Understanding the role of zingerone on biochemical and behavioral changes in rat brain inflicted with C6 glioma cells.

Malignant glioma is the deadliest form of brain cancer. Zingerone (ZO), a polyphenolic compound found in ginger, offers pharmacological properties that make it a promising agent for containing the growth of glioma cells. The present study was conducted to understand the efficacy of ZO in containing the growth of C6 glioma cells. The study also assessed the prophylactic role of ZO on rat brain glioma induced by C6 cell lines by addressing its antioxidative action on biochemical, behavioral, and histoarchitectural indices. For dose optimization, the animals were pretreated with different doses of ZO for a period of 2 weeks before the inoculation of glioma cells (1 × 105 /10 µL phosphate-buffered saline) in the caudate region of rat brain and the treatment with ZO continued for 4 more weeks post implantation. In vitro studies were done to assess the radical scavenging activity of ZO and also to determine its effects on viability of C6 glioma cells at different concentrations. Glioma-bearing rats showed significant alterations in memory; exploratory and muscular activities which were appreciably improved upon simultaneous supplementation of ZO administered at a dose of 50 mg/kg body weight and were also visible even at a higher dose. Glioma-bearing rats revealed a significant increase in reactive oxygen species, protein carbonyl contents, and lipid peroxidation, but showed a significant decrease in reduced glutathione and antioxidative enzymes in the brain tissue. Interestingly, all the biochemical indices and altered brain histoarchitecture displaying cellular atypia and hyperplasia showed appreciable improvement when supplemented with ZO at a dose of 50 mg/kg body weight.

Amelioration of cognitive and biochemical impairment in Aß-based rodent model of Alzheimer's disease following fractionated X-irradiation.

Alzheimer's disease is characterized by deposition of amyloid-beta plaques in the brain. Available pharmaceuticals provide temporary symptomatic relief without affecting disease progression. Use of radiation was found effective in treating extra-cranial amyloidosis, therefore, the present study was designed to investigate the neuroprotective role of fractionated X-irradiation in Aß1-42-based rodent model of Alzheimer's disease. S.D. female rats were randomly divided into four groups: sham control (Group 1), Aß1-42 injected (Group 2), cranial X-irradiated (Group 3) and Aß1-42 injected followed by cranial X-irradiation (Group 4). A single dose of 5 µL Aß1-42 peptide was administered through intracerebroventricular (icv) injection in Group 2 and 4 animals, while Group 1 animals were administered 5 µL of bi-distilled water (icv). The group 4 animals were further subjected to 10 Gy X-irradiation (fractionated dose, 2 Gy × 5 days) after 4 weeks of Aß1-42 infusion of peptide. The animals in Group 3 were subjected to same dose of cranial fractionated X-irradiation (2 Gy × 5 days) only. Significant decrease in amyloid deposits were observed in the Aß1-42 + radiation-treated animals confirmed by histopathological analysis. These finding were in concordance with neurobehavioral tests that showed a significant improvement in Aß1-42-induced memory impairment in the animals subjected to fractionated cranial X-irradiation. Restoration of alterations in neurochemical and antioxidant defense indices further supported our results. The present study highlights the underexplored role of fractionated X-irradiation in curtailing the Aß1-42-induced neurotoxicity, suggesting a novel treatment option for Alzheimer's disease-associated pathologies.

Quercetin plays protective role in oxidative induced apoptotic events during chronic chlorpyrifos exposure to rats.

Chlorpyrifos (CPF), an organophosphate insecticide has a wider application throughout the world to protect agricultural crops and vegetables from insects. Polyphenolic compounds are considered as beneficial against toxicities induced by organophosphates. The present study was conducted to understand the neuroprotective role of quercetin in chlorpyrifos-induced apoptotic events in rats. Twenty-four male Sprague Dawley rats weighing 170 to 200 g were divided into four groups viz: Control, chlorpyrifos treated (13.5 mg/kg body wt. alternate day), quercetin treated (50 mg/kg body wt. every day) and combined chlorpyrifos + quercetin treated. All the treatments were carried out for a total duration of 60 days. Protein carbonyl content and acetylcholinesterase activity were estimated in serum along with cerebrum and cerebellum to ascertain neurotoxicity. Further, for appraisal of neurodegeneration as a consequence of apoptosis, protein expressions of Bcl-2, Bax, cytochrome c, caspase-8, and caspase-9 were assessed. The results showed that protein carbonyl contents were markedly increased in both serum and brain tissues (cerebrum and cerebellum) of chlorpyrifos-treated rats when compared with control group and were appreciably improved upon simultaneous supplementation with quercetin. Further, chlorpyrifos treatment revealed a significant decrease in the enzyme activity of acetylcholinesterase in serum as well as in cerebrum and cerebellum, which however was increased upon concomitant treatment with quercetin. In chlorpyrifos-treated animals, we have observed a significant decrease in the protein expression level of Bcl-2, but a remarkable increase in the expression levels of Bax, cytochrome c, caspase-8, and caspase-9 in both cerebrum and cerebellum. Interestingly, when chlorpyrifos-treated animals were supplemented with quercetin, a significant increase in the expression of Bcl-2 and an appreciable decline in the expression levels of Bax, cytochrome c, caspase-8, and caspase-9 was observed. In conclusion, the present study advocates that quercetin may prove to be a useful candidate in containing the oxidative-induced apoptotic events during chlorpyrifos exposure.

Dose optimization of lithium to increase the uptake and retention of I-131 in rat thyroid.

The present study was undertaken to optimize the dose of lithium, with an aim to increase the retention of I-131 in the thyroid follicles while maintaining the euthyroid state. 24 female Wistar rats weighing 110 ± 20 g were segregated into four groups. Animals in group I were fed standard laboratory feed and water throughout the period of experimentation. Animals in group II, III and IV were additionally fed with lithium in the form of lithium carbonate orally, at a dose of 10 mg/kg body weight, 20 mg/kg body weight, 30 mg/kg body weight respectively. The dose of lithium was started 1 week prior to radioiodine administration and continued thereafter for another 8 days. After 7 days of lithium treatment, 0.48 MBq of carrier-free I-131 was injected intraperitoneally into each rat, of the four groups. I-131 thyroidal uptake and biokinetics, as well as serum TSH, T3, T4 levels were estimated in all the treatment groups. A significant increase in the thyroid and whole body counts was observed after 4 and 24 h of I-131 aministration in lithium treated rats, compared to control animals. An increase in thyroidal effective t1/2 and serum TSH levels, along with decrease in the levels of serum T3 and T4 was observed with a dose of 20 mg/kg or higher. In Conclusion, a Lithium dose of 10 mg/kg body weight in rats could increase the uptake of I-131 in the thyroid, without disturbing the control circulating levels of thyroid hormones.

68Ga-Glutathione radio-complex as a new diagnostic probe for targeting colon cancer in rats.

OBJECTIVE: Glutathione (GSH) plays an important role in a horde of cellular events that include cell proliferation and apoptosis.The present study describes the radio-synthesis and characterization of gallium-68 (68Ga)-labelled glutathione for its application in radionuclide imaging of cancer. SUBJECT AND METHODS: The radio-synthesis of radio-complex 68Ga-GSH was performed by the direct labeling method. The developed radio-complex was subjected to quality control tests. Colon tumors were developed in healthy male Sprague Dawley (S.D) rats by giving subcutaneous injections of dimethylhydrazine (DMH) in order to monitor the uptake of 68Ga-GSH radio-complex. RESULTS: Gallium-68-labelled glutathione was synthesized with a labeling efficiency of 73.5%±1%. Percentage plasma protein binding and log Po/w values for the radio-complex were found to be 20%-30% and -0.223±0.12, respectively. A significantly higher percentage specific uptake value of newly developed 68Ga-GSH complex was observed in colon tumor in comparison to soft tissue at 90 minutes post administration thereby exhibiting specificity for cancerous cells, which was also witnessed significantly increased overtime from the ratio of colon tumor uptake to normal colon uptake (P≤0.05). CONCLUSION: Therefore, 68Ga-labelled glutathione can further be exploited for radionuclide imaging and assessment of tumor drug resistance in patients.

Physiological uptake and retention of radiolabeled resveratrol loaded gold nanoparticles (99mTc-Res-AuNP) in colon cancer tissue.

When tagged with a suitable radionuclide, the cancer targeting properties of trans-resveratrol could be utilized to locate cancerous sites in the body using radionuclide imaging technique. However, the polyphenol due to its rapid and extensive metabolism exhibits low bioavailability in vivo. The study was designed to enhance the cancer targeting efficacy of radiolabeled resveratrol using nano-based technology. Technetium-99m labeled resveratrol loaded gold nanoparticles (Res-AuNP) were synthesized, characterized and evaluated for their cancer targeting efficacy in HT29 colon cancer cells and in animal cancer model. Results of various investigations were compared to corresponding results obtained for 99mTc-AuNP and 99mTc-resveratrol. Cancer cell internalization observed for 99mTc-Res-AuNP was significantly higher than that of 99mTc-AuNP and 99mTc-resveratrol. Also, a gradual rise in target to nontarget uptake with time was observed following i.v. administration of 99mTc-Res-AuNP to colon tumor bearing rats, demonstrating better in vivo targeting of colon adenocarcinoma with 99mTc-Res-AuNP when compared to 99mTc-resveratrol.

Increased Nuclear Factor-κB/RelA Expression Levels in Human Colorectal Carcinoma in North Indian Patients.

Colorectal cancer is a major cause of cancer-related death in many countries. Inflammatory pathway is considered to play a major role in colorectal carcinogenesis. Nuclear factor kappa B (NF-κB) pathway is a link between inflammation and cancer. NF-κB is a transcription factor which belongs to the Rel family. Activation of NF-κB has been shown to play a role in cell proliferation, apoptosis, cytokine production, and oncogenesis. The aim of the present study was to evaluate the expression levels of NF-κB/RelA in colorectal carcinoma using Real-time PCR. For this study, tumor tissue was taken from general surgery OT of PGIMER, Chandigarh from twenty-seven patients of colorectal cancer treated by surgery. Adjacent colonic mucosa specimens were also collected from all patients as normal control tissue. Real-time PCR was performed to determine the nuclear factor-κB/RelA expression levels in twenty-seven pairs of colorectal adenocarcinoma and adjacent normal colonic tissues. Out of 27 CRC patients, 18 were males and 9 females. Mean age of patients was 51.1 ± 14.8 years. Most of the cases were males (67%). Seventy percent of the cases were early (I-II) and 30% were advanced (III-IV) tumor stage. The quantitative relative expression of NF-kB mRNA was found to be significantly higher (p < 0.05) in CRC tissues as compared with that in adjacent normal colon tissues. From this study, we can conclude that RelA/NF-kB pathway is expressed constitutively in colorectal adenoma and adenocarcinomas. Thus, RelA/NF-kB might play an important role in colorectal tumorigenesis.

Sodium selenite enhances thyroid uptake of iodine-131 and regulates thyroid function in rats.

The aim of the present study was to evaluate the role of selenium (Se) on the thyroid uptake and retention of radioiodine ((131)I) and on the serum levels of thyroid hormones. Experimental rats were divided into four groups with 10 animals in each group viz: untreated controls, (131)II-treated, Se-treated and (131)I+Se-treated. Group II and Group IV animals were injected intraperitoneally with 3.7MBq of (131)I. Group III and Group IV animals received Se in the form of sodium selenite, everyday at a dose of 1ppm in drinking water. Thyroidal (131)II uptake measurements, determination of biological half life of (131)I and estimation of serum of tri-iodothyronine (T3) and tetra-iodothyronine (T4) and thyroid stimulating hormone (TSH) were carried out at two time intervals after 2 and 4 weeks. The statistical significance of the data was determined by using one-way analysis of variance (ANOVA) followed by Newman-Keuls test. The results showed lower serum levels of T3 and T4 and higher TSH levels in rats treated with (131)I when compared to untreated rats. Furthermore, the biological half life (Tbiol) of (131)I in thyroid and thyroidal (131)I uptake values at 2h and 24h were significantly lower in rats treated with (131)I compared with untrated control. Selenium treatment of (131)I treated rats resulted in a significant increase in the thyroid uptake as well as Tbiol of (131)I which indicated its increased retention. Moreover, normalization of the elevated serum TSH levels and a significant increase in the T3 and T4 levels was evident when Se was administered to the (131)I treated rats. In conclusion, this study indicates that Se when given to rats in the form of sodium selenite, at a dose of 1ppm in drinking water enhances the uptake and retention of (131)I in the thyroid as well as regulates thyroid hormone levels.

Advancing Cancer Theranostics Through Integrin αVß3-Targeted Peptidomimetic IAC: From Bench to Bedside.

Introduction: The expression of alpha-five beta-three (αVß3) integrins is upregulated in various malignancies undergoing angiogenesis. The development of integrin antagonists as diagnostic probes makes the αVß3 integrin a suitable candidate for targeting tumor angiogenesis. The goal of this study was to optimize the radiolabeling and evaluate the potential of conjugated integrin antagonist carbamate (IAC), a peptidomimetic, as a theranostic radiopharmaceutical for targeting tumor angiogenesis. Methodology: Radiolabeling of DOTAGA [2,2',2" -{10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl} triacetic-acid]-IAC with [68Ga]Ga, [177Lu]Lu, and [225Ac]Ac was optimized. The binding affinity (Kd) of DOTAGA-IAC for the αVß3 receptor and cancer cell lines was quantified. The biodistribution studies were conducted in healthy Wistar rats. Dosimetry analysis was performed on [177Lu]Lu-DOTAGA-IAC distribution data. A pilot study of [68Ga]Ga-DOTAGA-IAC and [18F]FDG Positron Emission Tomography (PET/CT) imaging was performed in five patients with histopathologically confirmed breast cancer. PET/CT findings were compared between [68Ga]Ga-DOTAGA-IAC and [18F]FDG in these patients. Results: Radiopharmaceuticals were prepared with high radiochemical purity (>99.9%). Kd and Bmax measurements were 15.02 nM and 417 fmol for αVß3 receptor protein: 115.7 nM and 295.3 fmol for C6 glioma cells. Biodistribution studies in rats suggested the excretion via kidneys and partially through the hepatobiliary route. The effective dose of [177Lu]Lu-DOTAGA-IAC was found to be 0.17 mSv/MBq. The dynamic study in patients revealed the optimal imaging time to be 30-35 mins postadministration. Out of the cohort, [68Ga]Ga-DOTAGA-IAC detected the primary lesions in all five patients with a mean standard uptake value (SUVmax) of 3.94 ± 0.58 compared with [18F]FDG (SUVmax 13.8 ± 6.53). Conclusion: The study demonstrates that DOTAGA-IAC exhibits strong binding to αVß3 integrin, positioning it as a promising PET agent for assessing primary and metastatic cancers. The outcomes from the pilot study suggest the potential of [68Ga]Ga-DOTAGA-IAC PET/CT in breast carcinoma diagnosis. While recognizing the theranostic potential of DOTAGA-IAC for αVß3 integrin-expressing tumors, further clinical investigations are warranted to comprehensively assess therapeutic efficacy.

Understanding the epigenetic mechanisms in SARS CoV-2 infection and potential therapeutic approaches.

COVID-19 pandemic caused by the Severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) has inflicted a global health challenge. Although the overwhelming escalation of mortality seen during the initial phase of the pandemic has reduced, emerging variants of SARS-CoV-2 continue to impact communities worldwide. Several studies have highlighted the association of gene specific epigenetic modifications in host cells with the pathogenesis and severity of the disease. Therefore, alongside the investigations into the virology and pathogenesis of SARS-CoV-2 infection, understanding the epigenetic mechanisms related to the disease is crucial for the rational design of effective targeted therapies. Here, we discuss the interaction of SARS-CoV-2 with the various epigenetic regulators and their subsequent contribution to the risk of disease severity and dysfunctional immune responses. Finally, we also highlight the use of epigenetically targeted drugs for the potential therapeutic interventions capable of eliminating viral infection and/or build effective immunity against it.

Role of epigenetic mechanisms in propagating off-targeted effects following radiation based therapies - A review.

Despite being an important diagnostic and treatment modality, ionizing radiation (IR) is also known to cause genotoxicity and multiple side effects leading to secondary carcinogenesis. While modern cancer radiation therapy has improved patient recovery and enhanced survival rates, the risk of radiation-related adverse effects has become a growing challenge. It is now well-accepted that IR-induced side effects are not exclusively restricted to exposed cells but also spread to distant 'bystander' cells and even to the unexposed progeny of the irradiated cells. These 'off-targeted' effects involve a plethora of molecular events depending on the type of radiation and tumor tissue background. While the mechanisms by which off-targeted effects arise remain obscure, emerging evidence based on the non-mendelian inheritance of various manifestations of them as well as their persistence for longer periods supports a contribution of epigenetic factors. This review focuses on the major epigenetic phenomena including DNA methylation, histone modifications, and small RNA mediated silencing and their versatile role in the manifestation of IR induced off-targeted effects. As short- and long-range communication vehicles respectively, the role of gap junctions and exosomes in spreading these epigenetic-alteration driven off-targeted effects is also discussed. Furthermore, this review emphasizes the possible therapeutic potentials of these epigenetic mechanisms and how beneficial outcomes could potentially be achieved by targeting various signaling molecules involved in these mechanisms.

Zinc: a promising agent in dietary chemoprevention of cancer.

Proper intake of dietary nutrients is considered crucial for preventing the initiation of events leading to the development of carcinoma. Many dietary compounds have been considered to contribute in cancer prevention including zinc, which plays a pivotal role in host defense against the initiation and promotion of several malignancies. Zinc is an essential element that is integral to many proteins and transcription factors which regulate key cellular functions such as the response to oxidative stress, DNA replication, DNA damage repair, cell cycle progression, and apoptosis. Zinc has been ascribed roles in the metabolism and interaction of malignant cells, particularly in apoptosis. Zinc is involved in structural stabilization and activation of the p53 that appears to be an important component of the apoptotic process and also in activation of certain members of the caspase family of proteases. Zinc exerts a positive beneficial effect against chemically induced preneoplastic progression in rats and provides an effective dietary chemopreventive approach to disease in vulnerable section of population with family history of carcinoma. The present review provides an insight into the research conducted on animals as well as on human subjects for providing the concept that zinc deficiency is an important factor in the development and progression of malignancy and that zinc could be efficacious in the prevention and treatment of several cancers viz., colon, pancreas, oesophageal and head and neck. However, it needs further exploration with regard to other definitive bioassays including protein expression and documentation of specific molecular markers to establish the exact mechanism for zinc-mediated cancer chemoprevention. Preclinical trials need to investigate the genetic and epigenetic pathways of chemoprevention by zinc.

Efficacy of dual use of Tc-99m-pertechnetate and Tc-99m-tetrofosmin scintigraphy for the assessment of thyroid nodules.

INTRODUCTION: Radioisotope methods have shown to be useful in the non-invasive diagnosis of thyroid nodules over the past years. The present prospective study aims to evaluate the efficacy of gamma imaging using single and dual tracer using Tc-99m pertechnetate and Tc-99m tetrofosmin for evaluation and management of thyroid nodules. METHODS: Dynamic (perfusion) imaging was performed after injecting 148-185 MBq (4-5 mCi) of Tc-99m pertechnetate followed by static imaging. A second, dynamic (perfusion) imaging study within same week was performed with 296-370MBq (8-10mCi) of Tc-99m tetrofosmin on same group of patients followed by early and delayed images. Results of radionuclide perfusion scan from both studies were compared qualitatively with postsurgical histopathology or fine needle aspiration cytology (FNAC). RESULTS: Total 65 nodules in 50 patients were included in the study. With single tracer, the specificity and accuracy of Tc-99m pertechnetate was 23% and 45% and for Tc-99m tetrofosmin scan was 40% and 49%. When dual tracers were evaluated for the same group of patients, the specificity was 56% and accuracy was 55%. CONCLUSION: Dual Tracer technique with Tc-99m pertechnetate and Tc-99m tetrofosmin could be helpful in selecting nodules need surgical intervention. This technique can be used for convenient and rapid diagnostic evaluation of thyroid nodules non-invasively. We suggest a combination of fine needle aspiration biopsy and dual use of Tc-99m-pertechnetate and Tc-99m-tetrofosmin as a routine diagnostic approach to thyroid nodules.

Uptake and retention of 65Zn in lithium-treated rat liver: role of zinc.

AIM: To evaluate the effects of zinc on the biokinetics of (65)Zn in rat and its distribution in various organs and in subcellular compartment following lithium therapy. METHODS: Female wistar rats received either lithium treatment at a dose of 1.1g/kg in diet, zinc alone at a dose of 227 mg/L in drinking water, and combined lithium plus zinc for duration of four months. RESULTS: After four months of lithium treatment, liver enzymes increased significantly (glutamic oxaloacetic transaminase, +66.73%; glutamic pyruvic transaminase, +63.70%; alkaline phosphatase, +40.28%; p< or =0.001); zinc supplementation to lithium-treated rats significantly reduced liver enzymes (glutamic oxaloacetic transaminase, -13.11%; glutamic pyruvic transaminase, -21.78%; alkaline phosphatase, -11.77%; p< or =0.001). The biological half-lives of (65)Zn showed an initial fast component (Tb(1)) and a slower component (Tb(2)). A significant increase in Tb(2) (38.82%, p< or =0.001) in liver was observed following lithium treatment, which significantly decreased following zinc treatment (21.71%, p< or =0.001). A significant decrease in the uptake of (65)Zn (53.93%, p< or =0.01) in liver was observed and in nuclear (p< or =0.01), mitochondrial (p< or =0.01), and microsomal (52.67%, p< or =0.001) fractions. A significant increase in the uptake of (65)Zn (82.92%, p< or =0.05) in liver microsomal fraction (34.09%, p< or =0.001) was observed in lithium-treated rats receiving zinc supplementation. CONCLUSION: The study suggests that zinc has the potential to regulate the biokinetics of (65)Zn and its subcellular distribution in rat liver following lithium therapy.