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Inclining mortality with a constant plummet in the survival rates associated with glioblastoma still stands as an inveterate predicament. The only promising therapy with temozolomide (TMZ) is now side-lined due to escalated resistance mediated by Poly (ADP-ribose) Polymerase-1 (PARP-1). In the light of this, the very study was designed to evaluate the potential of an active phyto component named naringin, in inhibiting PARP-1, using in silico and in vitro methods. Under in silico settings, inhibitor bound crystal structure of PARP-1, i.e., 4UND was retrieved and molecular docking studies were performed against naringin using Schrodinger software. In vitro cytotoxicity and apoptotic detection assay were performed using C6 glioma cells. Docking studies revealed high affinity and low binding energy at the inhibition site with good stability. An increase in cytotoxicity to C6 cells was observed with TMZ and naringin combination when compared to TMZ alone. Isobologram plot confirmed the synergistic effect of the drug combination. A significant increase in the number of apoptotic cells with combination drugs, as evaluated by acridine orange and ethidium bromide staining reassured the reversal of resistance. In conclusion, chemosensitivity to TMZ was restored by successful inhibition of PARP-1 using naringin and the drug combination was hence proven effective in reversing TMZ resistance.

Chemo-brain refers to the thinking and memory problems that occur in cancer patients during and after chemotherapy. It is also known as cognitive dysfunction or chemo-fog. Risk factors include brain malignancies, either primary or metastatic, radiotherapy and chemotherapy, either systemic or brain targeted. There are various mechanisms by which chemo-brain occurs in patients post-chemotherapy, including inflammation of neurons, stress due to free radical generation, and alterations in normal neuronal cell process due to biochemical changes. While chemotherapy drugs that are non-brain targeted, usually fail to cross the blood-brain barrier (BBB), this is not the case for inflammatory cytokines that are released, which easily cross the BBB. These inflammatory neurotoxic agents may represent the primary mediators of chemobrain and include the pro-inflammatory cytokines such as interleukins 1 and 6 and tumor necrosis factor. The pronounced rise in oxidative stress due to continuous chemotherapy also leads to a reduction in neurogenesis and gliogenesis, loss of spine and dendritic cells, and a reduction in neurotransmitter release. Based on recent research, potential agents to prevent and treat chemo brain have been identified, which include Lithium, Fluoxetine, Metformin, Rolipram, Astaxanthin, and microglial inhibitors. However, more defined animal models for cognitive dysfunction are required to study in detail the mechanisms involved in chemo-brain; furthermore, well-defined clinical trials are required to identify drug targets and their therapeutic significance. With these focused approaches, the future for improved therapies is promising.

Non-alcoholic fatty liver disease (NAFLD) is one of the major hepatic metabolic disorders that occurs because of the accumulation of lipids in hepatocytes in the form of free fatty acids (FFA) and triglycerides (TG) which become non-alcoholic steatohepatitis (NASH). NOTCH-1 receptors act as novel targets for the development of NAFLD/NASH, where overexpression of NOTCH-1 receptor alters the lipid metabolism in hepatocytes leading to NAFLD. SIRT-1 deacetylates the NOTCH-1 receptor and inhibits NAFLD. Hence, computer-aided drug design (CADD) was used to check the SIRT-1 activation ability of cinnamic sulfonyl hydroxamate derivatives (NMJ 1–8), resveratrol, and vorinostat. SIRT-1 (PDB ID: 5BTR) was docked with eight hydroxamate derivatives and vorinostat using Schrödinger software. Based on binding energy obtained (– 26.31 to – 47.34 kcal/mol), vorinostat, NMJ-2, NMJ-3, NMJ-5 were selected for induced-fit docking (IFD) and results were within – 750.70 to – 753.22 kcal/mol. Qikprop tool was used to analyse the pre pharmacokinetic parameters (ADME analysis) of all hydroxamate compounds. As observed in the molecular dynamic (MD) study, NMJ-2, NMJ-3 were showing acceptable results for activation of SIRT-1. Based on these predictions, in-vivo studies were conducted in CF1 mice, where NMJ-3 showed significant (p

Nanotechnology has now become a pivotal technology in medicine, capable of providing an innovative explanation for various unmet therapeutic needs. The core of nanomedicine is the development of diagnostic means and therapeutics into their nanoscopic form with the aid of different vehicles to achieve targeted drug delivery. These nanoparticles are typically less than 200 nm in diameter. Lipid nanoparticles, polymeric nanoparticles, inorganic nanoparticles, drug conjugates, and magnetic nanoparticles are a few examples of nanomedicines. Nanomedicines with their novel structural characteristics enhance the drug permeability, absorbability, and retention properties. They play a very important role in diagnostic imaging, tumor detection, photodynamic, and photothermal therapy. Physicochemical properties such as particle size, shape, and surface area show a greater influence on the absorption and elimination of nanomedicines. Besides several advantages, the major adverse effect of the nanomedicines is their toxicity. The smaller the size of the particle, the higher is its toxicity. In this chapter, we focus on the detailed pharmacokinetics, biodistribution, and toxicology of nanomedicines.

Background: Chronic administration of steroids like dexamethasone produces symptoms including weight loss and skeletal muscle dysfunction. Similar events are reported in chronic or high-intensity exercises, that can lead to fatigue and muscle damage. Objective: In the present study, the effect of Moringa oleifera leaf extract was evaluated against dexamethasone (Dex) and exercise (Exe)-induced muscle changes in rats. Materials and methods: Six groups each containing 6 rats, namely normal, Dex control, Exe Control, Dex + M. oleifera leaf extract (300mg/kgp.o.), Dex + Exe, Dex + Exe + M. oleifera leaf extract were assessed in the study. Dex was administered at 0.6 mg/kg i.p. daily for 7 days. Exercise was given for a total of 10 days after 30 minutes of dosing using treadmill equipment for 900 seconds at speed 18 m/min. Animals were assessed for variation in body weight, muscular endurance using treadmill, locomotor activity using actophotometer, motor coordination using rotarod on day zero, and day seven. Hemidiaphragm of rats were isolated and used for evaluation of the glucose uptake. Gastrocnemius muscle was isolated and subjected to hematoxylin and eosin staining. Results: Dex and Exe control animals showed a significant decrease in skeletal muscle activity when compared to normal control animals in the actophotometer test. Improvement in endurance were seen in Dex + M. oleifera leaf extract, and Dex + exercise + M. oleifera leaf extract groups compared to Dex control group. Improvement in locomotor activity was seen in Dex group subjected to exercise and was significant when treated with M. oleifera leaf extract. Histology reports were in accordance with the functional parameters. Conclusion: M. oleifera leaf extract supplemented with exercise showed a reversal in the dexamethasone-induced functional impairment in skeletal muscles.

Considering the cognitive impairment induced by temozolomide (TMZ) in glioblastoma survivors, the present study was aimed to evaluate the protective effect of dehydrozingerone (DHZ) against TMZ-induced cognitive impairment (chemobrain) and C6 cell line-induced glioma in male Wistar rats. In both chemobrain and glioma models, TMZ was administered at a dose of 18 mg/kg i.v every 5th day and DHZ at a dose of 100 mg/kg p.o. daily. Additionally, glioma was induced by intracerebral injection of 5 × 104 C6 rat glioma cells in the cortex in the glioma model. Upon disease induction and treatment with TMZ + DHZ, spatial memory was assessed by the Morris water maze (MWM) test and episodic memory by the novel object recognition test (NORT). The induction of glioma was confirmed by histology of the cortex. Hippocampus and frontal cortex were subjected to antioxidant evaluation. Significant loss of spatial and episodic memory was observed with TMZ treatment which was significantly restored by DHZ. DHZ showed significant improvement in oxidative stress markers reversed the histopathological features in the cortex. TMZ-induced elevation of the glutathione level was also reversed by DHZ, indicating the role of DHZ in the reversal of TMZ resistance. In the glioma model, the improvement in cognition by DHZ correlated with the decrease in tumor volume. Altogether, the study results reveal the role of TMZ in worsening the memory and DHZ in reversing it, besides, improving its anticancer potential.

Cognitive dysfunction by chemotherapy compromises the quality of life in cancer patients. Tea polyphenols are known chemopreventive agents. The present study was designed to evaluate the neuroprotective potential of (+) catechin hydrate (catechin), a tea polyphenol, in IMR-32 neuroblastoma cells in vitro and alleviation of episodic memory deficit in Wistar rats in vivo against a widely used chemotherapeutic agent, Doxorubicin (DOX). In vitro, neuroprotective studies were assessed in undifferentiated IMR-32 cells using percentage viability and in differentiated cells by neurite length. These studies showed catechin increased percentage viability of undifferentiated IMR-32 cells. Catechin pretreatment also showed an increase in neurite length of differentiated cells. In vivo neuroprotection of catechin was evaluated using novel object recognition task in time-induced memory deficit model at 50, 100 and 200 mg/kg dose and DOX-induced memory deficit models at 100 mg/kg dose. The latter model was developed by injection of DOX (2.5 mg/kg, i.p.) in 10 cycles over 50 days in Wistar rats. Catechin showed a significant reversal of time-induced memory deficit in a dose-dependent manner and prevention of DOX-induced memory deficit at 100 mg/kg. In addition, catechin treatment showed a significant decrease in oxidative stress, acetylcholine esterase and neuroinflammation in the hippocampus and cerebral cortex in DOX-induced toxicity model. Hence, catechin may be a potential adjuvant therapy for the amelioration of DOX-induced cognitive impairment which may improve the quality of life of cancer survivors. This improvement might be due to the elevation of antioxidant defense, prevention of neuroinflammation and inhibition of acetylcholine esterase enzyme.

Sesame (Sesamum indicum L.) seeds have been authenticated for its medicinal value in both Chinese and Indian systems of medicine. Its numerous potential nutritional benefits are attributed to its main bioactive constituents, sesamol. As a result of those studies, several molecular mechanisms are emerging describing the pleiotropic biological effects of sesamol. This review summarized the most interesting in vitro and in vivo studies on the biological effects of sesamol. The present work summarises data available from Pubmed and Scopus database. Several molecular mechanisms have been elucidated describing the pleiotropic biological effects of sesamol. Its major therapeutic effects have been elicited in managing oxidative and inflammatory conditions, metabolic syndrome and mood disorders. Further, compelling evidence reflected the ability of sesamol in inhibiting proliferation of the inflammatory cell, prevention of invasion and angiogenesis via affecting multiple molecular targets and downstream mechanisms. Sesamol is a safe, non‐toxic chemical that mediates anti‐inflammatory effects by down‐regulating the transcription of inflammatory markers such as cytokines, redox status, protein kinases, and enzymes that promote inflammation. In addition, sesamol also induces apoptosis in cancer cells via mitochondrial and receptor‐mediated pathways, as well as activation of caspase cascades. In the present review, several pharmacological effects of sesamol are summarised namely, antioxidant, anti-cancer, neuroprotective, cardioprotective, anti-inflammatory, hypolipidemic, radioprotective, anti-aging, anti-ulcer, anti-dementia, anti-depressant, antiplatelet, anticonvulsant, anti-anxiolytic, wound healing, cosmetic (skin whitening), anti-microbial, matrix metalloproteinase (MMPs) inhibition, hepatoprotective activity and other biological effects. Here we have summarized the proposed mechanism behind these pharmacological effects.

Glycosylated pH-sensitive mesoporous silica nanoparticles (MSNs) of capecitabine (CAP) were developed for targeting colorectal cancer. The MSNs possessed an average pore diameter of 8.12 ? 0.43 nm, pore volume of 0.73 ? 0.21 cm3/g, and particle size of 245.24 ? 5.75 nm. A high loading of 180.51 ? 5.23 mg/g attributed to the larger pore volume was observed. The surface of the drug-loaded MSNs were capped with chitosanglucuronic acid (CHS-GCA) conjugate to combine two strategies viz. pH-sensitive, and lectin receptor mediated uptake. In vitro studies demonstrated a pH-sensitive and controlled release of CAP which was further enhanced in the presence of rat caecal content. Higher uptake of the (CAP-MSN)CHS-GCA was observed in HCT 116 cell lines. The glycosylated nanoparticles revealed reduction in the tumors, aberrant crypt foci, dysplasia and inflammation, and alleviation in the toxic features. This illustrated that the nanoparticles showed promising antitumor efficacy with reduced toxicity and may be used as a effective carrier against cancer. Refereed/Peer-reviewed

Cancer has emanated as a daunting menace to human-kind even though medicine, science, and technology has reached its zenith. Subsequent scarcity in the revelation of new drugs, the exigency of salvaging formerly discovered toxic drugs such as doxorubicin has emerged. The invention of drug carrier has made drug delivery imminent which is ascribable to its characteristic traits of specific targeting, effective response to stimuli and biocompatibility. In this paper, the nanoscale polymeric drug carrier poly(N,N-diethyl acrylamide) nanohydrogel has been synthesized by inverse emulsion polymerization. Lower critical solution temperature of the polymeric carrier has been modified using graphene quantum. The particle size of pure nanohydrogel was in the range of 47 to 59.5 nm, and graphene quantum dots incorporated nanohydrogels was in the range of 68.1 to 87.5 nm. Doxorubicin (hydroxyl derivative of anthracycline) release behavior as a function of time and temperature was analyzed, and the Lower critical solution temperature of the synthesized nanohydrogels has been found to be in the range of 28–42 °C. Doxorubicin release characteristics have improved significantly as the surrounding temperature of the release media was increased near to physiological temperature. Further, the cumulative release profile was fitted in the different kinetic model and found to follow a Fickian diffusion release mechanism. The hydrogel was assessed for its cytotoxicity in B16F10 cells by MTT assay. In-vivo studies were done to study the lung metastasis by melanoma cancer and the results showed a rational favorable prognosis which was confirmed by evaluating hematological parameters and the non-immunogenic nature of nanohydrogel by cytokine assay. Comprehensively, the results suggested that poly(N,N-diethyl acrylamide) nanohydrogels have potential application as an intelligent drug carrier for melanoma cancer.

In this study, methanolic extract of Saraca asoca bark was evaluated for its aphrodisiac potential using male and female Wistar albino rats. Male rats were dosed daily for 54 days at a dose of 100 mg/kg p.o. Sexual activity of male rats was assessed after 14, 28, 42 and 54 days of the study. Male rats were placed in a glass chamber lit with a dim red light (10W) followed by the introduction of sexually receptive female rats in a ratio of 1:1. Improvement in sexual behaviour of male rats was characterised by an increase in both mount frequency and intromission frequency and decrease or reduction in mount latency and intromission latency compared to normal control. After completion of the study, the effect of the S. asoca extract on sperm count, sperm motility and sperm morphology was also assessed. The extract of S. asoca bark was found to be safe as it did not affect these sperm parameters. From this study, it was found that methanolic extract of S. asoca bark plays a role in enhancing sexual behaviour and potential without causing reproductive toxicity.

Stroke is considered to be one of the most important causes of death worldwide. Global ischemia causes widespread brain injury and infarctions in various regions of the brain. Oxidative stress can be considered an important factor in the development of tissue damage, which is caused because of arterial occlusion with subsequent reperfusion. Kapikacchu or Mucuna pruriens, commonly known as velvet bean, is well known for its aphrodisiac activities. It is also used in the treatment of snakebites, depressive neurosis, and Parkinson's disease. Although this plant has different pharmacological actions, its neuroprotective activity has received minimal attention. Thus, this study was carried out with the aim of evaluating the neuroprotective action of M. pruriens in bilateral carotid artery occlusion-induced global cerebral ischemia in Wistar rats. The carotid arteries of both sides were occluded for 30 min and reperfused to induce global cerebral ischemia. The methanolic plant extract was administered to the study animals for 10 days. The brains of the Wistar rats were isolated by decapitation and observed for histopathological and biochemical changes. Cerebral ischemia resulted in significant neurological damage in the brains of the rats that were not treated by M. pruriens. The group subjected to treatment by the M. pruriens extract showed significant protection against brain damage compared with the negative control group, which indicates the therapeutic potential of this plant in ischemia.

Grandhi Venkata Ramalingayya, Sri Pragnya Cheruku, Pawan G Nayak, Anoop Kishore, Rekha Shenoy, Chamallamudi MallikarjunaRao, Nandakumar Krishnadas Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka,India Abstract: Doxorubicin (DOX) is the most widely used broad-spectrum anticancer agent, either alone or in combination, for most cancers including breast cancer. Long-term use of chemotherapeutic agents to treat breast cancer patients results in cognitive complications with a negative impact on survivors’ quality of life. The study objective was to evaluate rutin (RUT) for its neuroprotective effect against DOX in human neuroblastoma (IMR32) cells in vitro and study its potential to ameliorate DOX-induced cognitive dysfunction in Wistar rats. Cell viability assay (3-[4,5 dimethyl thiazol-2-yl]-2,5-diphenyl tetrazolium bromide), neurite growth assay, detection of apoptosis by (acridine orange/ethidium bromide) staining, intracellular reactive oxygen species (ROS) assay, and flowcytometric analysis were carried out to assess neuroprotective potential against DOX. An in vivo study was conducted for assessing protective effect of RUT against memory deficit associated with DOX-induced chemobrain using object recognition task (ORT). Locomotion was assessed using open field test. Serum biochemistry, acetylcholinesterase, oxidative stress markers in hippocampus, and frontal cortex were assessed. Histopathological analysis of major organ systems was also carried out. Prior exposure to RUT at 100 µM protected IMR32 cells from DOX (1 µM) neurotoxicity. DOX exposure resulted in increased cellular death, apoptosis, and intracellular ROS generation with inhibition of neurite growth in differentiated IMR32 cells, which was significantly ameliorated by RUT. Cognitive dysfunction was induced in Wistar rats by administering ten cycles of DOX (2.5 mg/kg, intraperitoneal, once in 5 days), as we observed significant impairment of episodic memory in ORT. Coadministration with RUT (50 mg/kg, per os) significantly prevented memory deficits in vivo without any confounding influence on locomotor activity. RUT also offered protection against DOX-induced myelosuppression, cardiotoxicity, and nephrotoxicity. In conclusion, RUT may be a possible adjuvant therapeutic intervention to alleviate cognitive and other complications associated with DOX chemotherapy. Keywords: breast cancer, chemobrain, cognitive deficit, doxorubicin, episodic memory, object recognition test