The Connection between Chronic Liver Damage and Sporadic Alzheimer's Disease: Evidence and Insights from a Rat Model.

Junk foods are typically low in essential nutrients, such as vitamins, minerals, and antioxidants. They are also loaded with trans fats and saturated fats, which can increase the level of triglycerides in the blood. High triglyceride levels can contribute to the development of non-alcoholic fatty liver disease (NAFLD), a condition where excess fat accumulates in the liver. A high intake of junk foods can lead to insulin resistance, a condition where the body's cells become less responsive to insulin. A diet lacking in nutrients and loaded with unwanted toxins can impair the liver's ability to detoxify harmful substances and damage its overall function. It is known that the regular consumption of junk food can be linked to memory impairment and cognitive decline. Several studies have shown that diets high in unhealthy fats, sugars, and processed foods can negatively impact brain health, including memory function. In this study, Wistar rats were used to model Late-Onset Alzheimer's Disease (LOAD), which was inspired by knowledge of the liver-brain axis's role in causing dementia. The model mimicked junk-food-induced liver-brain damage, and was developed by using the toxins d-galactosamine, ethanol and d-galactose. To begin with, the model rats demonstrated insulin resistance, a characteristic of LOAD patients. Glucose levels in both the brain and liver tissues were significantly elevated in the model, paralleling clinical findings in LOAD patients. High glucose levels in the brain lead to the increased production of advanced glycation end-products (AGEs), which, along with amyloid beta, harm neighbouring neurons. Histopathological analysis revealed deformed glial nodules, apoptotic neurons, and amyloid plaques in the brain section in the later stages of the disease. Simultaneously, the liver section displayed features of cirrhosis, including an effaced lobular architecture and the extravasation of red blood cells. Liver enzymes ALT, AST and ALP were consistently elevated with disease progression. Furthermore, immunohistochemistry confirmed the presence of amyloid precursor protein (APP) in the diseased brain. The positive expression of Hypoxia-Inducible Factor 3-Alpha (HIF3A) in the brain indicated hypoxic conditions, which is consistent with other LOAD studies. This model also exhibited damaged intestinal villi and excessive bowel and urinary incontinence, indicating malnutrition and a disturbed gut microbiome, which is also consistent with LOAD patients. Bioinformatics analysis on serum protein suggests a few affected molecular pathways, like the amyloid secretase pathway, androgen/oestrogen/progesterone biosynthesis, the apoptosis signalling pathway, the insulin/IGF pathway-protein kinase B signalling cascade, the Metabotropic glutamate receptor group I pathway, the Wnt signalling pathway, etc. Behavioural analysis confirmed memory decline and the loss of muscle strength with disease progression. Overall, this rat model of LOAD sheds valuable light on LOAD pathology and highlights the potential link between liver dysfunction, particularly induced by the excessive consumption of junk food, and LOAD. This study contributes to a deeper understanding of the complex molecular mechanisms involved in LOAD, paving the way for new possibilities in therapeutic interventions.

Analysis of Inhibition Potential of Nimbin and its Analogs against NF-κB Subunits P50 and P65: A Molecular Docking and Molecular Dynamics Study.

BACKGROUND: Cancer remains the major cause of morbidity and mortality. The nuclear factor kappa-B (NF-κB) plays an indispensable role in cancer cell proliferation and drug resistance. The role of NF-κB is not only limited to tumor cell proliferation and suppression of apoptotic genes but it also induces EMT transition responsible for metastasis. Inhibition of the NF-κB pathway in cancer cells by herbal derivatives makes it a favorable yet promising target for cancer therapeutics. AIM: The purpose of the study is to explore the inhibition potential of Nimbin and its analogs against NF-κB subunits p50 and p65. METHODS: In the present study, an herbal compound Nimbin and its derivative analogs were investigated to examine their impact on the p50 and p65 subunits of the NF-κB signaling pathway using in-silico tools, namely molecular docking and simulation. RESULTS: The molecular docking analysis revealed that Nimbin and its analogs may bind to p50 and p65 subunits with dG bind values ranging from -33.23 to -50.49Kcal/mol. Interestingly, molecular dynamic simulation for the NO5-p65 complex displayed a stable conformation and convergence when compared to the NO4-p50 complex. CONCLUSION: These results indicate that NO5 may have a potential inhibitory effect against NF-κB subunit p65, which needs to be further validated in in-vitro and in-vivo systems. Also, the results obtained emphasize and pave the way for exploring the Nimbin scaffold against NF-κB inhibition for cancer therapeutics.

Cardiovascular diseases display etiological and seasonal trend in human population: Evidence from seasonal cardiovascular comorbid diseases (SCCD) index.

Seasonal changes in the human cardiovascular system are known to play an important role in the onset of many diseases. Confounding variables include behavioral and environmental factors; failing to address such variables makes measuring the true temporal impact of these diseases difficult. On the other hand, numerous clinical studies imply that only specific groups of people are more seasonal sensitive and that their maladaptation might contribute to various illnesses. As a result, it is critical to evaluate the etiological and seasonal sensitive patterns of cardiovascular diseases (CVD), which impact the majority of the human population. The hypothesis for this study formulated that cardiovascular and associated illnesses had substantial connections with seasonal and etiological variations. Thus in the present study, 4519 systematic screen-eligible studies were analyzed using data mining to uncover 852 disease association relationships between cardiovascular and associated disorders. A disease ontology-based semantic similarity network (DSN) analysis was performed to narrow down the identified CVDs. Further, topological analysis was used to predict the seven CVDs, including myocardial infarction (MI), in three clusters. Following that, Mann-Kendall and Cox-Stuart analyses were used to investigate the seasonal sensitivity and temporal relationship of these seven CVDs. Finally, temporal relationships were confirmed using LOESS and TBATS, as well as seasonal breakdown utilizing autocorrelation and fast Fourier transform results. The study provides indirect evidence of a severe etiological association among the three cardiovascular diseases, including MI, atrial fibrillation, and atherosclerosis, which are winter season sensitive in most of the world population. Hypertension has two seasonal falls and peaks due to its seasonal nature, that is, summer and winter hypertension. While, heart failure was also identified, with minor temporal trends. Hence, all five diseases could be classified as seasonal cardiovascular comorbid diseases (SCCD). Furthermore, these diseases could be studied for potential common risk factors such as biochemical, genetic, and physiological factors.

Foresee novel targets for Alzheimer's disease by investigating repurposed drugs.

BACKGROUND: Alzheimer's Disease (AD) is the most rampant neurodegenerative disorder which has caused havoc worldwide. More than a century has passed since the first case of AD was reported, but still no stable treatment is known to mankind. The available medications only provide temporary relief and are not a cure for the disease. The hunt for advanced techniques in drug development has paved the way for drug repurposing, i.e., repositioning or reutilizing drugs as an innovative approach. METHODOLOGY: Several drugs which were repurposed for AD were collected by following PRISMA 2020 systemic review. Databases like PubMed, ScienceDirect, JSTOR, and SciELO were used for data extraction. Further, Drugbank database was used to download all the identified drugs. Later, the Swiss Target Prediction tool was used to identify protein receptors for these drugs and the biological pathway followed by them. RESULTS: Drugs like Zileuton, Salbutamol, Baricitinib, Carmustine, Paclitaxel, and Nilotinib were observed to be involved in regulation of neurotransmitters. Similarly, Metformin, Liraglutide, UDCA, and Bexarotene are involved in protein kinase cascades which also is one of the prime processes in metabolic disorders like AD. Furthermore, drugs like Rosiglitazone, Pioglitazone, and Lonafarnib are involved in interleukin-3 biosynthetic processes, which is again one of the most important processes studied in AD treatment. CONCLUSION: The study concluded that the reviewed drugs that follow similar biological and molecular processes can be repurposed for AD if chosen judiciously with current medications and thus drug repurposing is a promising approach that can be utilized to find a cure for AD within a brief time and fewer resources compared to de novo drug synthesis. Although certain loopholes still need to be worked upon, the technique has great prospects. Furthermore, in silico methods can be utilized to justify the findings and identify the best drug candidate.

The Gut-Brain Axis: Two Ways Signaling in Parkinson's Disease.

Parkinson's disease (PD) is a chronic, progressive and second most prevalent neurological disorder affecting the motor system. Cardinal motor impairment and α-synucleinopathy are the characteristic features of PD. Recently, it has been identified that the gut-brain axis is substantially regulated by the gut microbiome (GM) through an immunological, neuroendocrine, and neural mechanism. However, disturbance in the gut-microbiome-brain axis in PD might proceed to gastrointestinal manifestations intermittently leading to the motor system and the PD pathogenesis itself. The gut microbial toxins may induce the production of α-synuclein (α-syn) aggregates in the enteric nervous system (ENS), which may proliferate and propagate in a prion-like-manner through the vagus nerve to the central nervous system (CNS); supporting the hypothesis that, GM might play a pivotal role in PD pathogenesis. Overstimulated innate immune system due to intestinal bacterial overgrowth or gut dysbiosis and the enhanced intestinal permeability may persuade systemic inflammation, while the activation of enteric glial cells and enteric neurons may contribute to α-synucleinopathy. Gut microbiota can bear a significant impact on neurological outcomes such as learning, memory and cognition. In this review paper, we summarize how the alterations in gut microbiota and ENS inflammation are associated with PD pathogenesis. The evidence supporting the causative role played by gut-associated dysbiosis and microbial byproducts, in the onset of PD is also discussed. We have highlighted the landmark discoveries in the field of PD particularly focusing on the gut-brain axis. A better comprehension of the interaction between the gut-brain axis, gut microbiota, and PD can usher in novel therapeutic and diagnostic approaches.

Identification of potential targets with high centrality indicated by diethylnitrosamine + thioacetamide-induced hepatocellular carcinoma model.

BACKGROUND AND AIM: Hepatocellular carcinoma (HCC), a primary liver malignancy, represents a continuous challenge to clinicians as it is a leading cause of death due to cancer widely. Early detection is the only hope to cure patients from this deadly disease or possibly increase life expectancy. Mouse models are most acceptable studies as they have ability to manipulate their genome and transcriptome to evaluate mechanistic changes. In addition, system biology can improvise the understanding of molecular mechanism of HCC and also can reveal the protein hub involved in every stage of HCC. MATERIALS AND METHODS: Herein, diethylnitrosamine and thioacetamide (TAA) were used to develop stage-specific HCC in Wistar rats. Histopathological changes, biochemical parameters, and the oxidative stress were measured in hepatocytes. We have reanalyzed the microarray dataset to identify the complex signaling pathways involved in hepatocarcinogenesis induced by TAA. GSE45050 dataset was downloaded from Gene Expression Omnibus database, and the gene expression profile of nontumor, cirrhosis, and HCC was compared. RESULTS: The study reveals stage-specific development of chronic HCC rat model and promising stage-specific targets (EHMT2, GMPS, and SPRY2) of HCC. CONCLUSIONS: EHMT2, GMPS, and SPRY found as high centrality nodes in protein-protein interaction studies using high-throughput microarray data which tend to be present in signaling pathways and co-occur in a biological state of HCC. These genes can be targeted to understand the possible pathology, molecular changes, and target strategy under cirrhosis and HCC condition.

Trachyspermum ammi and Cinnamomum verum as nutraceuticals: Spices rich in therapeutically significant protein tyrosine phosphatases.

Nutraceuticals need special attention as preventive molecules to create a natural barrier against various dreadful diseases like cancer and to regulate metabolism. In the present study, two spices, Trachyspermum ammi and Cinnamomum verum, been identified as excellent Protein Tyrosine Phosphatases (PTPases) sources that play significant role in the regulation of cell signal transduction and developmental processes in plants as well as animals, being lucrative and potential targets for pharmacological modulation. PTPases from both cases were partially purified into 0%-40% and 40%-80% fractions based on ammonium sulfate saturation levels. Fraction (40%-80%) exhibited a purification level of 4.44-fold and 2.86-fold with specific activity of 44.06 and 23.33 U/mg for PTPases from T. ammi and C. verum, respectively. PTPases being found to be thermally stable up to 70°C imply their industrial significance. Kinetic studies showed Km values to be 7.14 and 8.33 mM, whereas the activation energy (Ea ) values were 25.89 and 29.13 kJ/mol, respectively. Divalent cations: Cu2+ , Zn2+ , and Mn2+ acted as inhibitors of PTPases, from both sources. The Ki values of inhibitors varied from 0.014-0.125 mM in the descending order Cu2+  > Zn2+  > Mn2+ and Mn2+  > Cu2+  > Zn2+ for PTPases from T. ammi and C. verum, respectively. The inhibitory effect of sodium metavanadate aligns with prominent PTPase characteristics. In addition to these properties, the thermostability of PTPases from two spices enhances their significance in industries with therapeutically vital products. Although the source of PTPases is culinary spices, further studies are required to establish the utilization of PTPases as nutraceuticals and in therapeutic formulations. PRACTICAL APPLICATIONS: For a healthy lifestyle, awareness needs to be created by humankind towards food habits to minimize illnesses. Numerous studies have explored the consumption of nutraceutical products acts as a natural barrier and immune booster for various human ailments including SARS-COV-2. PTPases play important roles in regulating intracellular signaling and, ultimately, biological function along with their structural features. The importance of PTPases and their inhibitors has been implicated in various diseases like cancer, diabetes, and obesity. Further investigations need to be undertaken to explore the therapeutic properties of PTPases in both in vivo and in vitro for their clinical significance.

Liver-Brain Axis in Sporadic Alzheimer's Disease: Role of Ten Signature Genes in a Mouse Model.

AIM: Poor nutritional effect of junk food induces injuries to the liver and the brain but still most of the developing nations survive on these diets to compensate for the fast-paced lifestyle. The aim of the study is to infer the protein-connections behind the liver-brain axis and identify the role of these proteins in causing neurodegenerative disorders. BACKGROUND: Chronic consumption of fructose and fat-rich food works as a toxin in the body and has the ability to cause a negative metabolic shift. Recently a study was published in Annals of Internal Medicine (2019) citing the loss of vision and hearing in a 14-year-old boy whose diet was strictly restricted to fries and junk-food for almost a decade. This puts the entire body on insulin resistance and related co-morbidities and causes simultaneous damaging effects on the liver as well as the brain. This work provides insights into the liver-brain axis and explains how the liver is involved in brain related disorders. OBJECTIVE: In this study, transcriptomic data related to chronic eating of junk-food was analyzed and simultaneous damage that happens in the liver and the brain was assessed at the molecular level. METHODS: Transcriptomic study was taken from the GEO database and analysed to find out the genes dysregulated in both the liver and the brain during this metabolic stress. Cytoscapev3.7 was used to decipher the signalling between the liver and the brain. This connection between both is called as the liver-brain axis. RESULT: The results obtained from our study indicate the role of TUBB5-HYOU1-SDF2L1-DECR1- CDH1-EGFR-SKP2-SOD1-IRAK1-FOXO1 gene signature in the decline of concurrent liver and brain health. Dysregulated levels of these genes are linked to molecular processes like cellular senescence, hypoxia, glutathione synthesis, amino acid modification, increased nitrogen content, synthesis of BCAAs, cholesterol biosynthesis, steroid hormone signalling and VEGF pathway. CONCLUSION: We strongly advocate that prolonged consumption of junk food is a major culprit in brain related disorders like Alzheimer's disease and propose that receptors for brain diseases lie outside the brain and aiming them for drug discovery and design may be beneficial in future clinical studies. This study also discusses the connection between NAFLD (non-alcoholic fatty liver disease) and sAD (sporadic Alzheimer's disease) owing to liver-brain axis.

Protein Interaction Studies for Understanding the Tremor Pathway in Parkinson's Disease.

BACKGROUND: Tremor is one of the most noticeable features, which occurs during the early stages of Parkinson's Disease (PD). It is one of the major pathological hallmarks and does not have any interpreted mechanism. In this study, we have framed a hypothesis and deciphered protein- protein interactions between the proteins involved in impairment in sodium and calcium ion channels and thus cause synaptic plasticity leading to a tremor. METHODS: Literature mining for retrieval of proteins was done using Science Direct, PubMed Central, SciELO and JSTOR databases. A well-thought approach was used, and a list of differentially expressed proteins in PD was collected from different sources. A total of 71 proteins were retrieved, and a protein interaction network was constructed between them by using Cytoscape.v.3.7. The network was further analysed using the BiNGO plugin for retrieval of overrepresented biological processes in Tremor-PD datasets. Hub nodes were also generated in the network. RESULTS: The Tremor-PD pathway was deciphered, which demonstrates the cascade of protein interactions that might lead to tremors in PD. Major proteins involved were LRRK2, TUBA1A, TRAF6, HSPA5, ADORA2A, DRD1, DRD2, SNCA, ADCY5, TH, etc. Conclusion: In the current study, it is predicted that ADORA2A and DRD1/DRD2 are equally contributing to the progression of the disease by inhibiting the activity of adenylyl cyclase and thereby increases the permeability of the blood-brain barrier, causing an influx of neurotransmitters and together they alter the level of dopamine in the brain which eventually leads to tremor.

Differential Expression of TOM34, AL1A1, PADI2 and KLRBA in NNK Induced Lung Cancer in Wistar Rats and their Implications.

BACKGROUND: Lung cancer is the most common cancer with a high mortality rate. The diagnosis only at advanced stages and lack of effective treatment are the main factors responsible for high mortality. Tobacco smoke is the major responsible factor for inflammation and tumor development in lungs. OBJECTIVE: The present study was carried out to identify differentially expressed proteins and elucidate their role in carcinogenesis. METHODS: The lung cancer was developed in Wistar rats by using NNK as carcinogen and cancer development was confirmed by histopathological examination. The 2D SDS PAGE was used to analyse total proteins and find out differentially expressed proteins in NNK treated lung tissue vis-a-vis control tissue. The findings of proteomic analysis were further validated by quantification of corresponding transcripts using Real Time PCR. Finally, Cytoscape was used to find out protein-protein interaction. RESULTS: The histopathological examinations showed neoplasia at 9th month after NNK treatment. The proteomic analysis revealed several differentially expressed proteins, four of which were selected for further studies. (TOM34, AL1A1, PADI2 and KLRBA) that were up regulated in NNK treated lung tissue. The real time analysis showed over expression of the genes coding for the selected proteins. Thus, the proteomic and transcriptomic data corroborate each other. Further, these proteins showed interaction with the members of NF-κB family and STAT3. CONCLUSION: We conclude that these proteins play a substantial role in the induction of lung cancer through NF-κB and STAT3 pathway. Therefore, these may have the potential to be used as therapeutic targets and for early detection of lung cancer.

Juglans regia and Ribes nigrum as potential nutraceuticals: Source of thermostable superoxide dismutase enzyme.

In the present study, superoxide dismutase (SOD) extracted from dry fruits; Juglans regia (Walnut; W) and Ribes nigrum (Munakka; M) was partially purified into 0%-40% and 40%-80% fractions based on ammonium sulfate saturation levels. The partially purified fractions (0%-40%) exhibited purification level of 3.09- (W) and 3.22- (M) fold with specific activity 79.32 Umg-1 (W) and 125.23 Umg-1 (M). SOD from both the sources was found to be thermally stable, that is, 80°C (W) and 70°C (M). Kinetic studies showed Km values to be 3.33 mM (W) and 2.86 mM (M), whereas the activation energy (Ea ) calculated as 24.52 KJ mol-1 (W) and 26.25 KJ mol-1 (M). Na+ , Mn2+ , and Ba2+ ions acted as potential inhibitors, whereas Fe2+ stimulated SOD from both the sources. Among these metal ions, Na+ exhibited uncompetitive inhibition in both cases; with Ki values of 0.7 mM (W) and 0.9 mM (M), suggesting the more prominent binding affinity and effectiveness. PRACTICAL APPLICATIONS: Awareness need to be created among people for multifactorial health benefits of nutraceuticals in day-to-day life. Nutritional consumption from fruits, nuts, and vegetables safeguard against various maladies like cardiovascular diseases, diabetes, and cancers. Superoxide dismutase (EC 1.15.1.1) is a standout among the most critical metal-containing enzymes that act as a main line of defense against oxidative stress. Antioxidant-based drugs and formulations have been developed in the recent years and research is emphasized on its impact on oxidative stress levels. In this study, Juglans regia (W) and Ribes nigrum (M) were found to have thermostable SOD enzyme with excellent antioxidant properties. Thermal stability of an enzyme improves its significance making it industry friendly with therapeutically vital products, alongside their utilization as supplement in numerous therapeutic formulations.

Temporal dynamics of pre and post myocardial infarcted tissue with concomitant preconditioning of aerobic exercise in chronic diabetic rats.

The different ailments of heart including myocardial infarction (MI) and ischemic heart diseases are the foremost trigger of high mortality across the world which is instigated by sedentary life style, chronic hyperglycaemia and atherosclerosis. Albeit strenuous exercise itself induces temporary hypoxia which causes myocardial damage and this vitiosus circulus is poorly understood and has been assumed difficult to break. Present investigation targets temporal dynamics of aerobic exercise treatment induced preconditioning against diabetes associated pre- and post- myocardial injury. The persisting high blood sugar level leads to several biochemical alterations at pre- and post-MI phase. Here, we present the assessment of temporal expression of cardiac biomarkers (CKMB, LDH, cTnI and serum nitrite/nitrate), oxidative stress (myocardial TBARS and reduced NBT), inflammatory cytokines (IL-6, TNF-α and IL-10), renal biomarkers (BUN, serum creatinine and microproteinuria) and structural alterations of cardio-renal tissue. Aerobic exercise preconditioning significantly downregulate the pathological events or biomarkers and upsurge the physiological biomarkers at both pre- and post-MI phase. The attenuation or returning of pathological makers to lowest level at different time points endorses the therapeutic management of aerobic exercise against diabetic MI. Furthermore, the temporal expression of various cardio-renal biomarkers pattern elucidates that aerobic exercise preconditioning boost the strength and consolidate the cardiac muscles to work under stress. Despite the presence of traditional knowledge about health benefits of aerobic exercise, it is yet to be brought into the clinical arena. In spite of few impending challenges subjected to additional investigations, aerobic exercise preconditioning shows a high degree of promise.

Development and characterization of late-stage diabetes mellitus and -associated vascular complications.

Preclinical investigation is the key mark of medical research, as the major breakthroughs including treatment of devastating diseases in biomedical research have been led by animal studies. Type 2 diabetes mellitus (T2DM) is a predominant metabolic disorder having high prevalence of morbidity worldwide which create an urgent need to understand the pathogenesis, complication and other possible influences by development of appropriate animal model. High-fat diet (HFD) fed animals (21 days) were treated with single cycle of repetitive dose (SCRD) of streptozotocin (STZ; 40, 30 and 20 mg/kg/per day in three respective group at 1st, 3rd, and 5th day) and double cycle of repetitive dose (DCRD) of streptozocin (STZ) (20, 10 and 5 mg/kg/per day in three respective group at 1st, 3rd, and 5th day in one cycle and 21st, 23rd, 25th day in second cycle of treatment) to induce late-stage diabetic complications. Induction of hyperglycemia was assessed by fasting and postprandial blood glucose, HbA1c, insulin, C-peptide, pancreatic ß-cells and dyslipidaemia up to 12 weeks. Combined treatment of HFD and STZ (20 mg/kg) in the DCRD manner were significantly induced late-stage diabetic complication with sustained hyperglycaemia, no mortality, increased HbA1c and dyslipidaemia, reduced insulin, C-peptide and beta cells. Moreover, biochemical and histological assessment of micro and macrovascular tissues confirmed the significant cardio-renal injury, endothelial and hepatic damage. The study confirmed the development of chronic diabetic model in rat mimicked to clinical pathology with associated micro and macrovascular abnormalities which can further explore the molecular aspects of diseases.

Synergistic Combination for Chemoprevention of Hepatocellular Carcinoma: An In Silico and In Vitro Approach.

Combination therapy is one of the best methods to manage the fatality rate in hepatocellular carcinoma (HCC). This study aimed to formulate a synergistic combination of synthetic and herbal compounds for the treatment of HCC as well as to elucidate a possible signalling mechanism. MTT and enzymatic assay were performed to determine the synergistic effect of drug combination (sorafenib, vitamin K1 and trans-chalcone) on HepG2 cell lines after intoxication with H2 O2 . Protein-protein interaction and docking studies were performed using Pathwaylinker2.0 and Schrödinger's software application to find out the mechanism of action and major targets for drug combination. The overall in vitro result showed that combination of trans-chalcone, vitamin K1 and sorafenib (10, 5 and 5 µM concentration, respectively) enhanced the resistance against oxidative stress generated by H2 O2 . The interaction studies helped in identification of few targets for docking of ligands (trans-chalcone, vitamin K1 and sorafenib). The study reports the synergistic effects of the formulation that can protect the cells from oxidative stress and restore normal levels of cellular enzymes in HepG2 cell line. We were able to determine the mechanism of action of herbal and synthetic formulation through in silico studies. Finally, docking studies confirmed potential targets for inhibition of hepatocarcinogenesis.

Type 3 Diabetes: Cross Talk between Differentially Regulated Proteins of Type 2 Diabetes Mellitus and Alzheimer's Disease.

Type 3 Diabetes (T3D) is a neuroendocrine disorder that represents the progression of Type 2 Diabetes Mellitus (T2DM) to Alzheimer's disease (AD). T3D contributes in the increase of the total load of Alzheimer's patients worldwide. The protein network based strategies were used for the analysis of protein interactions and hypothesis was derived describing the possible routes of communications among proteins. The hypothesis provides the insight on the probable mechanism of the disease progression for T3D. The current study also suggests that insulin degrading enzyme (IDE) could be the major player which holds the capacity to shift T2DM to T3D by altering metabolic pathways like regulation of beta-cell development, negative regulation of PI3K/AKT pathways and amyloid beta degradation.

Shared links between type 2 diabetes mellitus and Alzheimer's disease: A review.

Epidemiological studies have proved that, there are pathophysiological connections between Type 2 Diabetes Mellitus (T2DM) and Alzheimer's disease (AD). Diabetic patients have higher incidences of cognitive impairment and hence they are more at the risk of developing AD. Some of the recent evidences have majorly stated the effects of insulin resistance in the disturbance of various biological processes and signaling pathways. Both hyperglycemia and hypoglycemic conditions contributes in dysfunctioning of cognitive abilities and functions. The present review summarizes the evidences which establish the possible links between the two pathologies on the account of molecular, biochemical and at histopathological level. The information regarding their interactions was collected from different databases and journals. The gathered information will clearly establish the link among the two pathologies and will be helpful in future for the development of drugs for Type 3 Diabetes.

Sesamin attenuates neurotoxicity in mouse model of ischemic brain stroke.

Stroke is a severe neurological disorder characterized by the abrupt loss of blood circulation into the brain resulting into wide ranging brain and behavior abnormalities. The present study was designed to evaluate molecular mechanism by which sesamin (SES) induces neuroprotection in mouse model of ischemic stroke. The results of this study demonstrate that SES treatment (30 mg/kg bwt) significantly reduced infarction volume, lipid per-oxidation, cleaved-caspase-3 activation, and increased GSH activity following MCAO in adult male mouse. SES treatment also diminished iNOS and COX-2 protein expression, and significantly restored SOD activity and protein expression level in the ischemic cortex of the MCAO animals. Furthermore, SES treatment also significantly reduced inflammatory and oxidative stress markers including Iba1, Nox-2, Cox-2, peroxynitrite compared to placebo MCAO animals. Superoxide radical production, as studied by DHE staining method, was also significantly reduced in the ischemic cortex of SES treated compared to placebo MCAO animals. Likewise, downstream effects of superoxide free radicals i.e. MAPK/ERK and P38 activation was also significantly attenuated in SES treated compared to placebo MCAO animals. In conclusion, these results suggest that SES induces significant neuroprotection, by ameliorating many signaling pathways activated/deactivated following cerebral ischemia in adult mouse.

A non-surgical method for induction of lung cancer in Wistar rats using a combination of NNK and high dietary fats.

Lung cancer is one of the most common malignant neoplasms all over the world. Smoking and a number of constituents of tobacco are responsible for development of lung tumours; however, the deleterious effects of tobacco-derived carcinogen, nitrosamine 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (nicotine-derived nitrosamine ketone (NNK)) remain unmatched. We report the development of a novel rodent model by administering multiple doses of NNK to male Wistar rats and feeding them with high-fat and low-protein diet. Tumour cells in lungs were observed in approximately 98 % rats after 8 months of NNK treatment, as evident by histopathological analysis. This rodent model showed slow progression of lung tumours which has helped us to assess early indicators of oxidative damage in lungs by studying the levels of lipid peroxidation and antioxidant parameters. LPO was elevated by 46.94 %, SOD, CAT, GSH and GR activity was decreased by 48.67 %, 22.04 %, 21.46 % and 20.85 %, respectively in serum of NNK treated rats when compared with control. These findings suggest that increased oxidative stress can represent a risk factor for the development of chronic disease in early future. This new animal model is an attempt to greatly facilitate studies of the pathophysiology, biochemistry and therapy of lung cancer.

DEN+2-AAF-induced multistep hepatotumorigenesis in Wistar rats: supportive evidence and insights.

Diethylnitrosamine (DEN), found in many commonly consumed foods, has been reported to induce cancers in animals and humans. Several models have been developed to study multistage carcinogenesis in rat liver; these include the Solt-Farber-resistant hepatocyte model. In the Solt-Farber model, the initiation consists of either a necrogenic dose of a hepatocarcinogen or a non-necrogenic dose in conjunction with partial hepatectomy (PH). We report a novel protocol for tumor induction in liver which eliminates the need for PH. Male Wistar rats were injected with single i.p. dose of DEN (200 mg/kg body weight), controls received saline only. After 1 week of recovery, the DEN-treated animals were administered with the repeated doses of 2-acetyamino fluorine (150 mg/kg body weight) orally in 1 % carboxymethyl cellulose that served as promoting agent. Thirty days after the DEN administration, hepatocellular damage was observed as evident by histopathological analysis. The marker enzyme analysis showed elevated levels of serum AST, ALT, and alkaline phosphatase and a decrease in the levels of liver superoxide dismutase and catalase. The oxidative stress in liver was confirmed by elevated levels of lipid peroxidation and a decrease in antioxidant parameters.

Elevated expression of complement C3 protein in chemically induced hepatotumorogenesis in Wistar rats: a correlative proteomics and histopathological study.

Liver cancer remains the leading cause of cancer-related mortality worldwide. Early detection of liver cancer is problematic due to the lack of a marker with high diagnosis sensitivity and specificity. The present study was designed to determine the differently expressed proteins at early stage in the serum of animals with liver cancer vis-à-vis controls and figure out the function of the proteins. One-dimensional electrophoresis (1D), two-dimensional electrophoresis (2DE) and liquid chromatography mass spectrometry (LC-MS/MS) were used to screen the serum proteins of liver cancer induced in animals by diethyl nitrosamine (DEN)+2-acetyl amino fluorine (2-AAF). From optimized 2DE image and computer assisted PD Quest analysis were found to be differentially expressed spots when the serum from normal and treated animals were compared. Among these, one spot was selected whose expression level was higher in DEN+2-AAF treated animal sera than in adjacent normal animal sera. The target spot was excised from the 2D gel of liver cancer sera and the peptide mass fingerprinting as obtained LC-MS/MS analysis after digesting the chosen protein spot. This was identified to be complement C3 protein. The changes in complement C3 expression level were validated by Western blot analysis. We reported that the changes in complement C3 concentration start at very early stage of tumorogenesis. The fully grown tumors were developed at 120 days and hepatotumorogenesis was confirmed by histopathological examination. This protein may therefore represent a powerful tool in search for candidate biomarkers for HCC.