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The management of breast cancer by chemotherapeutic agents has significantly increased the survival rates and, at the same time, raised concerns about the side effects caused by these agents on healthy tissues. Chemotherapy-induced cognitive impairment resulting from non-CNS malignancies like breast cancer has emerged as a significant challenge among cancer survivors due to its negative impact on the quality of day-to-day life activities. Using doxorubicin-based chemotherapy as a preclinical model for chemotherapy-induced cognitive impairment, we assessed the effect of quercetin on behavioral memory alterations in tumor-bearing female rats in vivo and changes in neurite length and apoptosis in PC12 cell lines in vitro. Quercetin is purported to have neuroprotective effects in different preclinical models of human neurological conditions because of its possible anti-inflammatory and antioxidant properties. Mammary carcinoma was induced by intraperitoneal administration of N-methyl-N-nitrosourea followed by doxorubicin administration once in 5 days (50 days). Pre-treatment with quercetin began 1 week before the chemotherapy and continued till the end of the chemotherapy cycle. Mechanistically, quercetin produced protection against doxorubicin-induced neurotoxicity by decreasing apoptosis and had a neurogenic effect evidenced by the prevention of toxicant-induced inhibition of neurite establishment. Quercetin reversed episodic and spatial memory deficits caused by doxorubicin treatment assessed by novel object recognition memory and Morris water maze, respectively. Taken together, our findings suggest that cytotoxic effects of doxorubicin may be a contributor to neurogenic impairment in tumor-bearing animals, leading to memory deficits. Therefore, quercetin could be a promising therapeutic strategy for doxorubicin-related cognitive impairment, thus imparting hope for improved quality of life among cancer survivors. Graphical Abstract

Background : Virgin coconut oil (VCO) has been identified as a potential cognitive strengthener associated with Alzheimer’s disease (AD). It contains medium chain fatty acids (MCFA) which are absorbed and easily metabolized by the liver to form ketone bodies. Ketone bodies are converted to acetyl Co-A in the brain which then enters the citric acid cycle to provide ATP and also serves as precursors of acetylcholine in neurons. Sunflower oil (SO) contains poly unsaturated fatty acids which has both anti-inflammatory and neuroprotective actions. To compare the neuroprotective effects of VCO and SO on biochemical parameters involved in the cognitive dysfunction induced by colchicine through intracerebroventricular (i.c.v) route.To assess the role of polyphenols and MCFA present in VCO in preventing oxidative stress and its influence on in neuroprotection and memory enhancement. Methods: In the present study, we induced dementia through i.c.v injection of colchicine after giving the diet enriched VCO and SO in rats for 60 days. Rats were sacrificed on the 22nd day after the administration of colchicine. Behavioral parameters were assessed during the study period and biochemical estimations were performed using frontal cortex and hippocampus isolated from rat brain. Results: From the memory and learning tests by Morris water maze, VCO treated group performed better than SO treated rats. VCO reversed the antagonistic effects induced by colchicine by decreasing the acetylcholinesterase and malondialdehyde levels and increasing the levels of catalase and superoxide dismutase. SO only reduced malondialdehyde levels in cortex and hippocampus. Conclusion: The results demonstrated potential beneficiary effects of VCO in the cognitive dysfunction induced by colchicine by enhancing acetylcholine levels in the frontal cortex and hippocampus and also by reducing oxidative stress induced by physiological oxidants.

Rationale Chemotherapy-induced cognitive impairment (CICI), chemobrain, and chemofog are the common terms for mental dysfunction in a cancer patient/survivor under the influence of chemotherapeutics. CICI is manifested as short/long term memory problems and delayed mental processing, which interferes with a person’s day-to-day activities. Understanding CICI mechanisms help in developing therapeutic interventions that may alleviate the disease condition. Animal models facilitate critical evaluation to elucidate the underlying mechanisms and form an integral part of verifying different treatment hypotheses and strategies. Objectives A methodical evaluation of scientific literature is required to understand cognitive changes associated with the use of chemotherapeutic agents in different preclinical studies. This review mainly emphasizes animal models developed with various chemotherapeutic agents individually and in combination, with their proposed mechanisms contributing to the cognitive dysfunction. This review also points toward the analysis of chemobrain in healthy animals to understand the mechanism of interventions in absence of tumor and in tumor-bearing animals to mimic human cancer conditions to screen potential drug candidates against chemobrain. Results Substantial memory deficit as a result of commonly used chemotherapeutic agents was evidenced in healthy and tumor-bearing animals. Spatial and episodic cognitive impairments, alterations in neurotrophins, oxidative and inflammatory markers, and changes in long-term potentiation were commonly observed changes in different animal models irrespective of the chemotherapeutic agent. Conclusion Dyscognition exists as one of the serious side effects of cancer chemotherapy. Due to differing mechanisms of chemotherapeutic agents with differing tendencies to alter behavioral and biochemical parameters, chemotherapy may present a significant risk in resulting memory impairments in healthy as well as tumor-bearing animals.

Rubrocurcumin, well-known for its application in photometric determination of boron in various matrices, has attracted substantial attention due to its applications in biological and pharmacological fields. Here, geometrical optimization, diverse bonding features and potential energy surface scans were studied by use of density functional theory. Vibrational analysis of rubrocurcumin was done by Fourier transform infrared and Fourier transform Raman spectroscopies. The electronic density distribution of atoms in the molecule was analyzed by use of natural bond orbital analysis. Conceptual density functional theory-based local reactivity descriptors were used to understand the relationship between structure, stability, and chemical reactivity.

The yellow colored pigment, curcumin present in turmeric is responsible for its various biological activities like antioxidant, anti-inflammatory and anticarcinogenic activity. Different functional group present in curcumin includes a β-diketone group, carbon-carbon double bond and two phenyl rings with hydroxy and methoxy substituents. A controversy exists in literature on the site and mechanism for the antioxidant activity (AOA), the keto-enol/phenolic moiety present in curcumin. In the present work AOA of curcuminoids and its boron complex with oxalic acid-rubrocurcumin analogues were conducted which differ in the substituent in the benzene ring. Since in rubrocurcumin analogue β-diketone group is blocked through bonding with boron its influence will be absent in its antioxidant activity.

Chronic low-grade inflammation and dysregulation of the stress defense system are cardinal features of obesity, a major risk factor for the development of insulin resistance and diabetes. Dual-specificity protein phosphatase 1 (DUSP1), known also as MAP kinase phosphatase 1 (MKP1), is implicated in metabolism and energy expenditure. Mice lacking DUSP1 are resistant to high-fat diet-induced obesity. However, the expression of DUSP1 has not been investigated in human obesity. In the current study, we compared the expression pattern of DUSP1 between lean and obese nondiabetic human subjects using subcutaneous adipose tissue (SAT) and peripheral blood mononuclear cells (PBMCs). The levels of DUSP1 mRNA and protein were significantly increased in obese subjects with concomitant decrease in the phosphorylation of p38 MAPK (p-p38 MAPK) and PGC-1α and an increase in the levels of phospho-JNK (p-JNK) and phospho-ERK (p-ERK). Moreover, obese subjects had higher levels of circulating DUSP1 protein that correlated positively with various obesity indicators, triglycerides, glucagon, insulin, leptin, and PAI-1 ( P < 0.05) but negatively with V̇o2max and high-density lipoprotein ( P < 0.05). The observation that DUSP1 was overexpressed in obese subjects prompted us to investigate whether physical exercise could reduce its expression. In this study, we report for the first time that physical exercise significantly attenuated the expression of DUSP1 in both the SAT and PBMCs, with a parallel increase in the expression of PGC-1α and a reduction in the levels of p-JNK and p-ERK along with attenuated inflammatory response. Collectively, our data suggest that DUSP1 upregulation is strongly linked to adiposity and that physical exercise modulates its expression. This gives further evidence that exercise might be useful as a strategy for managing obesity and preventing its associated complications.

Sedentary lifestyle and excessive energy intake are prominent contributors to obesity; a major risk factors for the development of insulin resistance, type 2 diabetes and cardiovascular diseases. Elucidating the molecular mechanisms underlying these chronic conditions is of relevant importance as it might lead to the identification of novel anti-obesity targets. The purpose of the current study is to investigate differentially expressed proteins between lean and obese subjects through a shot-gun quantitative proteomics approach using peripheral blood mononuclear cells (PBMCs) extracts as well as potential modulation of those proteins by physical exercise. Using this approach, a total of 47 proteins showed at least 1.5 fold change between lean and obese subjects. In obese, the proteomic profiling before and after 3 months of physical exercise showed differential expression of 38 proteins. Thrombospondin 1 (TSP1) was among the proteins that were upregulated in obese subjects and then decreased by physical exercise. Conversely, the histone deacetylase 4 (HDAC4) was downregulated in obese subjects and then induced by physical exercise. The proteomic data was further validated by qRT-PCR, Western blot and immunohistochemistry in both PBMCs and adipose tissue. We also showed that HDAC4 levels correlated positively with maximum oxygen consumption (VO2 Max) but negatively with body mass index, percent body fat, and the inflammatory chemokine RANTES. In functional assays, our data indicated that ectopic expression of HDAC4 significantly impaired TNF-α-dependent activation of NF-κB, establishing thus a link between HDAC4 and regulation of the immune system. Together, the expression pattern of HDAC4 in obese subjects before and after physical exercise, its correlation with various physical, clinical and metabolic parameters along with its inhibitory effect on NF-κB are suggestive of a protective role of HDAC4 against obesity. HDAC4 could therefore represent a potential therapeutic target for the control and management of obesity and presumably insulin resistance.

Background Obesity is characterized by a chronic low-grade inflammation and altered stress responses in key metabolic tissues. Impairment of heat shock response (HSR) has been already linked to diabetes and insulin resistance as reflected by decrease in heat shock proteins (HSPs) expression. However, the status of HSR in non-diabetic human obese has not yet been elucidated. The aim of the current study was to investigate whether obesity triggers a change in the HSR pattern and the impact of physical exercise on this pattern at protein and mRNA levels. Methods Two groups of adult non-diabetic human subjects consisting of lean and obese (n = 47 for each group) were enrolled in this study. The expression pattern of HSP-27, DNAJB3/HSP-40, HSP-60, HSC-70, HSP72, HSP-90 and GRP-94 in the adipose tissue was primarily investigated by immunohistochemistry and then complemented by western blot and qRT-PCR in Peripheral blood mononuclear cells (PBMCs). HSPs expression levels were correlated with various physical, clinical and biochemical parameters. We have also explored the effect of a 3-month moderate physical exercise on the HSPs expression pattern in obese subjects. Results Obese subjects displayed increased expression of HSP-60, HSC-70, HSP-72, HSP-90 and GRP-94 and lower expression of DNAJB3/HSP-40 (P

Introduction Obesity is characterized by a chronic-low grade inflammation and aberrant regulation of various forms of stress response in key metabolic sites. The white adipose tissue has been identified as the predominant site of obesity-associated inflammatory reactions, which are triggered as a consequence of immune cells infiltration. Physical exercise has been widely recognized for treating obesity and metabolic syndromes. The objectives of this study are: (1) To investigate the release pattern of pro- and anti-inflammatory mediators in obese participants, (2) To evaluate the effect of a defined exercise protocol on their release into the circulation, (3) To correlate their expression with the metabolic and stress markers. Methods A total of 600 healthy individuals divided into 3 groups using the body mass index as a reference (lean, overweight and obese) are being enrolled in a 6-month defined exercise protocol. Blood samples and abdominal subcutaneous adipose biopsies are collected at baseline (t0) and after 3 (t3) and 6 (t6) months of exercise. Plasma cytokine and metabolic markers levels were assessed simultaneously using the xMAP multiplex immunobead assay technology (Bioplex). Markers of the oxidative stress, namely ROS and TBARS were measured on plasma or serum using commercially available kits. Gene expression profile was done by RT-PCR using RT-profiler- array kits consisting of the heat shock protein panel, obesity panel and the oxidative stress panel. Western blotting and immunohistochemistry techniques were used to validate the gene expression data. Statistical analyses were performed using SAS software. Results The analysis carried out on a first set of samples indicated significant release of RANTES in obese individuals compared to lean participants ( P Conclusion Our result demonstrated a differential expression of RANTES chemokine in obese participants in comparison to lean control and highlighted its roles in obesity. Exercise was able to restore the normal expression of RANTES. The existence of a negative correlation between RANTES expression and the metabolic and stress responses is suggestive of a pathological role of RANTES and may be considered a potential therapeutic target.

Association of obesity with down-regulation of heat shock protein 40 expression and evidence that exercise retrieves its normal expression Jehad Abubakr, Mohamed Abu-Farha, Monira Al-Arouj, Fahad Al-Ghimlas, Irina Al-Khairi, Dalal Al-Mudhaf, Engin Baturcam, Abdullah Bennakhi, Preethi Cherian, Maha Hammad, Jeena John, Sina Kavalakatt, Abdelkrim Khadir, Ali Tiss, Samia Warsame, Said Dermime, Mohammed Dehbi