9218, ICC4958, JG16, JG63, and PG205 were selected as tolerant genotypes based on cumulative physio-biochemical selection indices and yield response. These identified drought-tolerant genotypes may be further employed in climate-smart chickpea breeding programs for sustainable production under a changing climate scenario.

Molecular epidemiology of Orientia tsutsugamushi from outbreak regions, Madhya Pradesh, central India.

Scrub typhus is a seriously neglected life threatening disease in Asia and the islands of the Pacific and Indian oceans. The causative agent is Orientia tsutsugamushi, an obligate intra-cytosolic bacterium transmitted to vertebrate animals such as human or rodent by larval trombiculid mites (chiggers). Here, we conducted an outbreak investigation in Madhya Pradesh state in central India after sudden upsurge in scrub typhus cases and mortality in humans. Sixty-five live traps were placed for capturing the rodents. The captured rodent species were identified and the samples were subjected to nested PCR targeting 56kDa TSA gene. Analysis revealed for the first-time predominant circulation of Karp genotype in this region. The vector species involved in transmission is Leptotrobidium deliense. In conclusion, we reported the circulation of Karp strain in outbreak regions of Madhya Pradesh and suggest that public health monitoring and surveillance needs to be improved. Studies on antigenic diversity, association of strains with clinical spectrum and pathogenicity in the local setup will be essential for development of region-specific diagnostics and vaccines.

Growing teratoma syndrome: Two case reports.

We present two cases of 10 and 27 years old girls with recurrence of immature teratoma after an incomplete surgical staging. In both cases, there were huge abdominopelvic masses despite decrease in tumor markers with chemotherapy. Complete surgical resection of these masses was done, and histopathology showed only mature teratoma.

Multi-hazard susceptibility and exposure assessment of the Hindu Kush Himalaya.

Mountainous regions are highly hazardous, and these hazards often lead to loss of human life. The Hindu Kush Himalaya (HKH), like many mountainous regions, is the site of multiple and overlapping natural hazards, but the distribution of multi-hazard risk and the populations exposed to it are poorly understood. Here, we present high-resolution transboundary models describing susceptibility to floods, landslides, and wildfires to understand population exposure to multi-hazard risk across the HKH. These models are created from historical remotely sensed data and hazard catalogs by the maximum entropy (Maxent) machine learning technique. Our results show that human settlements in the HKH are disproportionately concentrated in areas of high multi-hazard risk. In contrast, low-hazard areas are disproportionately unpopulated. Nearly half of the population in the region lives in areas that are highly susceptible to more than one hazard. Warm low-altitude foothill areas with perennially moist soils were identified as highly susceptible to multiple hazards. This area comprises only 31% of the study region, but is home to 49% of its population. The results also show that areas susceptible to multiple hazards are also major corridors of current migration and urban expansion, suggesting that current rates and patterns of urbanization will continue to put more people at risk. This study establishes that the population in the HKH is concentrated in areas susceptible to multiple hazards and suggests that current patterns of human movement will continue to increase exposure to multi-hazards in the HKH.

Determination of cut-off of diagnostic ELISA for Scrub typhus in endemic setup: Central India.

Serology remains the mainstay for diagnosis of scrub typhus. In central India, diagnosis of this neglected emerging zoonotic disease suffers due to lack of standardized region-specific cutoff value and diagnostic test. Henceforth, standardized region-specific cutoff value for diagnostic ELISA play a significant role in initial treatment of patients and to differentiate other febrile diseases in endemic setup. A total of 144 patients of all age groups with acute undifferentiated febrile illness patients, forty healthy controls, dengue and chikungunya positive thirty-five samples in each category, respectively were enrolled in the study and subjected to IgM ELISA (InBioS, International, Inc.). Samples showing OD value more than 0.5 in IgM ELISA, were subjected to nested PCR. Both, receiver operating characteristic (ROC) curve and healthy volunteer samples mean with +3 SD were considered to generate region specific cutoff OD value. A total of 48 patients were diagnosed as cases of scrub typhus through IgM ELISA. Out of 48 samples, 30 were positive by nested PCR. The ROC curve analysis revealed a diagnostic ELISA cutoff value of 0.73 with sensitivity and specificity of 95% and 100%, respectively. The cut off arrived from healthy volunteer is mean OD + 3 SD is 0.72. Considering the significance of scrub typhus diagnosis for treatment and to understand disease dynamics in region wise, the cutoff value of >0.72 for diagnostic ELISA for Madhya Pradesh in central India can be used.

Outcome of acetabulum fractures treated with open reduction and internal fixation through Kocher-Langenbeck Approach: A retrospective study.

BACKGROUND: Complex anatomy of acetabular fracture is quite challenging for the orthopedic surgeons. Many Acetabular fracture fixation approaches have been used for a long time to treat different fracture patterns of acetabulum. Kocher-Langenbeck Approach (K-L approach) of acetabulum fracture is usually used by most of orthopedic surgeons. In this retrospective study, we evaluated the clinical and functional outcome of subtypes of acetabulum fractures treated with K-L approach. Assessment of Intra and postoperative complications of subtypes of acetabulum fractures was also done. METHOD: Eighty patients (48 men and 32 women) were included in this retrospective study with a mean follow-up period of 2.6 years. Fractures were classified according to Letournal and Judet classification. K-L approach was performed in all these patients. Post operative reduction, Radiological outcome was quantified using Matta's criteria while the functional outcome was assessed according to Merle d'Aubigné and Postel scoring system. Postoperative complications were evaluated. RESULTS: The mean age of a total of 80 cases was 43.64 ±â€¯13.24 year. The type of fracture was found to be significantly associated with concentric/non-concentric reduction (p = 0.003) and with post op reduction (p = 0.005). The post operative reduction was found to be significantly associated with radiological (p < 0.001) and functional outcome (p < 0.001) at one year post op. The type of fracture was found to be significantly associated with radiological outcome (p < 0.001) while non-significantly found to be associated with functional outcome at 1 year (p = 0.050). The type of fracture was found to be significantly associated with post op complications (p = 0.003) and with arthritis (p = 0.001). CONCLUSION: K-L approach is a multifaceted and convenient approach for treating acetabulum fractures. Type of fracture and post-operative reduction are key factors for a satisfactory outcome. Transverse with posterior wall fracture has the worst prognosis.

Therapeutic efficacy of artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in four malaria endemic states of India.

BACKGROUND: Malaria is a major public health problem in India and accounts for about 88% of malaria burden in South-East Asia. India alone accounted for 2% of total malaria cases globally. Anti-malarial drug resistance is one of the major problems for malaria control and elimination programme. Artemether-lumefantrine (AL) is the first-line treatment of uncomplicated Plasmodium falciparum in north eastern states of India since 2013 after confirming the resistance against sulfadoxine-pyrimethamine. In the present study, therapeutic efficacy of artemether-lumefantrine and k13 polymorphism was assessed in uncomplicated P. falciparum malaria. METHODS: This study was conducted at four community health centres located in Koraput district of Odisha, Bastar district of Chhattisgarh, Balaghat district of Madhya Pradesh and Gondia district of Maharashtra state. Patients with uncomplicated P. falciparum malaria were administered with fixed dose combination (6 doses) of artemether-lumefantrine for 3 days and clinical and parasitological response was recorded up to 28 days as per World Health Organization protocol. Nucleotide sequencing of msp1 and msp2 gene was performed to differentiate between recrudescence and reinfection. Amplification and sequencing of k13 propeller gene region covering codon 450-680 was also carried out to identify the polymorphism. RESULTS: A total 376 malaria patients who fulfilled the enrolment criteria as well as consented for the study were enrolled. Total 356 patients were followed up successfully up to 28 days. Overall, the adequate clinical and parasitological response was 98.9% and 99.4% with and without PCR correction respectively. No case of early treatment failure was observed. However, four cases (1.1%) of late parasitological failure were found from the Bastar district of Chhattisgarh. Genotyping of msp1 and msp2 confirmed 2 cases each of recrudescence and reinfection, respectively. Mutation analysis of k13 propeller gene showed one non-synonymous mutation Q613H in one isolate from Bastar. CONCLUSIONS: The study results showed that artemether-lumefantrine is highly effective in the treatment of uncomplicated P. falciparum malaria among all age groups. No functional mutation in k13 was found in the study area. The data from this study will be helpful in implementation of artemether-lumefantrine in case of treatment failure by artesunate plus sulfadoxine-pyrimethamine.

Building climate change resilience by using a versatile toolkit for local governments and communities in rural Himalaya.

With the impacts of climate disruption becoming more evident there has been an increase in the uptake of climate change adaptation "toolkits" to assist local governments build community resilience and adapt to the impacts of climate change. There is increasing attention and call for practitioners to adopt proactive and participatory approaches to help in the adaptive response planning process. One such toolkit is the International Council for Local Environmental Initiatives (ICLEI) Asian Cities Climate Change Resilience Network (ACCRN) Process (IAP). This is a simple but rigorous toolkit developed to help local governments in Asian cities build resilience to the impacts of climate change. This paper outlines the application of the toolkit to determine its versatility in the rural context and was trialled in the Himalayan rural enclave of Ramgad in the Indian state of Uttarakhand. Given the differences between urban and rural environments, the outcomes highlighted the need for further investigation and analysis into the process to ensure that the methodology truly reflects the nature of rural systems and their level of vulnerability and adaptive capacity. Overall, the toolkit proved to be a simple but versatile toolkit to assess the vulnerability and adaptive capacity of communities in rural Himalaya. Over 40 resilience intervention strategies were developed for the Ramgad enclave and these were prioritized according to their technical, political, social and economic feasibility.

PI3K/Akt Pathway and miR-21 are Involved in N-Ethyl-N-Nitrosourea-Induced F1 Mouse Lung Tumorigenesis: Effect of Inositol Hexaphosphate.

The risk of cancer development in offspring due to carcinogen exposure during pregnancy is a serious issue. In this study, we explored the involvement of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and microRNA-21 (miR-21) in transplacental lung tumorigenesis and its prevention by dietary compound inositol hexaphosphate (IP6) in F1 mice. Balb/c mice were exposed to the N-ethyl-N-nitrosourea (ENU) intraperitoneally on the 17th day of gestation. After weaning, half of the litters were fed with oral 2% IP6. At the end of 30, 120, or 240 days, we did not observe any effect on fetal viability or weight between ENU-exposed and non-exposed litters and the same was true of IP6. Altered expressions of the PI3K/Akt pathway were observed in F1 mice. Further, miR-21 expressions were found to be modulated at the respective time as well, along with the activation of matrix metalloproteinase (MMP-9) and vascular endothelial growth factor expression. Akt activation also enhanced the expression of cyclin D1, cyclooxygenase-2 (COX-2), nuclear factor-κB (NF-κBp50), and mammalian target of rapamycin (mTOR). IP6-fed F1 mice showed reduced tumorigenesis along with reduced expression of the PI3K/Akt pathway miR-21 and downstream targets. The PI3K/Akt pathway and miR-21 are involved in transplacental lung tumorigenesis, whereas IP6 seemed to affect lung tumorigenesis by suppressing the expression of the PI3K/Akt pathway in F1 mice.

Visceral leishmaniasis from a non-endemic Himalayan region of Nepal.

Visceral leishmaniasis (VL) is endemic to the southern plains of Nepal. Here, we report the first case of VL from a non-endemic Himalayan region of Nepal. The patient presented with a history of high-grade fever, splenomegaly, and anemia but had not traveled to a VL-endemic region. Visceral leishmaniasis was diagnosed following microscopic detection of the Leishmania species amastigote in a bone marrow aspirate, positive result for the rK39 test, and further validation by nested polymerase chain reaction (PCR). The patient was treated with 5 mg/kg liposomal amphotericin B and was clinically improved upon discharge. Our result suggests that VL is expanding towards non-endemic regions of Nepal, and it should therefore be considered that VL surveillance systems be strengthened, particularly for non-program districts and VL be included as a differential diagnosis in febrile illnesses.

Colloidal Vesicular System of Inositol Hexaphosphate to Counteract DMBA Induced Dysregulation of Markers Pertaining to Cellular Proliferation/Differentiation and Inflammation of Epidermal Layer in Mouse Model.

Cancer is a global health problem and chemoprevention is a promising approach for reducing cancer burden. Inositol hexaphosphate (IP6), a natural bioactive constituent of cereals, legumes, etc., has momentous potential as an antiangiogenic agent, that specifically affects malignant cells. The shortcoming is its quick absorption on oral/topical administration. Niosomes are flexible carriers for topical drug delivery. The central venture of current research was to optimize and characterize niosomal delivery system of IP6 for treatment of skin cancer. Thin film hydration method was utilized to prepare IP6 niosomes, and these were dispersed as a suspension in a suitable base. Developed formulations were analyzed for various physicochemical and pharmacological parameters such as particle size, encapsulation efficiency, morphology, drug release, texture analysis, irritability, cell line studies, Western blotting, RT-PCR, and histopathology. IP6 niosomal suspension and IP6 in acetone displayed IC50 value at the concentration of 0.96 mM (0.63 mg/mL) and 1.39 mM (0.92 mg/mL), respectively. IP6 niosomal suspension showed significantly higher (p < 0.05) activity and showed cytotoxic effect in SK-MEL-2 cancer cell line. Crucial events of cellular proliferation and differentiation, like expression of ornithine decarboxylase (ODC), proliferating cell nuclear antigen (PCNA), cycloxygenase-2 (COX-2) and Cyclin D1 were initiated from the fourth hour through application of 7,12-dimethylbenzanthracene (DMBA) on albino mice. The DMBA altered expression of aforesaid enzymes was significantly (P < 0.001) prevented by concomitant application of niosomal formulations. Results of cell line study, Western blotting, RT-PCR, and histopathology suggested that IP6 niosomal suspension could constitute a promising approach for prevention of cellular proliferation as well as DMBA induced dysregulation of cellular proliferation/differentiation and inflammation.

Preventive effects of butyric acid, nicotinamide, calcium glucarate alone or in combination during the 7, 12-dimethylbenz (a) anthracene induced mouse skin tumorigenesis via modulation of K-Ras-PI3K-AKTpathway and associated micro RNAs.

Skin cancer is among the most common cancers worldwide and identifiable molecular changes for early and late stage of skin tumorigenesis can suggest the better targets for its control. In this study, we investigated the status of K-Ras-PI3K-AKTpathway followed by NF-κB, cyclin D1, MMP-9 and regulatory micro RNA during 7, 12-dimethylbenz[a]anthracene (DMBA) induced mouse skin tumorigenesis and its prevention by butyric acid (BA), nicotinamide (NA) and calcium glucarate (CAG), individually or in combination with respect to time. DMBA upregulated the K-Ras, PI3K, Akt, NF-κB, cyclin D1 and MMP-9, but downregulated the PTEN in a time dependent manner. DMBA also reduced the levels of micoRNA let-7a but induced the levels of miR-21 and miR-20a as a function of time. BA, NA and CAG were found to prevent DMBA induced changes, but they were most effective when used together in a combination. Reduced let-7a and miR-211 were correlated with the overexpression of K-Ras and MMP-9. Overexpression of miR-21 and miR-20a was correlated with the down regulation of PTEN and overexpression of Cyclin D1. Collectively, the enhanced chemopreventive potential of natural compound in combination via regulation of K-Ras-PI3K-AKTpathway along with regulatory micro RNAs provide a newer and effective mean for cancer management.

Onset of the lymphocytic infiltration and hyperplasia preceding the proliferation in F1 mouse lungs from the N-ethyl-N-nitrosourea exposed mothers: Prevention during the lactation period by inositol hexaphosphate.

Maternal exposure to a carcinogen is associated with increased risk of different cancers in the offspring. The foetus is highly sensitive to carcinogens and this contributes to the foetal basis of the onset of disease. The better understanding of the molecular mechanisms involved in the early stage of lung tumourigenesis in the offspring is needed for the newer preventive strategies. We evaluated the effects of N-ethyl-N-nitrosourea (ENU) given on the 17th day of gestation and antitumour agent inositol hexaphosphate (IP6) to the mothers at the early stage of lung tumourigenesis in F1 mice. There was no treatment related effects on the litter size or body weight of the F1 mice at the PND12 or 24. Analysis of PCNA, NF-κB (p50), IL-6, COX-2, pSTAT3, STAT3, caspase-3, caspase-9, PARP, Akt signalling and downstream cyclin D1 along with miR-155, suggested the modulation of proliferation, inflammation and apoptosis at PND12 and 24. IP6 administration to the predisposed mothers prevented the proliferation, inflammation and enhanced apoptosis in F1 lung as showed by a reduction in PCNA, NF-κB (p50), IL-6, COX-2, pSTAT3, STAT3, miR-155 and increase in caspases, cleavage of poly (ADP-ribose) polymerase. IP6 administration also inhibited the activation of Akt and cyclin D1. Our study shows that tumourigenic changes take place in the lungs of the F1 generation from the carcinogen predisposed mothers even before the onset of tumours and the simultaneous intake of chemopreventive agent during the gestation or lactation period could prevent the lymphocytic infiltration and hyperplasia preceding the tumourigenesis.

Combinatorial chemopreventive effect of butyric acid, nicotinamide and calcium glucarate against the 7,12-dimethylbenz(a)anthracene induced mouse skin tumorigenesis attained by enhancing the induction of intrinsic apoptotic events.

We explored the basis of the combinatorial chemopreventive effect of butyric acid (BA), nicotinamide (NA) and calcium glucarate (CAG) on mouse skin exposed to 7,12-dimethylbenz(a)anthracene (DMBA). We studied the effects of topical application of DMBA in the presence or absence of BA, NA and CAG on the regulators of apoptosis. DMBA treatment suppressed Bax, Bax/Bcl-2 ratio, release of cyt c, Apaf1, caspase-9, -3 mediated apoptosis. Downregulation of p21 and upregulation of Bcl-2, mut p53 were also observed in only DMBA treated mice. Simultaneous application of BA, NA and CAG induced a mitochondria-mediated apoptosis, characterized by a rise in the Bax, Bax/Bcl-2 ratio, release of cyt c, upregulation of Apaf1 with down-stream activation of caspase-9, -3. Furthermore treatment with BA, NA and CAG demonstrated an upregulation of p21 and downregulation of Bcl-2, mut p53. But this effect was enhanced in the presence of all the three compounds together in combination. Chemoprevention by a combination of BA, NA and CAG by inducing the apoptosis, the natural cell death, suggest the importance of the potential combinational strategies capable of preventing skin tumor development.

Involvement of EZH2, SUV39H1, G9a and associated molecules in pathogenesis of urethane induced mouse lung tumors: potential targets for cancer control.

In the present study, we showed the correlation of EZH2, SUV39H1 or G9a expression and histone modifications with the urethane induced mouse lung tumorigenesis in the presence or absence of antitumor agent, inositol hexaphosphate (IP6). Tumorigenesis and the molecular events involved therein were studied at 1, 4, 12 or 36 weeks after the exposure. There were no tumors at 1 or 4 weeks but tumors started appearing at 12 weeks and grew further till 36 weeks after urethane exposure. Among the molecular events, upregulation of EZH2 and SUV39H1 expressions appeared to be time dependent, but G9a expression was altered significantly only at later stages of 12 or 36 weeks. Alteration in miR-138 expression supports the upregulation of its target, EZH2. H3K9me2, H3K27me3 or H4K20me3 was found to be altered at 12 or 36 weeks. However, ChIP analysis of p16 and MLH1 promoters showed their binding with H3K9me2 and H3K27me3 which was maximum at 36 weeks. Thus, histone modification and their interactions with gene promoter resulted in the reduced expression of p16 and MLH1. IP6 prevented the incidence and the size of urethane induced lung tumors. IP6 also prevented the urethane induced alterations in EZH2, SUV39H1, G9a expressions and histone modifications. Our results suggest that the alterations in the histone modification pathways involving EZH2 and SUV39H1 expressions are among the early events in urethane induced mouse lung tumorigenesis and could be exploited for cancer control.