Synergistic Effects of Curcumin and Piperine as Potent Acetylcholine and Amyloidogenic Inhibitors With Significant Neuroprotective Activity in SH-SY5Y Cells via Computational Molecular Modeling and in vitro Assay.

Hallmarks of Alzheimer's disease (AD) pathology include acetylcholine (ACh) deficiency and plaque deposition. Emerging studies suggest that acetylcholinesterase (AChE) may interact with amyloid ß (Aß) to promote aggregation of insoluble Aß plaques in brains of patients. Current therapeutic options available for AD patients, such as AChE inhibitors, provide only symptomatic relief. In this study, we screened four natural compounds believed to harbor cognitive benefits-curcumin, piperine, bacoside A, and chebulinic acid. In the first section, preliminary screening through computational molecular docking simulations gauged the suitability of the compounds as novel AChE inhibitors. From here, only compounds that met the in silico selection criteria were selected for the second section through in vitro investigations, including AChE enzyme inhibition assay, 3-(4,5-dimenthylthiazol-2-yl)-2,5-dimethyltetrazolium bromide (MTT) assay, Thioflavin T (ThT) assay, and biochemical analysis via a neuronal cell line model. Of the four compounds screened, only curcumin (-9.6 kcal/mol) and piperine (-10.5 kcal/mol) showed favorable binding affinities and interactions towards AChE and were hence selected. In vitro AChE inhibition demonstrated that combination of curcumin and piperine showed greater AChE inhibition with an IC50 of 62.81 ± 0.01 µg/ml as compared to individual compounds, i.e., IC50 of curcumin at 134.5 ± 0.06 µg/ml and IC50 of piperine at 76.6 ± 0.08 µg/ml. In the SH-SY5Y cell model, this combination preserved cell viability up to 85%, indicating that the compounds protect against Aß-induced neuronal damage (p < 0.01). Interestingly, our results also showed that curcumin and piperine achieved a synergistic effect at 35 µM with an synergism quotient (SQ) value of 1.824. Synergistic behavior indicates that the combination of these two compounds at lower concentrations may provide a better outcome than singularly used for Aß proteins. Combined curcumin and piperine managed to inhibit aggregation (reduced ThT intensity at 0.432 a.u.; p < 0.01) as well as disaggregation (reduced ThT intensity at 0.532 a.u.; p < 0.01) of fibrillar Aß42. Furthermore, combined curcumin and piperine reversed the Aß-induced up-regulation of neuronal oxidative stress (p < 0.01). In conclusion, curcumin and piperine demonstrated promising neuroprotective effects, whereas bacoside A and chebulinic acid may not be suitable lead compounds. These results are hoped to advance the field of natural products research as potentially therapeutic and curative AD agents.

Bacopa monnieri, a Neuroprotective Lead in Alzheimer Disease: A Review on Its Properties, Mechanisms of Action, and Preclinical and Clinical Studies.

Alzheimer disease is a neurodegenerative disease that is signified by cognitive decline, memory loss, and erratic behavior. Till date, no cure for Alzheimer exists and the current Alzheimer medications have limited effectiveness. However, herbal medicines may slow down the disease's progression, which may hopefully reduce the number of cases in the years to come. Numerous studies have been done on characterizing the neuroprotective properties from plants belonging to Scrophulariaceae family, particularly Bacopa monnieri and its polyphenolic compounds known as bacosides. This review presents the findings on bacosides in therapeutic plants and their impact on Alzheimer disease pathology. These reports present data on the clinical, cellular activities, phytochemistry, and biological applications that may be used in new drug treatment for Alzheimer disease.

Mechanism involved in insulin resistance via accumulation of ß-amyloid and neurofibrillary tangles: link between type 2 diabetes and Alzheimer's disease.

The pathophysiological link between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) has been suggested in several reports. Few findings suggest that T2DM has strong link in the development process of AD, and the complete mechanism is yet to be revealed. Formation of amyloid plaques (APs) and neurofibrillary tangles (NFTs) are two central hallmarks in the AD. APs are the dense composites of ß-amyloid protein (Aß) which accumulates around the nerve cells. Moreover, NFTs are the twisted fibers containing hyperphosphorylated tau proteins present in certain residues of Aß that build up inside the brain cells. Certain factors contribute to the aetiogenesis of AD by regulating insulin signaling pathway in the brain and accelerating the formation of neurotoxic Aß and NFTs via various mechanisms, including GSK3ß, JNK, CamKII, CDK5, CK1, MARK4, PLK2, Syk, DYRK1A, PPP, and P70S6K. Progression to AD could be influenced by insulin signaling pathway that is affected due to T2DM. Interestingly, NFTs and APs lead to the impairment of several crucial cascades, such as synaptogenesis, neurotrophy, and apoptosis, which are regulated by insulin, cholesterol, and glucose metabolism. The investigation of the molecular cascades through insulin functions in brain contributes to probe and perceive progressions of diabetes to AD. This review elaborates the molecular insights that would help to further understand the potential mechanisms linking T2DM and AD.

An approach for developing integrated undergraduate medical curriculum.

BACKGROUND AND OBJECTIVES: Medical schools are to develop integrated medical curricula because the term 'integrated curriculum' has grown up and flourished globally and it has become mandatory to align the medical education with the global concept in Pakistan. This paper aims to present a guideline to design an undergraduate integrated medical curriculum. METHODS: Various themes are used to develop integrated curriculum which are basic medical science, simulation skills, clinical science, personality development, research, entrepreneurship and pre specialization. Each theme is subdivided, termed a module and its contents primarily focus on particular aspect. RESULTS: Knowledge, skill and attitude, embodied in themes or modules, are planted in specific way that they have horizontal as well as vertical integration. There is no boundary of various traditional disciplines in template of five years curriculum. For example, diagnosis is a theme which carries contents from medicine, surgery, orthopedics etc. CONCLUSION: The blueprint introduced in this paper would help medical educators to draft integrated medical curricula for those institutions which intend to switch their medical programs from traditional to integrated one.