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Karthik Gourishetti,1 Raghuvir Keni,1 Pawan Ganesh Nayak,1 Srinivas Reddy Jitta,2 Navya Ajitkumar Bhaskaran,2 Lalit Kumar,2 Nitesh Kumar,1 Nandakumar Krishnadas,1 Rekha Raghuveer Shenoy1 1Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India; 2Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, IndiaCorrespondence: Rekha Raghuveer ShenoyDepartment of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, IndiaTel +91-820-2922482Fax +91-820-2571998Email rekhaarunt@gmail.comBackground: Diabetic foot ulcer is an intractable complication of diabetes, characterized by the disturbed inflammatory and proliferative phases of wound healing. Sesamol, a phenolic compound, has been known for its powerful antioxidant, anti-inflammatory, anti-hyperglycaemic and wound healing properties. The aim of the present study was to develop a sesamol nano formulation and to study its effect on the various phases of the wound healing process in diabetic foot condition.Methods: Sesamol-PLGA (SM-PLGA) nanosuspension was developed using nanoprecipitation method. TEM, in vitro drug release assay and in vivo pharmacokinetic studies were performed for the optimised formulation. Diabetic foot ulcer (DFU) in high fat diet (HFD)-fed streptozotocin-induced type-II diabetic animal model was used to assess the SM-PLGA nanosuspension efficacy. SM-PLGA nanosuspension was administered by oral route. TNF-α levels were estimated using ELISA and Western blot analysis was performed to assess the effect on the expression of HSP-27, ERK, PDGF-B and VEGF in wound tissue. Wound re-epithelization, fibroblast migration, collagen deposition and inflammatory cell infiltration were assessed by H&E and Masson’s trichrome staining. Effect on angiogenesis was assessed by CD-31 IHC staining in wound sections.Results: The optimized SM-PLGA nanosuspension had an average particle size of < 300 nm, PDI< 0.200 with spherical shaped particles. Approximately 80% of the drug was released over a period of 60 h in in vitro assay. Half-life of the formulation was found to be 13.947 ± 0.596 h. SM-PLGA nanosuspension treatment decreased TNF-α levels in wound tissue and accelerated the collagen deposition. Whereas, HSP-27, ERK, PDGF-B and VEGF expression increased and improved new blood vessels’ development. Rapid re-epithelization, fibroblast migration, collagen deposition and reduced inflammatory cell infiltration at the wound site were also observed.Conclusion: Results indicate that sesamol-PLGA nanosuspension significantly promotes the acceleration of wound healing in diabetic foot ulcers by restoring the altered wound healing process in diabetic condition.Keywords: diabetes, diabetic foot ulcer, sesamol, PLGA, nanosuspension, controlled release, wound healing, re-epithelization, angiogenesis, TNF-α

Grandhi Venkata Ramalingayya, Sri Pragnya Cheruku, Pawan G Nayak, Anoop Kishore, Rekha Shenoy, Chamallamudi Mallikarjuna Rao, 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

Neurological disorders pose a huge worldwide challenge to the healthcare system, necessitating innovative strategies for targeted drug delivery to the central nervous system. Alzheimer's disease (AD) is an untreatable neurodegenerative condition characterized by dementia and alterations in a patient's physiological and mental states. Since ancient times, medicinal plants have been an important source of bioactive phytochemicals with immense therapeutic potential. This review investigates new and safer alternatives for prevention and treatment of disease related to inevitable side effects associated with synthetic compounds. This review examines how nanotechnology can help in enhancing the delivery of neuroprotective phytochemicals in AD. Nevertheless, despite their remarkable neuroprotective properties, these natural products often have poor therapeutic efficacy due to low bioavailability, limited solubility and imperfect blood brain barrier (BBB) penetration. Nanotechnology produces personalized drug delivery systems which are necessary for solving such problems. In overcoming these challenges, nanotechnology might be employed as a way forward whereby customized medication delivery systems would be established as a result. The use of nanocarriers in the design and application of important phytochemicals is highlighted by this review, which indicate potential for revolutionizing neuroprotective drug delivery. We also explore the complications and possibilities of using nanocarriers to supply nutraceuticals and improve patients' standard of living, and preclinical as well as clinical investigations displaying that these techniques are effective in mitigating neurodegenerative diseases. In order to fight brain diseases and improve patient's health, scientists and doctors can employ nanotechnology with its possible therapeutic interventions., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study aimed to investigate the effects of prenatal docosahexaenoic acid (DHA) supplementation on pregnancy outcomes through a systematic review and meta-analysis. We hypothesized that prenatal DHA intake through supplements will improve pregnancy outcomes. Detailed literature search was performed using online databases such as PubMed, EMBASE, and Google Scholar till November 2022, to identify the randomized controlled trials (RCT) with maternal intake of DHA supplementation during the latter half of pregnancy compared to the placebo/control. Based on the inclusion and exclusion criteria, nine RCTs involving 5710 subjects were included. This meta-analysis showed that DHA supplementation (450-800 mg/day) was associated with a significantly higher birth weight of infants (Inverse variance [IV]: 101.71 [57.36-146.06] at 95% CI, P = .00001, I 2 = 0%), and fewer low birth weights (LBWs) (Mantel-Haenszel [M-H]: 0.53 [0.33-0.86] at 95% CI, P = .01, I 2 = 72%), with lesser but statistically insignificant pre-term births (PTB) (M-H: -0.02 [-0.04 to 0.00] at 95% CI, P = .07, I 2 = 0%) compared to the placebo. However, the DHA supplementation has no effect on gestational length (IV: -2.26 [-9.64 to 5.12] at 95% CI, P = .55, I 2 = 100%) compared to the placebo. In conclusion, the outcomes of this meta-analysis showed that prenatal DHA supplementation (450-800 mg/day) may reduce the risk of preterm births and increase infant birth weight., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Proteins and peptides have secured a place as excellent therapeutic moieties on account of their high selectivity and efficacy. However due to oral absorption limitations, current formulations are mostly delivered parenterally. Oral delivery of peptides and proteins (PPs) can be considered the need of the hour due to the immense benefits of this route. This review aims to critically examine and summarize the innovations and mechanisms involved in oral delivery of peptide and protein drugs., Methods: Comprehensive literature search was undertaken, spanning the early development to the current state of the art, using online search tools (PubMed, Google Scholar, ScienceDirect and Scopus)., Results: Research in oral delivery of proteins and peptides has a rich history and the development of biologics has encouraged additional research effort in recent decades. Enzyme hydrolysis and inadequate permeation into intestinal mucosa are the major causes that result in limited oral absorption of biologics. Pharmaceutical and technological strategies including use of absorption enhancers, enzyme inhibition, chemical modification (PEGylation, pro-drug approach, peptidomimetics, glycosylation), particulate delivery (polymeric nanoparticles, liposomes, micelles, microspheres), site-specific delivery in the gastrointestinal tract (GIT), membrane transporters, novel approaches (self-nanoemulsifying drug delivery systems, Eligen technology, Peptelligence, self-assembling bubble carrier approach, luminal unfolding microneedle injector, microneedles) and lymphatic targeting, are discussed. Limitations of these strategies and possible innovations for improving oral bioavailability of protein and peptide drugs are discussed., Conclusion: This review underlines the application of oral route for peptide and protein delivery, which can direct the formulation scientist for better exploitation of this route., Competing Interests: The authors declare that they have no conflicts of interest., (©2024 The Authors.)

This review was aimed at summarizing the cellular and molecular mechanisms behind the various pharmacological actions of biochanin-A. Many studies have been reported claiming its application in cancers, metabolic disorders, airway hyperresponsiveness, cardiac disorders, neurological disorders, etc. With regard to hormone-dependent cancers like breast, prostate, and other malignancies like pancreatic, colon, lung, osteosarcoma, glioma that has limited treatment options, biochanin-A revealed agreeable results in arresting cancer development. Biochanin-A has also shown therapeutic benefits when administered for neurological disorders, diabetes, hyperlipidaemia, and other chronic diseases/disorders. Isoflavones are considered phenomenal due to their high efficiency in modifying the physiological functions of the human body. Biochanin-A is one among the prominent isoflavones found in soy (glycine max), red clover (Trifolium pratense), and alfalfa sprouts, etc., with proven potency in modulating vital cellular mechanisms in various diseases. It has been popular for ages among menopausal women in controlling symptoms. In view of the multi-targeted functions of biochanin-A, it is essential to summarize it's mechanism of action in various disorders. The safety and efficacy of biochanin-A needs to be established in clinical trials involving human subjects. Biochanin-A might be able to modify various systems of the human body like the cardiovascular system, CNS, respiratory system, etc. It has shown a remarkable effect on hormonal cancers and other cancers. Many types of research on biochanin-A, particularly in breast, lung, colon, prostate, and pancreatic cancers, have shown a positive impact. Through modulating oxidative stress, SIRT-1 expression, PPAR gamma receptors, and other multiple mechanisms biochanin-A produces anti-diabetic action. The diverse molecular mechanistic pathways involved in the pharmacological ability of biochanin-A indicate that it is a very promising molecule and can play a major impact in modifying several physiological functions., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Anuranjana PV et al.)

Statin-associated diabetes (SAD) is an issue that has come to light after a series of recent clinical trials that has led to the issue of a black box warning for statins by the US FDA. However, the benefit of statin outweighs its risk. Nevertheless, experiments have been conducted to identify the mechanism by which statins aggravate the risk of diabetes only in a select population who bear the risk factors of obesity, sedentary lifestyle, hypertension, and other associated risk factors of lifestyle disorders. In this study, the possibility of utilization of a phyto-molecule, sesamol, for its ability to combat statin-associated diabetes using atorvastatin as the agent of choice has been explored. MMP assay and western blot was conducted to investigate the effects of atorvastatin on apoptotic cascade with sesamol as a protective agent was conducted in MIN-6 cells. Effect of the combination was tested in L6 cells with 2-NBDG uptake assay and as well as western blot for GLUT-4. A diet-induced hypercholesterolemia model was developed in an in vivo model animals and treated with atorvastatin and sesamol with histopathological analysis being carried out to evaluate the apoptotic markers and GLUT-4 presence. It was found that sesamol can combat pancreatic beta cell apoptosis via the internal apoptotic pathway activated by atorvastatin. With regards to muscle cells, sesamol could improve the GLUT-4 vesical production, but not improve glucose uptake which is inhibited by atorvastatin. These findings are further confirmed by animal studies. These findings indicate that sesamol can serve as a prototype molecule for further development and investigation of similar compounds to tackle SAD., Competing Interests: Conflict of interestThe authors declare that there is no conflict of interest., (© King Abdulaziz City for Science and Technology 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Aims: Acute lung inflammation, particularly acute respiratory distress syndrome (ARDS), is caused by a variety of pathogens including bacteria and viruses. β-Glucans have been reported to possess both anti-inflammatory and immunomodulatory properties. The current study evaluated the therapeutic effect of β-glucans on polyinosinic:polycytidylic acid (Poly(I:C)) induced lung inflammation in both hamster and mice models., Main Methods: Poly(I:C)-induced ALI/inflammation models were developed in hamsters (2.5 mg/kg) and mice (2 mg/kg) by delivering the Poly(I:C) intratracheally, and followed with and without β-glucan administration. After treatment, lung mechanics were assessed and lung tissues were isolated and analyzed for mRNA/protein expression, and histopathological examinations., Key Findings: Poly(I:C) administration, caused a significant elevation of inflammatory marker's expression in lung tissues and showed abnormal lung mechanics in mice and hamsters. Interestingly, treatment with β-glucan significantly (p < 0.001) reversed the Poly(I:C)-induced inflammatory events and inflammatory markers expression in both mRNA (IL-6, IL-1β, TNF-α, CCL2 and CCL7) and protein levels (TNF-α, CD68, myeloperoxidase, neutrophil elastase, MUC-5Ac and iNOS). Lung functional assays revealed that β-glucan treatment significantly improved lung mechanics. Histopathological analysis showed that β-glucan treatment significantly attenuated the Poly(I:C) induced inflammatory cell infiltration, injury and goblet cell population in lung tissues. Consistent with these findings, β-glucan treatment markedly reduced the number of neutrophils and macrophages in lung tissues. Our findings further demonstrated that β-glucan could reduce inflammation by suppressing the MAPK pathway., Significance: These results suggested that β-glucan may attenuate the pathogenic effects of Poly(I:C)-induced ALI/ARDS via modulating the MAPK pathway, indicating β-glucan as a possible therapeutic agent for the treatment of viral-pulmonary inflammation/injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Organelle crosstalk is significant in regulating their respective functions and subsequent cell fate. Mitochondria and lysosomes are amongst the essential organelles in maintaining cellular homeostasis. Mitochondria-lysosome connections, which may develop dynamically in the human neurons, have been identified as sites of bidirectional communication. Aberrancies are often associated with neurodegenerative disorders like Parkinson's disease (PD), suggesting the physical and functional link between these two organelles. PD is often linked with genetic mutations of several mutations discovered in the familial forms of the disease; some are considered risk factors. Many of these genes are either associated with mitochondrial function or belong to endo-lysosomal pathways. The recent investigations have indicated that neurons with mutant glucosylceramidase beta (GBA1) exhibit extended mitochondria-lysosome connections in individuals with PD. This may be due to impaired control of the untethering protein, which aids in the hydrolysis of Rab7 GTP required for contact untethering. A GCase modulator may be used to augment the reduced GBA1 lysosomal enzyme activity in the neurons of PD patients. This review focuses on how GBA1 mutation in PD is interlinked with mitochondria-lysosome (ML) crosstalk, exploring the pathways governing these interactions and mechanistically comprehending the mitochondrial and lysosomal miscommunication in the pathophysiology of PD. This review is based on the limited literature available on the topic and hence may be subject to bias in its views. Our estimates may be conservative and limited due to the lack of studies under the said discipline due to its inherent complex nature. The current association of GBA1 to PD pathogenesis is based on the limited scope of study and further research is necessary to explore the risk factors further and identify the relationship with more detail., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© King Abdulaziz City for Science and Technology 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

The post-treatment status of breast cancer survivors has become a concern because of the toxicity induced by chemotherapeutic agents in the brain tissues resulting in cognitive deficits, which is generally referred as chemobrain. The aim of this study was to assess the effect of a proprietary ayurvedic formulation Mulmina Mango against chemotherapy-induced cognitive impairment (CICI). Mammary carcinoma was induced by subcutaneously inoculating 4T1 cells into the mammary fat pad of the animals. Intraperitoneal administration of Cyclophosphamide, Methotrexate, 5-Fluorouracil (CMF) regimen was carried out once a week for three weeks. Treatment of Mulmina began one week before chemotherapy and continued till the end of the chemotherapy cycle. After three cycles of chemotherapy, cognitive decline was assessed by Morris water maze task followed by assessment of locomotor activity by open-field test. Tumor progression was evaluated by measurement of tumor volume. Oxidative and neuroinflammatory markers were also evaluated from the isolated brain samples. CMF treatment resulted in a considerable reduction in tumour volume. We found chemotherapy negatively affected behavioral and biochemical parameters in animals and Mulmina treatment ameliorated these cognitive impairments by restoring antioxidant and maintaining cytokine levels. The combination of phytochemicals in Mulmina proved its possible ability to alleviate CICI without affecting chemotherapeutic efficiency and could pave the way for identifying treatment strategies to combat chemobrain., (© 2022. The Author(s).)

Diabetic wounds are of profound clinical importance. Despite immense efforts directed towards its management, it results in the development of amputations, following a diagnosis of diabetic foot. With a better understanding of the complexities of the microbalance involved in the healing process, researchers have developed advanced methods for the management of wounds as well as diagnostic tools (especially, for wound infections) to be delivered to clinics sooner. In this review, we address the newer developments that hope to drive the transition from bench to bedside in the coming decade., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

The aim of the present study was to evaluate a marketed formulation against chemotherapy-induced cognitive dysfunction. The formulation, Mulmina™, contains natural compounds which are known to help in improving function as well as in preventing cognitive decline. All of the phytoconstituents in the formulation have been tested individually but this is the first study where such a formulation has been evaluated against chemotherapy-induced cognitive decline (CICD) in a mouse model. CICD was induced by cyclophosphamide (50 mg/kg), methotrexate (5 mg/kg), and 5-fluorouracil (5 mg/kg) (CMF), administered intraperitonially. CMF was administered in three cycles, with one injection per week for three weeks. The decline in cognition of the mice was evaluated by a test of locomotor activity (Open Field Test) followed by a test for spatial memory (Morris Water Maze). Biochemical parameters evaluated include brain cytokine levels and BDNF levels via ELISA. Hematological counts were also performed to evaluate any changes in blood profile using a veterinary blood cell counter. Levels of oxidative stress markers with respect to catalase activity and lipid peroxidation were also evaluated in the brain using UV-spectrophotometric analysis. Mulmina™ was able to show significant improvement in cognitive function post chemotherapy when compared to the untreated animals. Apart from improvement in spatial memory, there was also an improvement in biochemical parameters. The particular combination of phytochemicals in Mulmina™ proved themselves successful in alleviating the CICD in this preliminary study and pave a path for future studies which can establish the solid grounds with respect to molecular and pharmacological basis for the mechanism of action of Mulmina™., (Copyright: © Kinra et al.)

Statins have transformed the treatment of cardiovascular diseases through primary and secondary prevention of events. Despite the success of statin's management of cardiovascular conditions, certain clinical trials, reviews, and meta-analysis point out that statins have the propensity to induce diabetes. The risk further increases with intensive statin therapy or in patients with diabetes. A proper mechanism for the induction of the diabetic condition has not yet been determined. The involvement of statin with beta cells in insulin secretion and peripheral cells in insulin resistance has been widely studied and established. The present review provides an update on the recent understanding of statin-induced diabetes. This covers the origin of statins, their development, possible mechanisms that explain the adverse effects in glucose homeostasis, and probable targets to remedy the condition., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Dementia is a neurodegenerative disorder majorly evidenced by cognitive impairment. Although there are many types of dementia, the common underlying etiological factors in all the types are neuro-inflammation or aging induced apoptosis. β-caryophyllene, a cannabinoid type-2 receptor agonist, has been reported to have promising neuroprotective effects in cerebral ischemia and neuro-inflammation., Objective: In the present study, we evaluated the effects of β-caryophyllene against animal models of dementia whose etiology mimicked neuro-inflammation and aging., Methods: Two doses (50 and 100 mg/kg of body weight) of β-caryophyllene given orally were tested against AlCl 3 -induced dementia in male Sprague Dawley (SD) rats using the Morris water maze test. Subsequently, the effect of the drug was assessed for episodic memory in female SD rats using novel object recognition task in doxorubicin-induced neuro-inflammation and chemobrain model. Moreover, its effects were evaluated in D-galactose-induced mitochondrial dysfunction leading to dementia., Results: β-caryophyllene, at both doses, showed significant improvement in memory when assessed using parameters like target quadrant entries, escape latency and path efficiency in the Morris water maze test for spatial memory. In the doxorubicin-induced chemobrain model, β-caryophyllene at 100 mg/kg significantly elevated acetylcholinesterase and catalase levels and lowered lipid peroxidation compared to the disease control. In the novel object recognition task, β-caryophyllene at 100 mg/kg significantly improved recognition index and discrimination index in the treated animals compared to the disease control, with a significant increase in catalase and a decrease in lipid peroxidation in both hippocampus and frontal cortex. However, in the D-galactose-induced mitochondrial dysfunction model, β-caryophyllene failed to show positive effects when spatial memory was assessed. It also failed to improve D-galactose-induced diminished mitochondrial complex I and II activities., Conclusion: Hence, we conclude that β-caryophyllene at 100 mg/kg protects against dementia induced by neuro-inflammation with no effect on neuronal aging induced by mitochondrial dysfunction., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Botroclot is a marketed preparation containing hemocoagulase, which is an enzyme having coagulant activity, isolated from the snake Botrops atrox. This formulation is used in dental surgeries and other minor surgical wounds. However, the formulation remains untested in diabetic wounds. Hence, we proposed a study for the topical application of Botroclot in high-fat diet (HFD) + Streptozotocin (STZ) induced diabetic rats. HFD was fed initially to rats which facilitates the development of insulin resistance. Thereafter, an injection of STZ (40 mg/kg, i.p.) was given. This resulted in the development of diabetes with elevated fasting glucose and impaired glucose tolerance. After stabilization of blood glucose values, wounds were created by punch biopsy on the dorsal side of the palm of the rat to mimic the diabetic wounds frequently seen in the case of humans. Later, the application of Botroclot on these wounds was carried out for 15 days. Topical application of hemocoagulase improved the wound closure and there was a gradual decrease in inflammatory markers and a substantial increase in collagen deposition occurred. Histopathological findings indicated the same, with an increase in granulation tissue suggesting that the topical application moderately improves the wound healing in diabetic rats. We conclude that Botroclot can have a mild to moderate effect in improving collagen deposition and thus wound contraction, improving wound closure in diabetic wounds in rats. This study also establishes the basis for exploration of agents from venom-based sources in diabetic wound healing., Competing Interests: Conflict of interestThe authors declare that the study has been funded by Jagadale Industries Pvt. Ltd., Bengaluru., (© The Author(s) 2020.)

The Coronavirus (CoV) is a large family of viruses known to cause illnesses ranging from the common cold to acute respiratory tract infection. The severity of the infection may be visible as pneumonia, acute respiratory syndrome, and even death. Until the outbreak of SARS, this group of viruses was greatly overlooked. However, since the SARS and MERS outbreaks, these viruses have been studied in greater detail, propelling the vaccine research. On December 31, 2019, mysterious cases of pneumonia were detected in the city of Wuhan in China's Hubei Province. On January 7, 2020, the causative agent was identified as a new coronavirus (2019-nCoV), and the disease was later named as COVID-19 by the WHO. The virus spread extensively in the Wuhan region of China and has gained entry to over 210 countries and territories. Though experts suspected that the virus is transmitted from animals to humans, there are mixed reports on the origin of the virus. There are no treatment options available for the virus as such, limited to the use of anti-HIV drugs and/or other antivirals such as Remdesivir and Galidesivir. For the containment of the virus, it is recommended to quarantine the infected and to follow good hygiene practices. The virus has had a significant socio-economic impact globally. Economically, China is likely to experience a greater setback than other countries from the pandemic due to added trade war pressure, which have been discussed in this paper., (Copyright © 2020 Keni, Alexander, Nayak, Mudgal and Nandakumar.)

Chemobrain is a significant post-chemotherapy complication for which no approved treatments are available. We had previously identified that rutin inhibits doxorubicin (Dox-) -induced cognitive decline in healthy rats. However, it was important to also establish that it does so in rats with mammary carcinoma without compromising Dox's antitumor potential. Mammary carcinoma was induced in female rats by intraperitonial administration of N-methyl-N-nitrosourea (i.p.). Rats that developed mammary carcinoma were treated with Dox after pretreatment with vehicle or rutin. After Dox exposure (50 days), episodic and spatial memory was assessed using the novel object recognition task and the Morris water maze, respectively. Tumor progression was evaluated by measurement of tumor weight and volume and histological analysis. Blood samples were collected to estimate hematological parameters. Oxidative status and TNF-α levels were estimated in brain homogenates. Dox treatment significantly reduced tumor size and volume. Pretreatment with rutin did not significantly alter Dox's tumor suppression potential, suggesting that it does not influence Dox's anticancer activity. In addition, rutin ameliorated Dox-induced cognitive decline, myelosuppression, and brain oxidative stress. The present study indicates that rutin protects against Dox-induced cognitive decline and myelosuppression without affecting its antitumor potential.

In this study, we aimed to develop an experimental animal model for type 2 diabetes mellitus (T2DM) using a combination of monosodium glutamate (MSG) and high sucrose diet (HSD). Young male Wistar rats (20-30 g) were injected with MSG (2 or 4 mg/g, i.p. for 4 days). These rats were also fed an HSD, while the control group was fed a starch diet (SFD) for 150 days. Parameters assessed periodically were body weight, feed intake, blood glucose level, and oral glucose tolerance test (OGTT), lipid profile, liver and kidney function tests, skeletal muscle glucose uptake, cognitive function tests, and microvascular changes using isolated rat aorta. Histological changes in pancreas, liver, and kidney tissue were assessed using hematoxylin and eosin staining, whereas brain tissue was assessed using cresyl violet stain. Feeding MSG in combination with HSD in rats significantly increased body weight, and produced hyperglycemia, dyslipidemia, and hyperinsulinemia. Animals developed frank diabetic complications, which included insulin resistance in skeletal muscle, hypertension, vascular dysfunction, nephropathy, and dementia. Histological studies revealed neuronal loss with necrotic bodies in the brain, reduction in glomerular count in kidney, and severe hypertrophy and hyperplasia in the islets of Langerhans. These results indicate the successful induction of type-2 diabetes along with several diabetic complications by combining MSG with HSD.

Background: Increasing number of scientific reports have highlighted the role of histone acetylation/deacetylation in neurodegenerative conditions, including chemotherapy-induced cognitive dysfunction (also known as chemobrain). Multiple sources state that increased activity of histone deacetylases (HDACs) play a detrimental role in chemobrain. In the present study, sodium valproate, a well-known HDAC inhibitor, was explored for its neuroprotective potential against chemobrain development., Methods: Doxorubicin (DOX), a chemotherapeutic agent, was used to induce chemobrain in experimental animals while treating with sodium valproate simultaneously. The animals were subjected to novel object recognition test (NORT) in order to assess their cognitive status and further, brain antioxidant levels were estimated. The animal body weights and survival were noted throughout the period of the study. Blood parameters such as red blood cell count, white blood cell count and haemoglobin levels were also measured., Results: Our findings are in contradiction to the known neuroprotective properties of valproic acid. We observed that sodium valproate failed to prevent chemobrain development in DOX treated animals. In fact, treatment with sodium valproate dose dependently worsened cognitive status in DOX treated animals including their brain antioxidant status, possibly leading to neuronal damage through free radical induced toxicity., Conclusion: The present study highlights the caution that needs to be exercised in projecting HDAC inhibitors as in vivo neuroprotective agents, due to the complexity of existing neurological pathways and the diverse roles of histone deacetylases., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

The present study was aimed at assessing the protective effect of insulin against doxorubicin (DOX)-induced cognitive dysfunction in Wistar rats. Cognitive function for episodic memory was assessed by a novel object recognition task (NORT) in male Wistar rats. Oxidative stress markers-SOD, catalase, glutathione, and lipid peroxidation-in the hippocampus and frontal cortex were assessed using colorimetric methods. Doxorubicin treatment (2.5 mg/kg, i.p., every 5 days for 50 days) reduced recognition and discriminative indices in NORT with increased oxidative stress in the brain. A nonhypoglycemic dose of insulin (0.5 IU/kg, i.p.) significantly reduced brain oxidative stress (MDA) induced by doxorubicin with an increase in the antioxidant defense systems (SOD, catalase, and GSH). Rats treated with combined insulin and DOX spent comparatively more time with the novel object when compared to the non-novel objects; however, the observed difference was not statistically significant. An apparent improvement (p < 0.26) in recognition of the novel object was observed against the damage induced by doxorubicin. These results suggest that insulin reduces brain oxidative stress and apparently improves doxorubicin-induced cognitive dysfunction in Wistar rats.

Orchids of the genus Bulbophyllum have been reported to possess antitumor activity. Present study investigated the possible antitumor activity of the active fraction of bulb and root of Bulbophyllum sterile. Alcoholic extract along with petroleum ether, dichloromethane and ethyl acetate fractions were subjected to SRB assay in HCT-116, MDA-MB-231 and A549 cell lines. The active fractions were further evaluated for apoptosis, expression of apoptotic signaling proteins, comet assay and cell cycle analysis. Furthermore, they were assessed for in vivo antitumor activity in Ehrlich ascites carcinoma model. Petroleum fraction of bulbs (PFB) and roots (PFR) was found to be most active in HCT-116 cell lines with IC 50 value of 94.2±6.0 and 75.7±9.8, respectively. Apoptosis was evident from acridine orange/ethidium bromide staining along with the expression of phospho-p53 and phospho-Bad. Both PFB and PFR arrested G 2 /M phase of the cell cycle with 32.6% and 49.4% arrest, respectively compared to 17.5% arrest with control. An increase in mean life span and hepatic antioxidant levels was observed with PFB and PFR treatment in EAC inoculated mice. The results suggested that the active fractions of bulbs and roots possess anticancer activity likely by inducing apoptosis through phospho-p53 dependent pathway., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

We had previously demonstrated the anti-diabetic potential and pancreatic protection of two thiazolidin-4-one derivatives containing nicotinamide moiety (NAT-1 and NAT-2) in STZ-induced diabetic mice. However, due to the limitations of the STZ model, we decided to undertake a detailed evaluation of anti-diabetic potential of the molecules on a high sucrose diet (HSD) fed diabetic mouse model. Further, in vitro mechanistic studies on the phosphorylation of AMPK, Akt and p38 MAP kinase in L6 myotubes and anti-inflammatory studies in RAW264.7 mouse monocyte macrophage cells were performed. 15 months of HSD induced fasting hyperglycaemia and impaired glucose tolerance in mice. Treatment with NAT-1 and NAT-2 (100 mg/kg) for 45 days significantly improved the glucose tolerance and lowered fasting blood glucose levels compared to untreated control. An improvement in the elevated triglycerides and total cholesterol levels, and favorable rise in HDL cholesterol were also observed with test drug treatment. Also, no major changes were observed in the liver (albumin, AST and ALT) and kidney (creatinine and urea) parameters. This was further confirmed in their respective histology profiles which revealed no gross morphological changes. In L6 cells, significant phosphorylation of Akt and p38 MAP kinase proteins were observed with 100 μM of NAT-1 and NAT-2 with no significant changes in phosphorylation of AMPK. The molecules failed to exhibit anti-inflammatory activity as observed by their effect on the generation of ROS and nitrite, and nuclear levels of NF-κB in LPS-stimulated RAW264.7 cells. In summary, the molecules activated Akt and p38 MAP kinase which could have partly contributed to their anti-hyperglycaemic and hypolipidemic activities in vivo .

The promising role of thiazolidin-4-ones (TZOs) against inflammatory conditions has been reported. From our lab, one of the TZO derivatives, compound 4C, exerted anti-inflammatory potential via inhibition of locally released cytokines and prostaglandin. In continuance, a detailed study was undertaken for the preclinical profiling of this promising TZO derivative against polyarthritis in rats, along with assessment of risk associated with the treatment. Male Sprague-Dawley rats were used for the adjuvant-induced arthritis (AIA) model. Based on the development of secondary lesion, the animals were randomized into different treatment groups. To establish the efficacy of the test compound, parameters such as inflammation, pain, disease progression, cytokines and prostaglandin (PG)-E2 levels and complete blood cell profile were recorded along with radiological and histological examinations of joints. The study also focused on evaluating the side effect of test compound on gastric, liver, renal, blood and cardiovascular components. Compound 4C exerted promising therapeutic effect against secondary lesions in polyarthritis in rats. It limited the progression of chronic inflammation and associated pain in rats. Modulation of cytokine signalling and arachidonate metabolism by 4C was evident from inhibition of interleukin (IL)-6, tumor necrosis factor (TNF)-α and PGE2 generation in AIA rats. Comparatively, compound 4C was safer than diclofenac to cause gastric, liver, renal, blood and cardiovascular toxicities. These finding supports the efficacy and safety profile of 4C, a TZO derivative in limiting the progression of arthritis when administered orally., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Various parts of Mimusops elengi Linn. (Sapotaceae) have been used widely in traditional Indian medicine for the treatment of pain, inflammation and wounds. The study was conducted to explore the use of stem bark of M. elengi on pharmacological grounds and to evaluate the scientific basis of cytotoxic and anti-tumor activity. Extract/fractions were prepared and in vitro cytotoxicity was assessed using SRB assay. Most effective fractions were subjected to fluorescence microscopy based acridine orange/ethidium bromide (AO/EB) and Hoechst 33342 staining to determine apoptosis induction and DNA fragmentation assay. Comet and micronuclei assay were performed to assess genotoxicity. Cell cycle analysis was also performed. In vivo anti-tumor potential was evaluated by Ehrlich ascites carcinoma (EAC) model in mice. The alcoholic stem bark extract of M. elengi along with four fractions showed potential in vitro cytotoxicity in SRB assay. Of these, dichloromethane and ethyl acetate fractions were selected for further studies. The fractions revealed apoptosis inducing potential in AO/EB and Hoechst 33342 staining, which was further confirmed by DNA fragmentation assay. Genotoxic potential was revealed by comet and micronuclei assay. Fractions also exhibited specific cell cycle inhibition in G0/G1 phase. In EAC model, ethyl acetate fraction along with the standard (cisplatin) effectively reduced the increase in body weight compared to control and improved mean survival time. Both fractions were able to restore the altered hematological and biochemical parameters. Hence, M. elengi stem bark may be a possible therapeutic candidate having cytotoxic and anti-tumor potential.

Background: Colon cancer (CC) is the third commonly diagnosed cancer and the second leading cause of mortality in the US when compared to India where prevalence is less. Possible reason could be the vegetarian diet comprising spices used in curry powders. Researchers believe that 70% of the cases are associated with diet. Spices have inherited a rich tradition for their flavor and medicinal properties. Researchers have been oriented towards spices present in food items for their antitumorigenic properties., Objective: We investigated the effects of sambar as a preventive measure for 1,2-dimethyl hydrazine (DMH)-induced CC in Wistar albino rats., Materials and Methods: The animals were divided into three groups ( n = 6) namely control, DMH, and sambar. At the end of the experimental period, the animals were killed using anesthesia and the colons and livers were examined., Results: All the treatment groups exhibited a significant change in the number of aberrant crypt foci (ACF). Sambar group showed a significant change in the colonic GSH when compared to both normal and DMH groups. A significant reduction in the liver GSH was noted in the sambar group. Only sambar group showed a significant change in the liver catalase levels when compared to DMH. There was a significant reduction in the colonic nitrite in the sambar-treated group; 2.94 ± 0.29 when compared to DMH control at 8.09 ± 1.32. On the contrary, a significant rise in the liver nitrite levels was observed in the sambar-treated rats., Conclusion: Sambar may prevent the risk of CC when consumed in dietary proportions., Summary: Consumption of sambar significantly reduced aberrant crypt foci in DMH-induced colon cancer modelSambar treatment prevented DMH-induced oxidative changes in the colonic tissue, indicating its antioxidant roleSambar comprises a variety of spices that exhibited both pro- and antioxidant properties in different tissues, leading to its overall beneficial effect in this model. Abbreviations used: ACF: aberrant crypt foci, CC: colon cancer, DMH: 1,2-dimethyl hydrazine, GSH: glutathione, IL-6: Interleukin-6, TNF-α: Tumor necrosis factor-alpha.

Multiple genetic mutations along with unusual epigenetic modifications play a major role in cancer development. Histone deacetylase (HDAC) enzyme overexpression observed in the majority of cancers is responsible for tumor suppressor gene silencing and activation of proto-oncogenes to oncogenes. Cinnamic acid derivatives exhibit anti-cancer potential through HDAC enzyme inhibition. We have synthesized a few cinnamyl sulfonamide hydroxamate derivatives (NMJ-1, -2 and -3) by already published in-house procedures and their purity, and chemical characterization were performed by NMR, mass spectrometry and elemental analysis. The anti-cancer activities were also evaluated against colon cancer. The rationale for synthesis was based on bioisosterism concept. To take the work forward, these compounds were considered for in vitro anti-angiogenic and anti-metastatic activities in cancer cells. The effectiveness of these compounds was determined by SRB assay. The compounds showed cancer cell cytotoxicity (IC50 range of 5.7 ± 0.43 to 20.5 ± 1.9 μM). The mechanism of compound-induced cell death involves an intrinsic apoptosis pathway which was supported by the following: increase in apoptotic index, arrest in cell cycle at G2/M phase, increase in annexin V binding and induction of p21(Waf1/Cip1) expression in the treated cells. Further, their target modulating effect, measured as the expression of acetyl-H3 histone and acetyl α-tubulin was determined by Western blots. Hyper acetylation of H3 histone and α-tubulin were observed. Furthermore, increased expression of cleaved caspase-3, cleaved PARP, total Bad was estimated by ELISA. The anti-angiogenic effect was examined through cobalt (II) chloride (CoCl2)-induced HIF-1α expression, where the compounds reduced the expression of induced HIF-1α. In addition, their anti-metastatic ability was determined through phorbol-12-myristate-13-acetate (PMA)-induced expression of MMP-2 and -9 by Western blotting and gelatin zymography. Inhibition of malignant cell migration was assessed by scratch wound assay. The compounds showed a decrease in cell migration and inhibition of induced MMP-2 and MMP-9 expression. NMJ-2 exhibited comparable activity to that of standard SAHA. Our findings indicate that NMJ series of compound have potent in vitro anti-cancer, anti-angiogenic and anti-metastatic activity through HDAC enzyme inhibition., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Ethnopharmacological Relevance: Glycosmis pentaphylla (Retz.) DC (Rutaceae) has been traditionally used for the treatment of rheumatism, cancer, liver disorders, inflammation etc., Aim of the Study: The present study is aimed at elucidating the effect of Glycosmis pentaphylla (Retz.) DC on the key markers of apoptosis, metastasis and angiogenesis, in vitro. The study also evaluated the effect of fractions in vivo in DMBA-induced mammary tumor model., Materials and Methods: Fractions of Glycosmis pentaphylla (Retz.) DC leaf extracts was studied for their effect on apoptotic markers in breast cancer cell lines, MCF-7 and MDA-MB-231 cells. They were also studied for their effect on metastatic and angiogenic markers, MMP-9 and HIF-1α in MCF-7 cells. The fractions were studied in vivo in DMBA-induced mammary tumor model in Sprague Dawley rats., Results: The studies showed that the fractions induced apoptosis in breast cancer cells through the intrinsic/mitochondrial apoptotic pathway. The fractions were also able to inhibit the metastatic and angiogenic markers, MMP-9 and HIF-1α. Anti-tumor studies in DMBA-induced mammary model in Sprague Dawley rats also showed favorable results., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Cognitive decline or dementia is a debilitating problem of neurological disorders such as Alzheimer's and Parkinson's disease, including special conditions like chemobrain. Dietary flavonoids proved to be efficacious in delaying the incidence of neurodegenerative diseases. Two such flavonoids, naringin (NAR) and rutin (RUT) were reported to have neuroprotective potential with beneficial effects on spatial and emotional memories in particular. However, the efficacy of these flavonoids is poorly understood on episodic memory, which comprises an important form of autobiographical memory., Objective: This study objective is to evaluate NAR and RUT to reverse time-delay-induced long-term and scopolamine-induced short-term episodic memory deficits in Wistar rats., Materials and Methods: We have evaluated both short-term and long-term episodic memory forms using novel object recognition task. Open field paradigm was used to assess locomotor activity for any confounding influence on memory assessment. Donepezil was used as positive control and was effective in both models at 1 mg/kg, i.p., Results: Animals treated with NAR and RUT at 50 and 100 mg/kg, p.o. spent significantly more time exploring novel object compared to familiar one, whereas control animals spent almost equal time with both objects in choice trial. NAR and RUT dose-dependently increased recognition and discriminative indices in time-induced long-term as well as scopolamine-induced short-term episodic memory deficit models without interfering with the locomotor activity., Conclusion: We conclude that, NAR and RUT averted both short- and long-term episodic memory deficits in Wistar rats, which may be potential interventions for neurodegenerative diseases as well as chemobrain condition., Summary: Incidence of Alzheimer's disease is increasing globally and the current therapy is only symptomatic. Curative treatment is a major lacuna. NAR and RUT are natural flavonoids proven for their pleiotropic pharmacological effects with potential neuroprotective benefits. The study evaluated these flavonoids for their potential to improve the most common form of episodic memory (memory of autobiographical events in relation to time, places etc.) in two differential animal models assessing short-term and long-term memory, respectively. We also found that NAR and RUT were able to reverse both short-term and long-term memory deficits dose dependently in female Wistar rats. Abbreviations used: AD: Alzheimer's disease, AChE: Acetylcholinesterase, COX: Cyclooxygenase, DI: Discriminative index, ITI: Inter trial interval, NAR: Naringin, RUT: Rutin, NORT: Novel object recognition task, NOS: Nitric oxide synthase, QOL: Quality of life, RI: Recognition index, WFI: Water for injection.

Background: The present study was aimed at examining the effect of dehydrozingerone (DHZ), half analogue of curcumin which is the active constituent of turmeric (Curcuma longa) in the di-nitrochlorobenzene (DNCB) induced model for inflammatory bowel disease (IBD)., Materials and Methods: Male Wistar rats (200-220 g) were divided into four groups (n = 6). Chemical induction of IBD was done by sensitizing with 300 µL of 20 g/L of DNCB (in acetone) onto the nape of rats for 14 days followed by intra-colonic instillation of 250 µL of DNCB (0.1% DNCB in 50% alcohol) solution on day 15. Rats in Group 1 (normal control) and Group 2 (DNCB control) were treated with vehicle. Rats in Group 3 were treated with DHZ (100 mg/kg, p.o.; 8 days) and Group 4 animals were treated with sulfasalazine (SS) (100 mg/kg, p.o.; 8 days). On 24(th) day, the rats were killed, colon removed and the macroscopic, biochemical, and histopathological evaluations were performed., Results: The levels of myeloperoxidase, thiobarbituric acid reactive substrate, and nitrite increased significantly (P < 0.05) in the DNCB group whereas reduced significantly in the DHZ and SS treated groups. Serum nitrite levels were found to be insignificant between the different groups. Interleukin-6, tumor necrosis factor-alpha level was significantly high in the DNCB group., Conclusion: These findings show that DHZ can be a promising molecule for the treatment of IBD.

Ethnopharmacological Relevance: Glycosmis pentaphylla (Retz.) DC belonging to the family Rutaceae has been traditionally used for the treatment of rheumatism, anaemia, jaundice, skin diseases, bronchitis etc. The plant is traditionally considered as anti-cancer medicine and used by the healers of Bangladesh to treat all types of cancers. Perhaps the key to many of its medicinal applications is its inherent anti-inflammatory property., Aim of the Study: The present study is aimed at evaluating the effect of various fractions of G. pentaphylla (Retz.) DC leaves on the cell cycle and apoptosis of breast cancer cells viz. MCF-7 and MDA-MB-231., Materials and Methods: Various extracts and fractions of the leaves of G. pentaphylla (Retz.) DC were studied for their cytotoxicity with the help of Sulforhodamine B assay, in MCF-7, MDA-MB-231 and Vero cell lines. The most active fractions were studied for their effect on the cell cycle of MCF-7 and MDA-MB-231 cells. Apoptotic studies were done using Hoechst staining, DNA fragmentation, Annexin V staining and caspase-3/7 activation assay in breast cancer cells. HPLC and HPTLC profiling of the active fractions were done., Results: HPTLC and HPLC profiling revealed the presence of lupeol, chrysin, quercetin, β-sitosterol and kaempferol as components in active fractions. Lupeol and chrysin are being reported in this plant for the first time. The studies showed that the selected fractions possess cell cycle inhibitory and apoptosis inducing effect on both MCF-7 and MDA-MB-231 cells. Apoptotic effect of the fractions on MCF-7 and MDA-MB-231 cells may be through the mitochondrial pathway by the activation of caspase-3/7., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The potential of cinnamic acid as an anti-inflammatory and anti-cancer agent has been studied previously. In our investigation, novel bio-isosters of cinnamyl sulfonamide hydroxamate were synthesized, characterized and confirmed for their structure and evaluated for cytotoxicity. Three NCEs namely, NMJ-1, -2 and -3 showed cell-growth inhibition in 6 human cancer cell lines with IC50 at the range of 3.3±0.15-44.9±2.6 μM. The hydroxamate derivatives of cinnamyl sulfonamide are reported inhibitors of HDAC enzyme. Thus, the effectiveness of these molecules was determined by whole cell HDAC assay in HCT 116 cell line. NMJ-2 (0.41±0.01 μM) exhibited better enzyme inhibition (IC50) compared to SAHA (2.63±0.07). In order to evaluate induction of apoptosis by treatment, Hoechst 33342 and AO/EB nuclear staining methods were used. Further, cell cycle analysis, Annexin V binding and caspase 3/7 activation assays were performed by flow cytometry where NMJ-2 significantly arrested the cell cycle at G2/M phase, increased Annexin V binding to the cell surface and activation of caspase-3/7. Bax/Bcl-2 ratio was observed by Western blot and showed an increase with NMJ-2 treatment. This was comparable to standard SAHA. The acute toxicity study (OECD-425) showed that NMJ-2 was safe up to 2000 mg/kg in rats. 1,2-Dimethyl hydrazine (DMH) was used to produce experimental colon adenocarcinoma in Wistar rats. 5-FU and NMJ-2 (100 mg/kg p.o. and 10 mg/kg i.p. once daily for 21 days, respectively) were administered to the respective groups. Both treatments significantly reduced ACFs, adenocarcinoma count, TNF-α, IL-6, nitrite and nitrate levels in colonic tissue. Our findings indicate that NMJ-2 has potent anti-cancer activity against colon cancer, by acting through HDAC enzyme inhibition and activation of intrinsic mitochondrial apoptotic pathway, with additional anti-inflammatory activity., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Three thiazolidin-4-one derivatives were synthesized, purified and characterized by chromatographic and spectroscopic methods. In the in vitro assays, these compounds inhibited reactive oxygen species (ROS), nitrite and cytokine generation in RAW 264.7 murine macrophages and whole blood. These derivatives attenuated carrageenan-induced acute inflammation in rats. The most effective compound 4C possessed identical anti-inflammatory action at two doses (50 and 100 mg/kg). Further, the effect of compound 4C on locally induced inflammatory mediators was investigated in carrageenan-induced air pouch inflammation in rats. In this model, compound 4C inhibited the cytokines, tumor necrosis factor (TNF)-α and interleukin (IL)-6 (systemic and local). Additionally, compound 4C was able to reduce locally elevated prostaglandin-E₂ (PGE₂). Inhibition of leukocyte infiltration by compound 4C was correlated with reduced locally released myeloperoxidase (MPO). To conclude, compound 4C corrected the inflammatory condition by negative effect on cytokine (TNF-α, IL-6) network and prostaglandin-E₂ generation., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of gastrointestinal tract of immune, genetic, and environmental origin. In the present study, we examined the effects of sesamol (SES), which is the active constituent of sesame oil in the acetic acid (AA) induced model for IBD in rats., Methods: The groups were divided into normal control, AA control, SES, and sulfasalazine (SS). On day 7, the rats were killed, colon was removed, and the macroscopic, biochemical, and histopathological evaluations were performed., Results: The levels of MPO, TBARS, and tissue nitrite increased significantly (P < 0.05) in the AA group whereas they reduced significantly in the SES and SS treated groups. Serum nitrite levels were found to be insignificant between the different groups., Conclusions: The mucosal protective effects of sesamol in IBD are due to its potential to reduce the myeloperoxidase and nitrite content.

The aim of the present study was to evaluate the antitumor potential of iminoflavones in in vitro and in vivo anticancer models. Preliminary screening in various cancer cell lines revealed four potential iminoflavones out of which IMF-8 was taken based on its activity against colon cancer cells. This was further confirmed by observing the nuclear changes in the cells by AO/EB and Hoechst 33342 staining studies. In vivo activity was assessed by dimethyl hydrazine-(DMH-) induced colon cancer model in rats. Animals were administered DMH (20 mg/kg, b.w. for 10 weeks and 30 mg/kg b.w., i.p. for 10 weeks) and were supplemented with (IMF-8) iminoflavone-8 (200 mg/kg, p.o. for 14 days). Results showed that DMH induced 100% aberrant crypt foci (ACF) and polyps which were significantly reduced in the IMF-8 treated group. IMF-8 significantly increased the catalase and GSH levels whereas it reduced the TNF- α and IL-6 levels markedly which suggests the antioxidative and anti-inflammatory actions of flavonoids present in IMF-8. The histopathological images of the IMF-8 treated colon showed no signs of mucosal crypt abscess. These findings suggest that the semi-synthetic iminoflavones, IMF-8, effectively inhibit DMH-induced ACFs and colonic crypts by alleviating the oxidative stress and suppressing the inflammation.

We synthesized twenty thiazolidin-4-one derivatives, which were then characterized by standard chromatographic and spectroscopic methods. From the in vitro glucose uptake assay, two compounds behaved as insulin sensitizers, where they enhanced glucose uptake in isolated rat diaphragm. In high-carbohydrate diet-induced insulin resistant mice, these two thiazolidin-4-ones attenuated hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and glucose intolerance. They raised the plasma leptin but did not reverse the diabetes-induced hypoadiponectinemia. Additionally, compound 3a reduced adiposity. The test compounds were also able to reverse the disturbed liver antioxidant milieu. To conclude, these two novel thiazolidin-4-ones modulated multiple mechanisms involved in metabolic disorders, reversing insulin resistance and thus preventing the development of type-2 diabetes.

The Terminalia genus includes plants that are used in a variety of food, nutritional products, and traditional medicines. Aqueous bark extract of Terminalia paniculata (TPW) was screened for its antioxidant and analgesic potential. The major polyphenols were identified by high-performance liquid chromatography. In vitro antioxidant potential of TPW was investigated by 1,1-diphenyl-2-picryl hydrazyl (DPPH), 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS(2-)) radical assay, nitric oxide (NO) scavenging, superoxide scavenging (O(2-)), Fe(2+) chelating (O-phenanthroline), and ferric reducing/antioxidant power (FRAP) assay. We evaluated the effects of TPW on cell viability, lipopolysaccharide (LPS)-stimulated reactive oxygen species (ROS), nitrite, and cytokines (interleukin [IL] 6 and tumor necrosis factor alpha [TNF-α]) in RAW 264.7 murine macrophages. Evaluation of analgesic activity of TPW was performed using acetic acid-induced writhing and hot plate test in mice. Phytochemical analysis showed the presence of four polyphenols, namely, gallic acid, ellagic acid, rutin, and quercetin. TPW showed maximum superoxide, ABTS(2-), NO, DPPH inhibition, and Fe(2+-)chelating property at 400 μg/mL, respectively. FRAP value was 4.5±0.25 μg Fe(II)/g. TPW, per se, did not affect RAW 264.7 cell viability. In LPS-induced RAW 264.7 cells, TPW attenuated the elevation in ROS, nitrite, IL-6, and TNF-α levels. TPW (100-400 mg/kg, orally) significantly reduced the number of writhes in a dose-dependent manner compared with the control. Similarly, TPW (400 mg/kg, orally) evoked a significant increase in the maximum percentage effect in the hot plate test. The study suggests the efficacy of aqueous bark extract of T. paniculata as a potential antioxidant and analgesic agent.

Objective: Literature favours the in vitro neuroprotective role of caffeic acid, a naturally derived polyphenolic compound. This study was aimed to investigate the role of caffeic acid in experimental model of Alzheimer's disease., Methods: Firstly, caffeic acid was tested for in vitro anticholinesterase potential using rat brain homogenate. Later, in vivo antidementia activity of caffeic acid was assessed against aluminium chloride (AlCl3 )-induced dementia in rats. Behavioural (Morris water maze test) and brain biochemical parameters (acetylcholinesterase (AChE), catalase, glutathione-S-transferase (GST) activity, glutathione (GSH) and nitrite levels) were assessed to correlate the cognitive function with cholinergic transmission and oxidative stress., Key Findings: Rats administered with caffeic acid showed improved cognitive function in Morris water maze test. The antidementia activity of caffeic acid was confirmed by the reduction in brain AChE activity and nitrite levels. Further, caffeic acid corrected the diminished level of antioxidant enzymes such as catalase, GSH and GST in brain., Conclusion: These findings suggest the antidementia activity of caffeic acid against AlCl3 -induced dementia in rats. The outcome of present study offers a wider scope to screen caffeic acid against neurodegeneration associated disorders., (© 2013 Royal Pharmaceutical Society.)

Objectives: Exposure to toxicants like doxorubicin (Dox) damages cellular components by generating reactive oxygen species (ROS). This can be attenuated using free radical scavengers and/or antioxidants., Methods: Dox-exposed cardiac myoblasts (H9c2 cells) were treated with sesamol (12.5, 25 and 50 μm), a natural phenolic compound. Intracellular ROS inhibition, cell viability and analysis of antioxidant and biochemical markers such as superoxide dismutase, catalase, glutathione-S-transferase, glutathione peroxidase, reduced/oxidized glutathione, lipid peroxidation and protein carbonyl content were performed. The effect of sesamol treatment on the cytotoxic and genotoxic parameters was studied by monitoring the signalling proteins involved in the apoptotic pathway., Key Findings: Dox triggered cellular and genetic damage by increasing levels of intracellular ROS, thereby decreasing cell viability and increasing apoptosis. Sesamol reversed the cytotoxic and genotoxic effects of Dox. In addition, sesamol attenuated the pro-apoptotic proteins and improved the anti-apoptotic status. Sesamol pre-treatment also alleviated the disturbed antioxidant milieu by preventing ROS production and improving endogenous enzyme levels., Conclusions: Among the different doses tested, 50 μm of sesamol showed maximum protection against Dox-induced oxidative damage. This reflects the significance of sesamol in ameliorating the deleterious effects associated with cancer chemotherapy., (© 2013 Royal Pharmaceutical Society.)

Background: Based on the reported antioxidant and anti-inflammatory potential of Terminalia paniculata, the bark aqueous extract (TPW) was investigated against liver damage., Methods: Intrinsic cytotoxicity was tested on normal human liver (Chang) cell lines, followed by acute and sub-chronic toxicity studies in mice. TPW was then evaluated against CCl4-induced liver toxicity in rats. Liver enzymes (AST, ALT, and ALP) and antioxidant markers were assessed. The effect of TPW on isolated hepatic cells, post-CCl4 administration, was assessed by isolated mitochondrial membrane staining. The actions of TPW on apoptotic pathway in CCl4-treated Chang cells were also elucidated., Results: TPW was found to be safe at all doses tested in both in vitro and in vivo toxicity studies. TPW (400 mg/kg, p.o.) significantly (*p <0.05) improved liver enzyme activity as compared to CCl4. Also, it improved antioxidant status (GSH, GST, MDA and total thiol) and preserved hepatic cell architecture. TPW pre-treatment significantly attenuated the levels of phospho-p53, p53, cleaved caspase-3, phospho-Bad, Bad and cleaved PARP in CCl4-treated Chang cells, improving the viability considerably., Conclusion: The findings support a protective role for Terminalia paniculata in pathologies involving oxidative stress.

The active constituents of Sesamum indicum, sesamin and sesamolin, have already been explored for hypolipidemic action. In this study we have explored the anti-dyslipidemic activity of another active component and metabolite of sesamolin (sesamol), by using acute models of hyperlipidemia viz., a fat tolerance test, a tyloxapol-induced hyperlipidemia model and a chronic model of hyperlipidemia viz., a high-fat diet-induced hyperlipidemia model in Swiss albino mice. Sesamol (100 and 200 mg/kg) significantly (P < 0.05) decreased triacylglycerol absorption in the fat tolerance test by showing a dose-dependent decrease in triacylglycerol levels. The hypolipidemic effect of sesamol at 200 mg/kg was equivalent to 10 mg/kg of orlistat. In the tyloxapol-induced hyperlipidemia model, Sesamol at 200 mg/kg reversed the elevated levels of cholesterol and triacylglycerol compared with the tyloxapol group at 12 and 24 h, which indicates its probable effect on cholesterol synthesis. Chronic hyperlipidemia in mice was produced by feeding a high-diet, a mixture of cholesterol (2 % w/w), cholic acid (1 % w/w) and coconut oil 30 % (v/w) with standard powdered standard animal chow (up to 100 g). Niacin (100 mg/kg) and sesamol (100 mg/kg) significantly (P < 0.05) reduced the elevated body weight compared with the high fat diet control group. Elevated levels of cholesterol and triacylglycerol were significantly (P < 0.05) reversed by the sesamol (50 and 100 mg/kg), implying that it might reduce the absorption and increase the excretion of cholesterol as well.

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory condition of gastrointestinal tract of immune, genetic and environmental origin. In the present study, we examined the effect of sesamol (SES), the main anti-oxidative constituent of Sesamum indicum (sesame seed) Linn. in the dinitrochlorobenzene (DNCB)-induced model for IBD in rats., Methods: The groups were divided into normal control, DNCB control, SES and sulfasalazine (SS). On day 24, the rats were killed, colon removed and the macroscopic, biochemical and histopathological evaluations were performed., Results: The levels of MPO, TBARS and nitrite increased significantly (p < 0.05) in the DNCB group, whereas reduced significantly in the SES, SS treated groups. Serum nitrite levels were found to be insignificant between the different groups. IL-6 and TNF-α levels were significantly high in the DNCB group., Conclusions: We conclude the mucosal protective effect of SES on colon due to its potent antioxidant actions. Further investigation is required in a chronic model of different rodent strain for its role involved in the cytokine pathway.

1,4-Disubstituted bis-chromenyl triazole hybrids 5a-m have been synthesized in a three-step reaction sequence from 4-(bromomethyl)-2H-chromen-2-ones 3a-m. The intermediate azides 4a-m underwent a regioselective 1,3-dipolar cycloaddition with a 2H-chromen-2-one linked acetylenic dipolarophile in the presence of Cu (II)/ascorbate/water/n-butanol reaction medium. Three compounds 5h-j exhibited 6.25 μg/mL MIC against M. tuberculosis. Among the compounds screened for antifungal activity, lowest MIC of 6.25 μg/mL was observed for 5c against A. niger that also exhibited DNA cleavage observed by agarose gel electrophoresis. All the compounds were moderately active against both Gram-positive and Gram-negative bacterial strains. The cytotoxic effect of potent compounds on normal cells (V79 and HBL100) was assessed by MTT assay., (© 2012 John Wiley & Sons A/S.)

The present study describes the antidiabetic effect of the flavonoid rich fraction of Pilea microphylla (PM1). HPLC characterization of PM1 revealed the presence of polyphenols viz., chlorogenic acid, rutin, luteolin-7-O-glucoside, isorhoifolin, apigenin-7-O-glucoside, and quercetin. PM1 inhibited dipeptidyl peptidase IV (DPP-IV) in vitro with an IC(50) of 520.4±15.4 μg/ml. PM1, at doses of 300, 600 and 900 mg/kg i.p., also produced dose-dependent mean percent reductions of 9.9, 30.6 and 41.0 in glucose excursion (AUC(0-120 min)) respectively in lean mice. However, even the highest dose of PM1 did not alter normoglycemic condition. PM1 at dose of 100 mg/kg/day, i.p. for 28 days produced significant (p<0.05) reduction in body weight, plasma glucose (PG), triglycerides (TG) and total cholesterol (TC) content in high-fat streptozotocin-induced diabetic mice. PM1 also improved oral glucose tolerance significantly (p<0.05) with mean percentage reduction of 48.0% in glucose excursion (AUC(0-120 min)) and significantly (p<0.05) enhanced the endogenous antioxidant status in mice liver compared to diabetic control. PM1 preserved islet architecture and prevented hypertrophy of hepatocytes as evident from the histopathology of pancreas and liver. PM1 did not show any detectable hematological toxicity at therapeutic doses. In conclusion, PM1 exhibits antidiabetic effect possibly by inhibiting DPP-IV and improving antioxidant levels in high fat diet/streptozotocin (HFD/STZ) diabetic mice., (Copyright © 2010 Elsevier GmbH. All rights reserved.)

Context: Berberis aristata DC (Berberidaceae) is an important medicinal plant with claims of widespread medicinal value in indigenous medicine. It is used by herbal healers to treat oral cancers., Objective: To evaluate the antineoplastic activity of the extracts of Berberis aristata in Ehrlich ascites carcinoma (EAC)-bearing mice with cisplatin as positive control in the advanced stage of tumorigenesis., Materials and Methods: Brine shrimp lethality bioassay (BSL) of extracts and effect on the tumor cell viability in vitro were carried out. EAC was induced in Swiss albino mice by injecting 10(6) cell/mL of tumor cell suspension i.p. Antineoplastic activity of the aqueous and ethanol extracts (100 and 6.5 mg/kg i.p., respectively) was compared with that of cisplatin (3.5 mg/kg i.p.) on the parameters such as percentage increase in weight, median survival time, and hematology., Results: Ethanol extract attenuated percentage increase in weight gain (-6.86 ± 1.50) due to tumor cell proliferation and increased the survival time (19.5 days) when compared to control group (19.10 ± 2.31 and 16 days, respectively). However, the effect was less than that of cisplatin. In vitro cytotoxicity assay as well as BSL test showed the cytotoxic effect of the extracts. Cisplatin and the extracts reversed the tumor-induced alterations in total white blood cell count, differential leukocyte counts, total red blood cell count, and hemoglobin contents., Discussion and Conclusion: Of the two extracts, the ethanol extract was observed to be more efficient and the presence of alkaloids and flavonoids may be responsible for the observed anticancer effects.

Present study was designed to compare cytoprotective and antigenotoxic activity of the polyphenolic fraction of Pilea microphylla (PM1) with that of its active polyphenolic constituents against γ-radiation in V79 cells. PM1 was standardized with respect to the polyphenols present by RP-HPLC. It was evaluated for its free radical scavenging potential using Fenton reaction-induced DNA damage and lipid peroxidation. Further, PM1 was subjected against γ-radiation-induced cytotoxicity and genotoxicity in V79 cells. PM1 significantly reduced free radical-mediated calf thymus DNA damage and lipid peroxidation. Among the concentrations tested (12.5, 25 and 50 μg/ml) for radioprotection, PM1 at 25 μg/ml exhibited maximum protection. Further, when compared with constituent polyphenols viz., rutin, quercetin and chlorogenic acid (concentrations equivalent to that present in PM1-25 μg/ml), a combination of polyphenols was found most effective in preventing γ-radiation-induced cytotoxicity and genotoxicity. To conclude, radioprotection is possibly a synergistic effect of the phytochemicals present in the herbal extract, rather than any single component., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: The aim of the study was to investigate the effects of morin on skin breaking strength, hydroxyproline, lysyl oxidase, DNA and RNA content of experimentally inflicted wounds in rats., Methods: This study was performed on albino rats of either sex at the Central Animal Research Facility (CARF), Manipal University., Results: Morin showed significant wound contraction on day 7 as compared to control with mean closure of 47.44±6.07% in excision wound model. Granulation tissue breaking strength was significantly increased (p<0.05) in the morin treated group with 180.2±7.94 g when compared to control at 151.2±6.99 g. There was a significant increase in hydroxyproline content with the morin treated group when compared to control with 3.41±0.33 μg/mg of granulation tissue. Similarly, the wound parameters were improved with the morin treated group in dexamethasone delayed healing., Conclusions: Our results suggest that morin treatment accelerates the healing process delayed by concurrent use of steroids.

Oxidative stress is triggered by the wound which results in the production of reactive oxygen species (ROS), thereby delaying normal wound repair. Therefore, it is important to reduce the level of ROS to improve healing. A known antioxidant, dehydrozingerone (DHZ) was synthesized and selected for the study. The authors aimed to investigate the wound healing action of topical (100 mg/wound) and systemic (100 mg/kg, p. o.). DHZ on different wound models in normal and dexamethasone (DEX)-suppressed healing. Topical DHZ showed a significant (P < 0.05) rise in tensile strength when compared to control in normal healing. Significant (P < 0.05) wound closure was observed from 3 to 9 days in DHZ oral and gel treated groups. There was a significant (P < 0.05) rise in hydroxyproline content with the DHZ treated groups when compared to control. Systemic DHZ exhibited a significant (P < 0.05) increase in lysyl oxidase (LO) levels of 3.73 ± 0.15 nmol of H(2)O(2) when compared to control. In DEX-suppressed healing, showed good pro-healing activity with respect to the parameters mentioned above. DHZ treatment exhibited a parabolic dose response of ROS inhibition with a plateau effect at 75 μM. There was a steady and constant increase in the % NO inhibition with increasing doses of DHZ. Oral DHZ is effective in accelerating the healing process in both normal and dexamethasone-suppressed wounds. Our study suggests that DHZ (half analog of curcumin) supplementation reduces the steroid-induced delay in wound healing.