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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.

Background: Formononetin (FNT), a methoxy isoflavone, is a potential phytoconstituent utilized for refurbishing fractures in bone tissue. Conceding to its involvement in first-pass metabolism followed by glucuronidation, its absorption efficacy is limited. Hence, it belongs to the BCS class II classification. Background: Formononetin (FNT), a methoxy isoflavone, is a potential phytoconstituent utilized for refurbishing fractures in bone tissue. Conceding to its involvement in first-pass metabolism followed by glucuronidation, its absorption efficacy is limited. Hence, it belongs to the BCS class II classification. Objective: We designed the present work to enhance FNT oral bioavailability by using Phospholipids (PL) as a promising carrier. Formononetin Phospholipid Complex (FNT-PC) was prepared by the solvent evaporation method and characterized. Objective: We designed the present work to enhance FNT oral bioavailability by using Phospholipids (PL) as a promising carrier. Formononetin Phospholipid Complex (FNT-PC) was prepared by the solvent evaporation method and characterized. Method: FNT-PC was prepared by solvent evaporation method and characterization (FNT-PC) was performed using aqueous/n-octanol solubility and partition coefficient, FTIR, NMR, SEM, and in vivo pharmacokinetic study in female SD rats at 50mg/kg. Results: Physicochemical properties like aqueous/n-octanol solubility and partition coefficient were enhanced in FNT-PC. The FTIR spectrum confirmed there was no involvement of functional groups in the preparation of FNT-PC. Whereas, the NMR study resulted in the attachment of carbon (C-8) position of FNT by replacing the quaternary amine of PL to form FNT-PC. When scrutinized for its surface morphology, the FNT-PC exhibited the amorphous geometry that remarkably enhanced the dissolution of FNT (p Conclusion: To summarize, FNT-PC could substantially reduce the first-pass metabolism with enhanced free concentration, improving oral bioavailability for therapeutic use.

Malaria is a major life-threatening tropical disease affecting about half of the world’s population. Due to the increasing resistance of Plasmodium falciparum against the marketed drugs, the non-endemic areas of malaria are also at risk which demands for continuous and a compelling need to investigate the bioactive natural products for their pharmacological activity against malaria parasite and undoubtedly satisfactory outcomes are being observed with less adverse events in such endeavours. Flavonoids have emerged as the most important bio-therapeutic class possessing anti-malarial activity. Flavonoids have also been reported to reverse anti-malarial drug resistance, thus exerting dual therapeutic benefit. The pharmacological outcome of these bioactive constituents essentially depends on their circulating levels reaching the target site of action thus, necessitating the quantification in bio-matrices which is required for personalized therapy. Furthermore, the estimation of drug level in biological system is crucial for therapeutic drug monitoring. The development and validation of high-throughput bio-analytical methods for estimation of phytochemicals in biological fluids is a preliminary requirement for establishing such PK–PD relationship. The present review intends to shed an insightful focus on the available bio-analytical methods for assessment of natural anti-malarial flavonoids which will be of immense help in their further exploration.

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.

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.

Neurodegenerative disorders are one of the most terrible consequences of aging and damage due to unbalanced biochemical reactions occur in the body. Numbers of research has been conducted to digout the reason and possible therapeutic strategies against the neurodegenerative damage and many more are on the way to be studied. There are many commercial drugs available in the market to cure neurodegenerative disorders but with many side effects. Therefore, researchers are searching for key therapies with minimum side effects. Many phytochemicals attract the researchers due to promising therapeutic effects and least side effects. Nigella sativa is one among many herbal plants. The chemical constituents of the plants are also studied against many diseases like inflammatory, bacterial/fungal disease, oxidative stress, and neurodegenerative disorders. In this chapter, the authors have focused the therapeutic role of N. sativa and its chemicals against neurodegenerative disorders.

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.

Biochanin A and biochanin B (Formononetin) are the principal dietary isoflavones extensively found in herbal formulations of red clover extract (Trifolium pratense). The red clover-derived isoflavonoids have therapeutic application for mitigating the postmenopausal symptoms in women and are commercially available and marketed as tablets, capsules, and tea preparations. These are also consumed widely with the allopathic medicines without any prescription. However, the phytopharmaceuticals have less or minimum adverse effects and side effects, but the multidrug therapy is also one of the crucial aspects responsible for many serious clinical drug-drug and drug-herb interactions. Further, the main mechanism underlying the pharmacokinetic interactions is the potency to modulate the cytochrome P450 enzymes that are dynamically involved in the metabolic conversion of the drugs into their metabolites and alteration in membrane ATP-binding cassette transporters activity. In the present chapter, the phytochemistry and pharmacological importance of biochanin A and formononetin, along with their pharmacokinetic characteristics will be discussed. Furthermore, alteration in functional efficacy of cytochromes, transporters and mechanistic incrimination of their interaction potential with other prescribed drugs will also be exhaustively reviewed after considering the past ten years literatures based on available pre-clinical and clinical data.

Plants have been, since time immemorial, solutions to many of the human problems, be it food, fodder, shelter, clothing, or other major or minor forest products besides their present use as sources of pharmaceuticals or neutraceuticals. Intensive research is being undertaken to validate the leads obtained while realizing the health benefits of phytoconstituents present in plant-based food and medicinal plants, as such. These studies are reinforcing their roles as important and irreplaceable dietary components. As evidenced by numerous in vitro and in vivo studies on the various classes (phenolics, flavonoids, saponins, alkaloids, essential oils etc.) of plant secondary metabolites (PSMs), their role is not only limited to being indicators of plant immunity/stress response or attractants for pollinators or dispersal agents for reproduction and survival. Their extended role exclusively as a drug candidate or collectively in a balanced diet is also being suitably highlighted. Although PSMs have been widely reported alongside the macro- and micronutrients for their bioactivities such as antioxidant, antiinflammatory, antiobesity, and antidiabetic effects, their mechanism of action, dosage, and selectivity toward particular metabolic targets is still being explored. Therefore, the subcategorization of phenolics, saponins, alkaloids, etc., is necessary for studies on plant-derived nutrition and health, while the major emphasis has so far been on carbohydrates, proteins, fats, and essential macronutrient followed by micronutrients, primarily due to their direct involvement in growth and development. Hence, this chapter is an effort to consolidate the available literature on PSMs. An attempt has been made to subclassify them on the basis of their utilization in select metabolic complications, mechanism of action, and possible interactions among different subclasses of PSMs or different bioactivities as well.

Forest is an important and has always been an integral part of our ecosystem. Forests have various significance like socio-economic significance, an integral component of water cycle, conservator of biological diversity, tribal population etc. Forest fire is the most common hazard that brings harm to forests, environment, wildlife and economics. There are three major factors of forest fire, which are fire sources, fuels and fire environment. The change in weather also plays a big role, like in summer season if the amount of precipitation is low for couple of months in that case forest is full of dry leaves, and if there occurs even a slight spark it may lead to burn in flames. Sometimes this could be controlled and sometimes it spreads in such a large scale that it could go out of control. The fire environment is really difficult to control, so to prevent that a constant monitoring is kept. Fire sources are still in controllable situations, and also the fuels could be controlled by various measures. Management of fuel can help to control forest fires. This paper brings out a deep analysis of forest fire and how it could be controlled. Nowadays, a major role is played by wireless sensors to prevent fires in advance.

Aims Ritonavir (RIT) is a human immune deficiency virus (HIV) protease inhibitor (PI) active against HIV-1 and HIV-2. Among various adverse effects of PIs, hepatotoxicity is a very common adverse reaction of RIT which is concentration dependent. Red clover isoflavones are found to possess anti-inflammatory, antioxidant and anti-apoptosis activity. Furthermore, recent studies have demonstrated that these isoflavones can be used to alleviate the side-effects of drugs. Hence, the present study was inquested to ascertain the effect of Formononetin (FMN) and Biochanin A (BCA) on RIT induced hepatotoxicity. Main methods Five groups of animals were subjected to treatment as control, toxic control (RIT), third group (RIT + FMN), fourth group (RIT + BCA), the fifth group (RIT + FMN + BCA) and sixth group (FMN + BCA) for 14 days. The animals were evaluated for estimation of liver toxicity markers, inflammatory biomarkers, in-vivo biochemical antioxidant parameters. The liver tissues were further evaluated histopathologically and western blotting examination for localization of apoptotic gene expression that plays a pivotal role in hepatotoxicity. Key findings FMN and BCA ameliorated the increased levels of biochemical markers of liver, attenuated the RIT induced Bax, caspase-3, NFκB and eNOS activation and persuaded the Bcl2 and pAkt level. Alteration in the levels of inflammatory markers was also observed in both hepatic tissue and serum. Significance FMN and BCA exerts hepatoprotective effect through modulating the oxidative stress, inflammation, apoptosis and reversing the tissue degeneration suggesting its therapeutic role in hepatotoxicity and other hepatocellular diseases.

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.

Cladrin, an isoflavone is a major bioactive constituent found in stem bark of Butea monosperma with remarkable osteogenic activity. A speedy and sensitive UPLC coupled tandem mass spectrometry (UPLC-MS/MS) method was developed, validated and successfully applied to bioavailability, blood partitioning, plasma protein binding, intravenous and multiple-dose oral pharmacokinetics of cladrin in rats. Separation was done on C18 column (5.0 μm, 4.6 × 50 mm) using mobile phase containing acetonitrile and 0.10% formic acid in the ratio of 65:35 (v/v) with 0.60 mL/min flow rate. The method was highly sensitive and has a short run time of 2.50 min with an excellent linearity (R2 > 0.99) in the range of 0.20–200 μg/L. Absolute bioavailability was found to be 16.58, 19.04 and 6.76% at oral doses of 5, 10, and 20 mg/Kg, respectively. Cladrin was rapidly absorbed (Tmax 3.0 h) with a high apparent volume of distribution (15.03 ± 1.79L/Kg), high clearance (2.27 ± 0.30L/h/Kg) and high plasma protein binding. The present study is a first comprehensive in-vitro as well as the in-vivo preclinical pharmacokinetic report of cladrin giving insights about its drug-likeness and further development as a potential therapeutic agent.

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-1β 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.

We report the development of 10 new cocrystal forms of the nutraceutical compound resveratrol obtained through a rational coformer screening by utilizing the interaction site pairing energy differences computed based on molecular electrostatic potential calculations. A new monohydrate form of resveratrol and 10 novel cocrystals with 9 different coformers were characterized in the study. Among the newly developed solid forms of resveratrol, two of its cocrystals with (1) a Generally Recognized As Safe compound piperazine and (2) the bioactive compound methenamine were subjected to aqueous solubility determination. The newly developed piperazine cocrystal exhibits the highest aqueous solubility among the previously known cocrystals of resveratrol.

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.

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/β-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/β-catenin signaling in rat model of PD-like phenotypes.

The development of plant-derived dietary supplements and drugs to treat the obesity epidemic has increased. These supplements may target oxidative stress and pancreatic lipase (PL) catalyzed fat digestion to manage lipid metabolism. Therefore, inhibition of PL and neutralization of reactive oxidants may be potential solutions to obesity management. In the present study, various extracts of 4 parts of Beta vulgaris (BV) were quantified for total phenolics, flavonoids, and saponins contents. Of these, methanolic extracts of leaves (BVLM), acetone extracts of petiole (BVPA), and leaves and petiole saponin extracts (BVLS and BVPS) were further evaluated using the FRAP assay and free radicals scavenging (DPPH• and ABTS•+ radicals) potentials. BVLM (DPPH• - EC50 100 ± 10 μg/ml) and BVLS (ABTS•+ - EC50 6.7 ± 2.0 μg/ml) showed the strongest scavenging activities whereas, BVPS had the highest FRAP value (107 ± 4 μg Trolox equivalents/mg dry extract). Their porcine PL inhibition potential was evaluated. BVLS showed the most effective inhibition (68 ± 2% at maximum concentration and mixed mode) followed by BVLM. GC-MS characterization of bioassay-guided potential extracts (BVLS and BVLM) showed the presence of many volatile compounds, their derivatives, and other drug candidates. The data was visualized using principal component analysis that explained the data variance by 70.1 and 79.3% for crude solvent extracts and saponin extracts, respectively. 2-Benzylpiperidine and phytol were docked with PL to complement the inhibition results. Therefore, BVLS and BVLM extracts may be studied further as potentially beneficial sources of bioactives to regulate fat assimilation.

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/β-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/β-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.

Biochanin A (BCA) is a natural methoxylated-isoflavone and has been stated to have various therapeutic potentials. However, poor aqueous solubility and low oral bioavailability circumscribed its usage as a therapeutic molecule. Therefore, nano-sized BCA-phospholipid complex (nBCA-PLCs) was developed using solvent evaporation and ultra-sonication method to enhance the poor aqueous solubility and low oral bioavailability of BCA. The optimized nBCA-PLCs showed monodisperse spherical particles with a mean diameter of 329.63 ± 35.71 nm (PDI 0.288 ± 0.03), the zeta potential of (−) 53.9 ± 1.24 mV and drug entrapment efficiency of about 94.62 ± 4.19%. In vitro release study revealed that more than 99% drug was released from developed nBCA-PLCs. The formation of nBCA-PLCs complex and the loss of a crystalline state of BCA in the developed formulation were confirmed by solid-state characterizations including DSC, FTIR, and powder XRD. In situ single-pass intestinal permeability (SPIP) study showed a significant increase (2.04 fold) in the effective intestinal permeability (Peff) of BCA from nBCA-PLCs as compared with plain BCA suspension. Similarly, the oral administration of BCA-PLCs and nBCA-PLCs in Sprague Dawley (SD) rats showed 2.4-fold and 7.2 fold increase in relative bioavailability of BCA from BCA-PLCs and nBCA-PLCs, respectively as compared with plain BCA suspension. Thus, the developed nBCA-PLCs can be promising to overcome the poor aqueous solubility and increase the oral bioavailability of this poorly aqueous soluble molecule.

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.

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.

Introduction: Erythromycin (ERY) is known to induce hepatic toxicity which mimics other liver diseases. Thus, ERY is often used to produce experimental models of drug-induced liver-toxicity. The serum metabolic profiles can be used to evaluate the liver-toxicity and to further improve the understanding of underlying mechanism. Objective: To establish the serum metabolic patterns of Erythromycin induced hepatotoxicity in albino wistar rats using 1H NMR based serum metabolomics. Experimental: Fourteen male rats were randomly divided into two groups (n = 7 in each group): control and ERY treated. After 28 days of intervention, the metabolic profiles of sera obtained from ERY and control groups were analyzed using high-resolution 1D 1H CPMG and diffusion-edited nuclear magnetic resonance (NMR) spectra. The histopathological and SEM examinations were employed to evaluate the liver toxicity in ERY treated group. Results: The serum metabolic profiles of control and ERY treated rats were compared using multivariate statistical analysis and the metabolic patterns specific to ERY-induced liver toxicity were established. The toxic response of ERY was characterized with: (a) increased serum levels of Glucose, glutamine, dimethylamine, malonate, choline, phosphocholine and phospholipids and (b) decreased levels of isoleucine, leucine, valine, alanine, glutamate, citrate, glycerol, lactate, threonine, circulating lipoproteins, N-acetyl glycoproteins, and poly-unsaturated lipids. These metabolic alterations were found to be associated with (a) decreased TCA cycle activity and enhanced fatty acid oxidation, (b) dysfunction of lipid and amino acid metabolism and (c) oxidative stress. Conclusion and Recommendations: Erythromycin is often used to produce experimental models of liver toxicity; therefore, the established NMR-based metabolic patterns will form the basis for future studies aiming to evaluate the efficacy of anti-hepatotoxic agents or the hepatotoxicity of new drug-formulations.

Pyrazinamide (PYZ)-an essential component of primary drug regimen used for the treatment and management of multidrug resistant or latent tuberculosis-is well known for its hepatoxicity. However, the mechanism of PYZ-induced hepatotoxicity is still unknown to researchers. Studies have shown that the drug is metabolized in the liver to pyrazinoic acid (PA) and 5-hydroxy pyrazinoic acid (5-OHPA) which individually may cause different degrees of hepatotoxicity. To evaluate this hypothesis, PYZ, PA, and 5-OHPA were administered to albino Wistar rats orally (respectively, at 250, 125, and 125 mg kg-1 for 28 days). Compared to normal rats, PYZ and its metabolic products decreased the weights of dosed rats and induced liver injury and a status of oxidative stress as assessed by combined histopathological and biochemical analysis. Compared to normal controls, the biochemical and morphological changes were more aberrant in PA- and 5-OHPA-dosed rats with respect to those dosed with PYZ. Finally, the serum metabolic profiles of rats dosed with PYZ, PA, and 5-OHPA were measured and compared with those of normal control rats. With respect to normal control rats, the rats dosed with PYZ and 5-OHPA showed most aberrant metabolic perturbations in their sera as compared to those dosed with PA. Altogether, the study suggests that PYZ-induced hepatotoxicity might be associated with its metabolized products, where 5-OHPA contributes to a higher degree in its overall toxicity than PA.

Isoformononetin (methoxy isoflavone) is a potent osteogenic isoflavone abundantly present in Butea monosperma, Pisum sativum, Mung bean, Machaerium villosum, Medicago sativa, and Glycine max. In the current study, an LC–ESI-MS/MS method for the simultaneous evaluation of isoformononetin (IFN), daidzein (DZN) and equol (EQL) was developed and validated in rat plasma using biochanin A as an internal standard. IFN, DZN, and EQL separation was achieved by using acetonitrile and acetic acid (0.1%) in the ratio of 90:10 (% v/v) as mobile phase under isocratic conditions at a flow rate of 0.6 mL/min on Atlantis C18 (4.6 × 250 mm, 5.0 μm) column. The achieved method was linear within the concentration range of 0.5–500 ng/mL. The method was effectively applied to investigate the permeability, protein binding estimation and pharmacokinetics studies of IFN in rats. The PAMPA permeability of IFN was found to be high at pH 4.0 and 7.0. The protein binding was found to be about 91% of IFN. The oral bioavailability of IFN was found to be poor (21.6%). IFN was found to have a moderate clearance (2.9 L/h/kg) and a large apparent volume of distribution (12.1 L/kg). The plasma half-life (t1/2) and maximum attainable concentration (Cmax) of IFN at systemic circulation was found to be 1.9 ± 0.6 h and 269.3 ± 0.4 after oral administration.

Inflammasomes are multiprotein complexes having nucleotide-binding domain and leucine-rich repeat consisting members along with pyrin and HIN domain family. An inflammasome mainly consists of cytoplasmic sensor molecule, such as NLRP3, the adaptor apoptosisassociated speck-like protein containing caspase recruitment domain) protein along with effector procaspase-1. The inflammasome regulates caspase-1 activation, resulting in secretion of interleukin- 1β and interleukin-18. The inflammasome activation is linked with infection, stress, or other immunological signals involved in inflammation. The pathophysiological role of NLRP3 inflammasome in immune regulation, inflammatory receptor-ligand interactions, microbial-associated molecular patterns, danger as well as pathogen associated molecular patterns has been demonstrated in last few years. Furthermore, the role of the inflammasome in peripheral and central nervous system involved with cytokine and chemokine inflammatory responses has been demonstrated in preclinical and clinical studies. The understanding of molecular regulation of inflammasome associated pathways is crucial for drug design and delivery. The use of natural product as an alternate therapy is gaining focus because of easy access and cost effectiveness. A number of herbal extracts and its bioactive constituents known as phytochemicals have shown to be effective in inflammatory response mediated by NLRP3 inflammasomes pathways. To understand the interaction of phytochemicals and inflammasome at the molecular level, it is vital to develop effective drugs that can be evaluated further in the clinical settings. Therefore, this review renders an extensive account of all the phytochemicals which are evaluated either in inflammatory experimental animal models or in immortalized human/animal cell lines that modulate NLRP3 inflammasome mediated pathways to mitigate inflammatory responses with the hope that this pathway modulation by phytochemicals may provide a another class of drugs in the armamentarium as well as novel molecular mechanism of natural products targeting NLRP3 inflammasome.

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.

Background: Formononetin (FMN), one of the major isoflavones in red clover, has been shown to possess antioxidant, anti-inflammatory, antitumor, neuroprotective, and cytoprotective activities. However, there is no report on the gastroprotective effect of FMN against ethanol-induced gastric ulcer. Objective: Excessive alcohol consumption can lead to gastric ulcer, and the purpose of the present study was to examine the protective effect of FMN on mucosal lesions induced by ethanol. Materials and Methods: Fasted rats were orally administered with FMN at different doses, omeprazole (20 mg/kg), followed by intragastrical ingestion of ethanol (5 ml/kg) after 1 h and sacrificed after 1 h of exposure. Gross microscopic, macroscopic, and biochemical assays were scrutinized. Results: Compared with ethanol, FMN pretreatment showed a significant increase in the gastric levels of glutathione while decreased the malondialdehyde content remarkably. FMN pretreatment also bestowed the cytoprotective efficacy against ethanol-induced ulceration by reestablishing the decreased level of nitrite (NO). Furthermore, in histopathological sections, reduced pathological changes of gastric lesions were markedly observed in the FMN-pretreated groups compared with those in the ethanol group. Western blot analysis showed upregulation of BcL2 while downregulation of Bax in FMN-pretreated gastric tissue of rats. Conclusion: These results indicate that FMN exerts gastroprotective effects through the antioxidative, anti-inflammatory, and antiapoptotic that are probably mediated by enhanced NO release, suggesting its therapeutic use to treat gastric ulceration by preserving mucosal glycoproteins and diminishing oxidative stress. Abbreviations used: NSAIDs: Nonsteroidal anti-inflammatory drugs; FMN: Formononetin; CMC: Carboxymethylcellulose; UI: Ulcer index; MDA: Malondialdehyde; GSH: Reduced glutathione; NO: Nitrite; TNF-α: Tumor necrosis factor-alpha; Hgb: Hemoglobin; T-RBC: Total red blood cells; Hct: Hematocrit; MCV: Mean corpuscular volume; MCH: Mean corpuscular hemoglobin; MCHC: Mean corpuscular hemoglobin concentration; TLC: Total leukocyte count

The present study was conducted in Meerut district of Western Uttar Pradesh during the year 2017–18. To know the gap between knowledge and adoption level regarding the package of practices of cole crops cultivation. It was observed that higher knowledge found in name of fertilizers with a mean percentage score of 62.50, it was ranked in first and lowest in weed management with a mean percentage score of 49.37, it was ranked in fourteenth. The highest adoption was found in name of fertilizer with a mean percentage score of 58.12, it was ranked in first and lowest adoption was found in seed treatment with a mean percentage score of 42.50, it was ranked in fourteenth. The higher gap between knowledge and adoption was found in the mode of application of FYM, fertilizer and chemicals i.e. 12.50 percent, while the lowest gap was found in use of improved varieties i.e. 2.50 percent. The overall average gap between knowledge and adoption level of the respondents with regard to improved cultivation package of practices was 06.61 percent, which clearly indicated that still there had been a considerable gap between the knowledge possessed by them and extent of adoption.