Nanomedicines targeting the inflammasome as a promising therapeutic approach for cell senescence.

Technological advancements in the present era have enhanced drug discovery and development. Nanomedicines are valuable pharmacotherapeutic tools against several diseases and disorders including aging related disorders. The mechanistic association between nanomedicines and molecular modulation have been investigated by many researchers. Notwithstanding the availability of tremendous amount of data, role of nanomedicines in aging related disorders intending inflammasome transfiguration have not been thoroughly reviewed till now. In the present review, we discuss the application of nanomedicines in aging related disorders. Further, we highlight the recent updates on modulated upstream and downstream signalling molecules of inflammasome cascade due to nanomedicines. The review will benefit researchers targeting nanomedicines as a therapeutic approach towards treatment age related disorders through inflammasome inflection.

4-Phenylbutyrate Mitigates the Motor Impairment and Dopaminergic Neuronal Death During Parkinson's Disease Pathology via Targeting VDAC1 Mediated Mitochondrial Function and Astrocytes Activation.

Parkinson's disease (PD) is a progressive motor neurodegenerative disorder significantly associated with protein aggregation related neurodegenerative mechanisms. In view of no disease modifying drugs, the present study was targeted to investigate the therapeutic effects of pharmacological agent 4-phenylbutyric acid (4PBA) in PD pathology. 4PBA is an FDA approved monocarboxylic acid with inhibitory activity towards histone deacetylase and clinically treats urea cycle disorder. First, we observed the significant protective effects of 4PBA on PD specific neuromuscular coordination, level of tyrosine hydroxylase, α-synuclein level and neurotransmitter dopamine in both substantia nigra and striatal regions of the experimental rat model of PD. Further results revealed that treatment with 4PBA drug exhibited significant protection against disease related oxidative stress and augmented nitrite levels. The disease pathology-related depletion in mitochondrial membrane potential and augmented level of calcium as well as mitochondrion membrane located VDAC1 protein level and cytochrome-c translocation were also significantly attenuated with 4PBA administration. Inhibited neuronal apoptosis and restored neuronal morphology were also observed with 4PBA treatment as measured by level of pro-apoptotic proteins t-Bid, Bax and cleaved caspase-3 along with cresyl violet staining in both substantia nigra and striatal regions. Lastly, PD-linked astrocyte activation was significantly inhibited with 4PBA treatment. Altogether, our findings suggest that 4PBA exerts broad-spectrum neuroprotective effects in PD animal model.

New therapeutic activity of metabolic enhancer piracetam in treatment of neurodegenerative disease: Participation of caspase independent death factors, oxidative stress, inflammatory responses and apoptosis.

Piracetam, a nootropic drug that has been clinically used for decades but remains enigmatic due to no distinct understanding of its mechanism of action. The present study aimed to investigate the role of caspase independent pathway in piracetam mediated neuroprotection. LPS administration caused significant alterations in oxidative stress related parameters like glutathione, glutathione reductase and increased lipid peroxidation. LPS administration also caused augmented expression of inflammatory cytokines and astrocytes activation. Piracetam treatment offered significant protection against LPS induced oxidative and inflammatory parameters and inhibited astrocytes activation. LPS administration caused augmented level of reactive oxygen species and depleted mitochondrial membrane potential which were attenuated with piracetam treatment. This study for the first time demonstrates the role of caspase independent death factors in piracetam induced neuroprotective effects in rat brain. Translocation of mitochondrial resident apoptosis inducing factor and endonuclease G to nucleus through cytosol after LPS administration was significantly blocked with piracetam treatment. Further, LPS induced DNA fragmentation along with up regulated Poly [ADP-ribose] polymerase 1 (PARP1) levels were also inhibited with piracetam treatment. Apoptotic death was confirmed by the cleavage of caspase 3 as well as histological alteration in rat brain regions. LPS administration caused significantly increased level of cleaved caspase 3, altered neuronal morphology and decreased neuronal density which were restored with piracetam treatment. Collectively our findings indicate that piracetam offered protection against LPS induced inflammatory responses and cellular death including its antioxidative antiapoptotic activity with its attenuation against mitochondria mediated caspase independent pathway.

Synthesis and biological evaluation of some novel triazole hybrids of curcumin mimics and their selective anticancer activity against breast and prostate cancer cell lines.

The anti-cancer property of curcumin, an active component of turmeric, is limited due to its poor solubility, stability and bioavailability. To enhance its efficacy, we designed a novel series of twenty-four monocarbonyl curcumin analogue-1,2,3-triazole conjugates and evaluated their anti-cancer activity towards endocrine related cancers. The new compounds (17-40) were synthesized through CuAAC click reaction and SAR analysis carried out. Out of these all, compound 17 showed most significant anti-cancer activity against prostate cancer cells with IC50 values of 8.8µM and 9.5µM in PC-3 and DU-145 cells, respectively. Another compound 26 showed significant anti-cancer activity against breast cancer cells with IC50 of 6µM, 10µM and 6.4µM in MCF-7, MDA-MB-231 and 4T1 cells, respectively while maintaining low toxicity towards non-cancer originated cell line, HEK-293. Compounds 17 and 26 arrested cell cycle and induced mitochondria-mediated apoptosis in cancer cells. Further, both of these compounds significantly down-regulated cell proliferation marker (PCNA), inhibited activation of cell survival protein (Akt phosphorylation), upregulated pro-apoptotic protein (Bax) and down-regulated anti-apoptotic protein (Bcl-2) in their respective cell lines. In addition, in vitro stability, solubility and plasma binding studies of the compounds 17 and 26 showed them to be metabolically stable. Thus, this study identified two new curcumin monocarbonyl-1,2,3-triazole conjugate compounds with more potent activity than curcumin against breast and prostate cancers.

Assessment of Perception of Dental Students to OSCE Exams: A Cross-Sectional Study.

Aims and Objective: To assess the knowledge as well as attitude of dental students to OSCE exams. Materials and Methods: With the aim of evaluating the knowledge and attitude of dental students to OSCE exams, the present study was planned and it consisted of total 1000 dental students (Third year, Final year, and Interns) who have taken the OSCE examinations. The survey included a questionnaire in addition to a subsection on participants' demographic information. In addition, a 3-point scale was used to rate the OSCE's impartiality, complexity, education level, as well as favored frequency of usage in comparison with various evaluation formats. Results: 562 were males while the remaining 438 were females. While evaluating the student's perception, 36.3 percent of the students agreed that OSCE examination gave precise measure of clinical dental skills. 23.1 percent of the students said OSCE was uniform in terms of standardization, while 25 percent of the students agreed that OSCE score was independent of personality, ethnicity, and gender. Conclusion: To recapitulate, the outcomes of this research gave rise to the notion that the OSCE represents a valid as well as objective evaluation tool for clinical abilities.

ACE2/ANG-(1-7)/Mas receptor axis activation prevents inflammation and improves cognitive functions in streptozotocin induced rat model of Alzheimer's disease-like phenotypes.

Activation of the renin-angiotensin system (RAS), by Angiotensin converting enzyme/Angiotensin II/Angiotensin receptor-1 (ACE/Ang II/AT1 R) axis elicits amyloid deposition and cognitive impairment. Furthermore, ACE2 induced release of Ang-(1-7) binds with the Mas receptor and autoinhibits ACE/Ang II/AT1 axis activation. Inhibition of ACE by perindopril has been reported to improve memory in preclinical settings. However, the functional significance and mechanism by which ACE2/Mas receptor regulate cognitive functions and amyloid pathology is not known. The present study is aimed to determine the role of ACE2/Ang-(1-7)/Mas receptor axis in STZ induced rat model of Alzheimer's disease (AD). We have used pharmacological, biochemical and behavioural approaches to identify the role of ACE2/Ang-(1-7)/Mas receptor axis activation on AD-like pathology in both in vitro and invivo models. STZ treatment enhances ROS formation, inflammation markers and NFκB/p65 levels which are associated with reduced ACE2/Mas receptor levels, acetylcholine activity and mitochondrial membrane potential in N2A cells. DIZE mediated ACE2/Ang-(1-7)/Mas receptor axis activation resulted in reduced ROS generation, astrogliosis, NFκB level and inflammatory molecules and improved mitochondrial functions along with Ca2+ influx in STZ treated N2A cells. Interestingly, DIZE induced activation of ACE2/Mas receptor significantly restored acetylcholine levels and reduced amyloid-beta and phospho-tau deposition in cortex and hippocampus that resulted in improved cognitive function in STZ induced rat model of AD-like phenotypes. Our data indicate that ACE2/Mas receptor activation is sufficient to prevented cognitive impairment and progression of amyloid pathology in STZ induced rat model of AD-like phenotypes. These findings suggest the potential role of ACE2/Ang-(1-7)/Mas axis in AD pathophysiology by regulating inflammation cognitive functions.

Therapeutic Role of ELOVL in Neurological Diseases.

Fatty acids play an important role in controlling the energy balance of mammals. De novo lipogenesis also generates a significant amount of lipids that are endogenously produced in addition to their ingestion. Fatty acid elongation beyond 16 carbons (palmitic acid), which can lead to the production of very long chain fatty acids (VLCFA), can be caused by the rate-limiting condensation process. Seven elongases, ELOVL1-7, have been identified in mammals and each has a unique substrate specificity. Researchers have recently developed a keen interest in the elongation of very long chain fatty acids protein 1 (ELOVL1) enzyme as a potential treatment for a variety of diseases. A number of neurological disorders directly or indirectly related to ELOVL1 involve the elongation of monounsaturated (C20:1 and C22:1) and saturated (C18:0-C26:0) acyl-CoAs. VLCFAs and ELOVL1 have a direct impact on the neurological disease. Other neurological symptoms such as ichthyotic keratoderma, spasticity, and hypomyelination have also been linked to the major enzyme (ELOVL1). Recently, ELOVL1 has also been heavily used to treat a number of diseases. The current review focuses on in-depth unique insights regarding the role of ELOVL1 as a therapeutic target and associated neurological disorders.

Self-Fluorescent Lone Tryptophan Nanoparticles as Theranostic Agents Against Alzheimer's Disease.

Aggregation of ß-amyloid (Aß42) peptide in the neural extracellular space leads to cellular dysfunction, resulting in Alzheimer's disease (AD). The hydrophobic core of the amyloidogenic Aß42 peptide contains aromatic residues that play an important role in the self-assembly and subsequent aggregation of the peptide. Hence, targeting these hydrophobic core residues by potent low molecular agents can be a promising therapeutic approach toward AD. In the current work, we have developed self-fluorescent solo tryptophan nanoparticles (TNPs) as nanotheranostic systems against AD. We demonstrated that TNPs could significantly inhibit as well as disrupt the fibrils formed by both Aß42 peptide and another reductionist approach-based amyloid model dipeptide, phenylalanine-phenylalanine (FF). More importantly, these nanostructures were nontoxic to neural cells and could protect the neurons from Aß42 peptide and FF aggregate-induced cytotoxicity. In addition, efficacy studies performed in animal model further revealed that the TNPs could rescue spatial and learning memory in intracerebroventricular streptozotocin-administration-induced AD phenotype in rats. Moreover, our pharmacokinetics study further established the BBB permeability and brain delivery potency of TNPs. The inherent excellent fluorescent properties of these nanoparticles could be exploited further to use them as imaging modalities for tagging and detecting FF and Aß42 peptide fibrils. Overall, our results clearly illustrated that the solo TNPs could serve as promising nanotheranostic agents for AD therapy.

Evaluation of Bioactive Metabolites and Antioxidant-Rich Extracts of Amaranths with Possible Role in Pancreatic Lipase Interaction: In Silico and In Vitro Studies.

Fat/carbohydrate-rich diet consumption or elevated secretion of pancreatic lipase (PL) in pancreatic injury results in increased fat digestion and storage. Several metabolites in plant-based diets can help achieve the requirements of nutrition and fitness together. Presently, nutritional metabolites from Amaranthus tricolor, A. viridis, and Achyranthes aspera were assessed and predicted for daily intake. The volatile-metabolite profiling of their extracts using GC-MS revealed various antioxidant and bioactive components. The implication of these specialized components and antioxidant-rich extracts (EC50 free radical scavenging: 34.1 ± 1.5 to 166.3 ± 14.2 µg/mL; FRAP values: 12.1 ± 1.0 to 34.0 ± 2.0 µg Trolox Equivalent/mg) in lipolysis regulation by means of interaction with PL was checked by in silico docking (Betahistine and vitamins: ΔGbind -2.3 to -4.4 kcal/mol) and in vitro fluorescence quenching. Out of the various compounds and extracts tested, Betahistine, ATRA and AVLA showed better quenching the PL fluorescence. The identification of potential extracts as source of functional components contributing to nutrition and fat regulation can be improved through such study.

Mechanism for antiParkinsonian effect of resveratrol: Involvement of transporters, synaptic proteins, dendrite arborization, biochemical alterations, ER stress and apoptosis.

The present study was undertaken to evaluate the mechanism for antiParkinsonian effect of resveratrol employing 6-hydroxydopamine (6-OHDA) induced experimental model of Parkinson's disease (PD). Resveratrol treatment significantly protects the PD related pathological markers like level of tyrosine hydroxylase, dopamine and apoptotic proteins (Bax and cleaved caspase-3). Disease pathology involves significantly decreased level of dopamine transporter, synaptophysin and postsynaptic density protein 95 (PSD-95) along with augmented level of vesicular monoamine transporter and considerably affected the dendrite arborization. Such affected neuronal communication was significantly restored with resveratrol treatment. Biochemical alterations include the depleted level of glutathione (GSH), mitochondrial complex-I activity with concomitant increased level of lipid peroxidation, nitrite level and calcium levels, which were also significantly inhibited with resveratrol treatment. Altered calcium level induces the endoplasmic reticulum (ER) stress related signalling and phosphorylated Nuclear factor erythroid 2-related factor 2 (Nrf2), and with resveratrol treatment the level of phosphorylated Nrf2 was further increased. The concurrent depleted level of proteasome activity was observed which was attenuated with resveratrol treatment. Proinflammatory cytokines and activated astrocytes were observed which was inhibited with resveratrol treatment. In conclusion, findings suggested that resveratrol exhibits the interference in neuronal communication, oxidative stress, mitochondrial pathophysiology, ER stress, protein degradation mechanism and inflammatory responses and could be utilize in clinics to treat the PD patients.

Isoformononetin, a dietary isoflavone protects against streptozotocin induced rat model of neuroinflammation through inhibition of NLRP3/ASC/IL-1 axis activation.

AIMS: Isoformononetin (IFN), a methoxyl isoflavone present in most of human dietary supplements. However, being a highly potent antioxidant and anti-inflammatory molecule, its activity against neuronal oxidative stress and neuroinflammation has not been explored till now. The present study was inquested to assess the antioxidant, anti-apoptotic and anti-inflammatory activity of IFN against streptozotocin induced neuroinflammation in different brain regions of rat. MAIN METHODS: Four groups of animals were subjected to treatment as control, toxic control (STZ; single intracerebrovascular injection), third group (STZ + IFN; 20 mg/kg p.o.), fourth group (IFN) for 14 days. The different brain regions of rats were evaluated for inflammatory, apoptotic and biochemical antioxidant markers. The brain tissues were further assessed for gene expression, immunohistochemical and western blotting examination for localization of inflammasome cascade expression that plays a pivotal role in neuroinflammation. KEY FINDINGS: The modulation in oxidant/antioxidant status after exposure of STZ was significantly balanced after administration of IFN to rats. Further, IFN was also found to be an apoptotic agent as it modulates the apoptotic gene (Bax) and anti-apoptotic gene (BcL2) expression. IFN significantly curtailed the augmented protein expression of NLRP3, NLRP2, ASC, NFκBP65, IL-1ß and caspase-1 due to STZ administration in cortex and hippocampus rat brain regions. SIGNIFICANCE: The aforementioned results proclaim the neuroprotective functioning of IFN against STZ induced inflammation. IFN significantly prevents the neuroinflammation by decreasing the generation of ROS that reduces the activation of NLRP3/ASC/IL-1 axis thereby exerting neuroprotection as evidenced in rat model of STZ induced neuroninflammation.

Chronic unpredictable stress negatively regulates hippocampal neurogenesis and promote anxious depression-like behavior via upregulating apoptosis and inflammatory signals in adult rats.

Psychological and physical stress play a pivotal role in etiology of anxiety and depression. Chronic psychological and physical stress modify various physiological phenomena, as a consequence of which oxidative stress, decreased neurotransmitter level, elevated corticosterone level and altered NSC homeostasis is observed. However, the precise mechanism by which chronic stress induce anxious depression and modify internal milieu is still unknown. Herein, we show that exposure to CUS increase oxidative stress, microgliosis, astrogliosis while it reduces hippocampal NSC proliferation, neuronal differentiation and maturation in adult rats. CUS exposure in rats reduce dopamine and serotonin level in cortex and hippocampus, which result in increased anxiety and depression-like phenotypes. We also found elevated level of NF-κB and TNF-α while decreased anti-inflammatory cytokine IL-10 level, that led to increased expression of Bax and cleaved Caspase-3 whereas down regulation of antiapoptotic protein Bcl2. Additionally, CUS altered adult hippocampal neurogenesis, increased gliosis and neuronal apoptosis in cerebral cortex and hippocampus which might be associated with reduced AKT and increased ERK signaling, as seen in the rat brain tissue. Taken together, these results indicate that CUS induce oxidative stress and neuroinflammation which directly affects NSC dynamics, monoamines levels and behavioral functions in adult rats.

Piperine and Celecoxib synergistically inhibit colon cancer cell proliferation via modulating Wnt/ß-catenin signaling pathway.

BACKGROUND: Celecoxib (CXB), a selective COX-2 inhibitor NSAID, has exhibited prominent anti-proliferative potential against numerous cancers. However, its low bioavailability and long term exposure related cardiovascular side effects, limit its clinical application. In order to overcome these limitations, natural bioactive compounds with lower toxicity profile are used in combination with therapeutic drugs. Therfore, in this study Piperine (PIP), a natural chemo-preventive agent possessing drug bioavailability enhancing properties, was considered to be used in combination with low doses of CXB. PURPOSE: We hypothesized that the combination of PIP with CXB will have a synergistic anti-proliferative effect on colon cancer cells. STUDY DESIGN: The potency of PIP and CXB alone and in combination was evaluated in HT-29 human colon adenocarcinoma cells and mechanism of growth inhibition was investigated by analyzing the players in apoptotic and Wnt/ß-catenin signaling pathways. METHODS: The effect of PIP on the oral bioavailability of CXB in mice was investigated using HPLC analysis. The study investigated the synergistic anti-proliferative effect of CXB and PIP on HT-29 cells and IEC-6 non-tumorigenic rat intestinal epithelial cells by SRB cell viability assay. Further, the cellular and molecular mechanism(s) involved in the anti-proliferative combinatorial effect was extensively explored in HT-29 cells by flow cytometry and western blotting. The in vivo efficacy of this combination was studied in CT26.WT tumor syngeneic Balb/c mice model. RESULTS: PIP as a bioenhancer increased the oral bioavailability of CXB (129%). The IC50 of CXB and PIP were evaluated to select doses for combination treatment of HT-29 cells. The drug combinations having combination index (CI) less than 1 were screened using CompuSyn software. These combinations were significantly cytotoxic to HT-29 cells but IEC-6 were least effected. Further, the mechanism behind CXB and PIP mediated cell death was explored. The co-treatment led to reactive oxygen species generation, mitochondrial dysfunction, caspase activation and enhanced apoptosis in HT-29 cells. Additionally, the combination treatment synergistically modulated Wnt/ß-catenin pathway, downregulated the stemness markers and boosted therapeutic response in CT26 syngeneic Balb/c mice. CONCLUSION: The outcomes of the study suggests that combining CXB and PIP offers a novel approach for the treatment of colon cancer.

Mechanistic exploration of quercetin against metronidazole induced neurotoxicity in rats: Possible role of nitric oxide isoforms and inflammatory cytokines.

AIM: Metronidazole, a nitroimidazole derived antibiotic used to treat many bacterial infections, is reported to penetrate the blood brain barrier after long term administration resulting into neuronal toxicity. Further, quercetin, a polyphenol flavonoid is reported to exhibit neuroprotective activity but its pharmacodynamics interaction against metronidazole induced neurotoxicity. Therefore, the present study was designed to evaluate the postulated mechanism of metronidazole induced neurotoxicity and potential neuroprotective role of quercetin. MAIN METHODS: Animals (Sprague Dawley) rats were randomly divided into five groups such as control, metronidazole (135 mg/kg), quercetin (100 mg/kg), metronidazole (135 mg/kg) + quercetin (50 mg/kg), and metronidazole (135 mg/kg) + quercetin (100 mg/kg). The brain tissues were evaluated for tissue cyclo-oxygenase, lipoxygenase, nitrite levels, inflammatory and antioxidant biomarkers. The brain tissues were further scrutinized histopathologically for neuronal degeneration. Western blotting analysis was performed for the localization of protein expression for Bax, Bcl2, iNOS, eNOS and caspase-3. KEY FINDINGS: The metronidazole significantly alters the antioxidant levels, inflammatory mediators and morphological changes in the brain tissue. Metronidazole also induces iNOS, Bax and caspase 3 protein expressions whilst decreases the expression of Bcl2 and eNOS in the brain tissue. Metronidazole administration causes a momentous increase in tissue inflammatory markers. SIGNIFICANCE: The metronidazole (oral) administration causes remarkably neurotoxicity effects and the same could be attributed to the fact that metronidazole has the ability to cross the blood brain barrier and transforms the enzymatic activity of various biomarkers present in the brain. From the results, it could be hypothesized that metronidazole causes neurotoxicity by hindering the proportion of antioxidants in the brain tissue and inducing nitric oxide synthesis along with apoptosis. However, quercetin demonstrated a significant protective effect on neuronal toxicity precipitated through metronidazole.

Celecoxib reduces Deoxynivalenol induced proliferation, inflammation and protein kinase C translocation via modulating downstream targets in mouse skin.

Exposure to mycotoxins is mostly by ingestion but also occurs by the dermal and inhalation routes. The present study for the first time demonstrated that mycotoxin Deoxynivalenol (DON), permeates through Swiss albino mice skin, which demands awareness of health risks in people who are dermally exposed to mycotoxins especially agricultural farmers. Despite the widespread contamination of DON in food commodities studies to alleviate DON's toxicity are sparsely reported. Thus effective measures to combat mycotoxins associated toxicity remains an imperative aspect to be considered from the angle of dermal exposure. Topical application of Celecoxib (1-2 mg), followed by DON (100 µg) application on the dorsal side of mice, resulted in substantial decrease in DON-induced (i) edema, hyperplasia, cell proliferation (ii) inhibition of cytokine and prostaglandin-E2 levels (iii) phosphorylation of ERK1/2, JNK, p38, MAPKKs, CREB, P90-RSK (iv) downregulation of c-Jun, c- Fos, phospho-NF-kB and their downstream target proteins cyclin D1 and COX-2. Using Ro-31-8220 (Protein-Kinase-C inhibitor), it was observed PKC was responsible for DON induced upregulation of COX-2 and iNOS proteins. Treatment of Celecoxib decreased DON-induced translocation of Protein Kinase C isozymes (α,ε,γ), demonstrating the role of PKC in DON-mediated biochemical and molecular alterations responsible for its dermal toxicity. The present findings indicate that topical application of celecoxib is effective in the management of inflammatory skin disorders induced by foodborne fungal toxin DON. The skin permeation potential of Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor NSAID, was also assessed, and the results indicated that the permeation was relatively lower as compared to the oral mode of administration. Hence topical use of celecoxib may be preferred over oral dosing because of lower systemic absorption and to avoid the unwanted side effects. This study provides a prospect for exploring the clinical efficacy of topically applied COX-2 inhibitors for the management of inflammatory skin disorders induced by foodborne fungal toxins.

N-acetyl-cysteine in combination with celecoxib inhibits Deoxynivalenol induced skin tumor initiation via induction of autophagic pathways in swiss mice.

Deoxynivalenol is a trichothecene mycotoxin which naturally contaminates small grain, cereals intended for human and animal consumption. Investigations for dermal toxicity of DON has been needed and highlighted by WHO. Previous studies on dermal toxicity suggest that DON has DNA damaging potential leading to skin tumor initiation in mice skin. However, considering its toxicological manifestations arising after dermal exposure, strategies for its prevention/protection are barely available in literatute. Collectively, our study demonstrated that N-acetylcysteine (NAC), precursor of glutathione, significantly alters the genotoxic potential of DON. Further NAC in combination with Celecoxib (CXB) inhibits tumor growth by altering antioxidant status and increasing autophagy in DON initiated Swiss mice. Despite the broad spectrum use of CXB, its use is limited by the concerns about its adverse effects on the cardiovascular system. Serum parameters and histology analysis revealed that CXB (2 mg) when applied topically for 24 weeks did not impart any cardiovascular toxicity which could be because skin permeation potential of CXB was quite low when analyzed through HPLC analysis. Although the anticancer effects of CXB and NAC have been studied, however, the combination of NAC and CXB has yet not been explored for any cancer treatment. Therefore our observations provide additional insights into the therapeutic effects of combinatorial treatment of CXB and NAC against skin tumor prevention. This approach might form a novel alternative strategy for skin cancer treatment as well as skin associated toxicities caused by mycotoxins such as DON. This combinatorial approach can overcome the limitations associated with the use of CXB for long term as topical application of the same seems to be safe in comparison to the oral mode of administration.

Dopamine receptor activation mitigates mitochondrial dysfunction and oxidative stress to enhance dopaminergic neurogenesis in 6-OHDA lesioned rats: A role of Wnt signalling.

Nigral dopaminergic (DAergic) cell degeneration and depletion of dopamine neurotransmitter in the midbrain are cardinal features of Parkinson's disease (PD). Dopamine system regulates different aspects of behavioural phenotypes such as motor control, reward, anxiety and depression via acting on dopamine receptors (D1-D5). Recent studies have shown the potential effects of dopamine on modulation of neurogenesis, a process of newborn neuron formation from neural stem cells (NSCs). Reduced proliferative capacity of NSCs and net neurogenesis has been reported in subventricular zone, olfactory bulb and hippocampus of patients with PD. However, the molecular and cellular mechanism of dopamine mediated modulation of DAergic neurogenesis is not defined. In this study, we attempted to investigate the molecular mechanism of dopamine receptors mediated control of DAergic neurogenesis and whether it affects mitochondrial biogenesis in 6-hydroxydopamine (6-OHDA) induced rat model of PD-like phenotypes. Unilateral administration of 6-OHDA into medial forebrain bundle potentially reduced tyrosine hydroxylase immunoreactivity, dopamine content in substantia nigra pars compacta (SNpc) and striatum region and impaired motor functions in adult rats. We found decreased D1 receptor expression, mitochondrial biogenesis, mitochondrial functions and DAergic differentiation associated with down-regulation of Wnt/ß-catenin signalling in SNpc of 6-OHDA lesioned rats. Pharmacological stimulation of D1 receptor enhanced mitochondrial biogenesis, mitochondrial functions and DAergic neurogenesis that lead to improved motor functions in 6-OHDA lesioned rats. D1 agonist induced effects were attenuated following administration of D1 antagonist, whereas shRNA mediated knockdown of Axin-2, a negative regulator of Wnt signalling significantly abolished D1 antagonist induced impairment in mitochondrial biogenesis and DAergic neurogenesis in 6-OHDA lesioned rats. Our results suggest that dopamine receptor regulates DAergic neurogenesis and mitochondrial functions by activation of Wnt/ß-catenin signaling in rat model of PD-like phenotypes.

Neuropharmacokinetics: a bridging tool between CNS drug development and therapeutic outcome.

WHO classified neurological disorders to be among 6.3% of the global disease burden. Among the most central aspects of CNS drug development is the ability of novel molecules to cross the blood-brain barrier (BBB) to reach the target site over a desired time period for therapeutic action. Based on various aspects, brain pharmacokinetics is considered to be one of the foremost perspectives for the higher attrition rate of CNS biologics. Although drug traits are important, the BBB and blood-cerebrospinal fluid barrier together with transporters become the mechanistic approach behind CNS drug delivery. The present review emphasizes neuropharmacokinetic parameters, their importance, an assessment approach and the vast effect of transporters to brain drug distribution for CNS drug discovery.

Bioavailability Enhancement of Poorly Soluble Drugs: The Holy Grail in Pharma Industry.

BACKGROUND: Bioavailability, one of the prime pharmacokinetic properties of a drug, is defined as the fraction of an administered dose of unchanged drug that reaches the systemic circulation and is used to describe the systemic availability of a drug. Bioavailability assessment is imperative in order to demonstrate whether the drug attains the desirable systemic exposure for effective therapy. In recent years, bioavailability has become the subject of importance in drug discovery and development studies. METHODS: A systematic literature review in the field of bioavailability and the approaches towards its enhancement have been comprehensively done, purely focusing upon recent papers. The data mining was performed using databases like PubMed, Science Direct and general Google searches and the collected data was exhaustively studied and summarized in a generalized manner. RESULTS: The main prospect of this review was to generate a comprehensive one-stop summary of the numerous available approaches and their pharmaceutical applications in improving the stability concerns, physicochemical and mechanical properties of the poorly water-soluble drugs which directly or indirectly augment their bioavailability. CONCLUSION: The use of novel methods, including but not limited to, nano-based formulations, bio-enhancers, solid dispersions, lipid-and polymer-based formulations which provide a wide range of applications not only increases the solubility and permeability of the poorly bioavailable drugs but also improves their stability, and targeting efficacy. Although, these methods have drastically changed the pharmaceutical industry demand for the newer potential methods with better outcomes in the field of pharmaceutical science to formulate various dosage forms with adequate systemic availability and improved patient compliance, further research is required.