A Neutral Flavin-Triphenylamine Probe for Mitochondrial Bioimaging under Different Microenvironments.

A bioinspired design built around a neutral flavin-triphenylamine core has been investigated for selective mitochondrial bioimaging capabilities in different microenvironments. Significant advantages with respect to long-term tracking, faster internalization, penetrability within the spheroid structures, and strong emission signal under induced hypoxia conditions have been observed, which could offer an alternative to the existing mitotrackers for hypoxia-related biological events.

Photocatalytic and antibacterial activities of green synthesized Ag doped MgO nanocomposites towards environmental sustainability.

The utilization of MgO nanoparticles (NPs) for Photocatalytic and antimicrobial activities has gained lots of attention in recent years. Since silver is an expensive material, it's of interest to check that doping of very small concentration of silver will increase the pollutant degradation efficiency of composites. Here Aloe Vera plant extract was used for synthesis of MgO, Ag NPs and Ag/MgO-nanocomposites (NCs). Green synthesized NPs and NCs were confirmed by using different techniques like UV-Vis, BET, TGA, FTIR, PL, XRD (optical, functional, Thermal, Structural) EDX, TEM, SEM, XPS, EIS and EPR (morphological, elemental, photoelectrical and ROS) studies respectively. Then NPs and NCs were applied for the photocatalytic activity of methylene blue (MB), phenol and antimicrobial studies of E. coli bacteria. Ag/MgO-NCs showed 90.18% dye and 80.67% phenol degradation in 120 min which killed E. Coli pathogenic bacteria in 25 min under solar light irradiations. In disk diffusion methods, it inactivates 24 mm area of bacterial cell growth. Thus, among these green synthesized NPs and NCs, Ag/MgO-NCs exhibited enhanced photocatalytic and antimicrobial activities.

Mesenchymal stem cells are prospective novel off-the-shelf wound management tools.

Chronic/non-healing cutaneous wounds pose a debilitating burden on patients and healthcare system. Presently, treatment modalities are rapidly shifting pace from conventional methods to advanced wound care involving cell-based therapies. Mesenchymal stem cells (MSCs) have come across as a prospective option due to its pleiotropic functions viz. non-immunogenicity, multipotency, multi-lineage plasticity and secretion of growth factors, cytokines, microRNAs (miRNA), exosomes, and microvesicles as part of their secretome for assisting wound healing. We outline the therapeutic role played by MSCs and its secretome in suppressing tissue inflammation, causing immunomodulation, aiding angiogenesis and assisting in scar-free wound healing. We further assess the mechanism of action by which MSCs contribute in manifesting tissue repair. The review flows ahead in exploring factors that influence healing behavior including effect of multiple donor sites, donor age and health status, tissue microenvironment, and in vitro expansion capability. Moving ahead, we overview the advancements achieved in extending the lifespan of cells upon implantation, influence of genetic modifications aimed at altering MSC cargo, and evaluating bioengineered matrix-assisted delivery methods toward faster healing in preclinical and clinical models. We also contribute toward highlighting the challenges faced in commercializing cell-based therapies as standard of care treatment regimens. Finally, we strongly advocate and highlight its application as a futuristic technology for revolutionizing tissue regeneration.

A rapid green synthesis of Ag/AgCl-NC photocatalyst for environmental applications.

The present study focuses on extract-mediated Ag nanoparticles (NPs), AgCl-NPs, and Ag/AgCl nanocomposites (NCs) as photocatalysts along with its antimicrobial and dye degradation activities. The synthesis of these NPs and NCs was performed by using Azadirachta indica plant fruit extract and analyzed using UV-Vis spectroscopy to confirm the synthesis and band gap of these NPs and NCs, X-ray diffraction (XRD) to determine its size and crystalline nature. Fourier transform infrared spectroscopy (FTIR) to discern phytochemicals, responsible for the reduction and capping of the synthesized NCs. Scanning electron microscopy analysis (SEM), transmission electron microscopy analysis (TEM), and energy dispersive X-ray (EDX) spectroscopy analysis were performed to validate the morphology and presence of silver and chloride percentage in the composites. Later, these NPs and NCs were used for their potential role in photocatalytic degradation of methylene blue dye and antibacterial activity against Escherichia coli and Staphylococcus aureus of human pathogen. The prepared Ag/AgCl-NCs exhibited an enhanced photocatalytic and antibacterial activities in comparison with pure Ag and AgCl nanomaterials. However, green-synthesized NPs and NCs played dual roles as a photocatalyst and antibacterial agent in various biomedical and industrial sectors. Moreover, we found that it might be a hot research in many other environmental applications in upcoming days.

Advances and clinical challenges for translating nerve conduit technology from bench to bed side for peripheral nerve repair.

Injuries to the peripheral nervous system remain a large-scale clinical problem. These injuries often lead to loss of motor and/or sensory function that significantly affects patients' quality of life. The current neurosurgical approach for peripheral nerve repair involves autologous nerve transplantation, which often leads to clinical complications. The most pressing need is to increase the regenerative capacity of existing tubular constructs in the repair of large nerve gaps through development of tissue-engineered approaches that can surpass the performance of autografts. To fully realize the clinical potential of nerve conduit technology, there is a need to reconsider design strategies, biomaterial selection, fabrication techniques and the various potential modifications to optimize a conduit microenvironment that can best mimic the natural process of regeneration. In recent years, a significant progress has been made in the designing and functionality of bioengineered nerve conduits to bridge long peripheral nerve gaps in various animal models. However, translation of this work from lab to commercial scale has not been achieve. The current review summarizes recent advances in the development of tissue engineered nerve guidance conduits (NGCs) with regard to choice of material, novel fabrication methods, surface modifications and regenerative cues such as stem cells and growth factors to improve regeneration performance. Also, the current clinical potential and future perspectives to achieve therapeutic benefits of NGCs will be discussed in context of peripheral nerve regeneration.

Cartilage repair using stem cells & biomaterials: advancement from bench to bedside.

Osteoarthritis (OA) involves gradual destruction of articular cartilagemanifested by pain, stiffness of joints, and impaired movement especially in knees and hips. Non-vascularity of this tissue hinders its self-regenerative capacity and thus, the application of reparative or restorative modalities becomes imperative in OA treatment. In recent years, stem cell-based therapies have been explored as potential modalities for addressing OA complications. While mesenchymal stem cells (MSCs) hold immense promise, the recapitulation of native articular cartilage usingMSCs remains elusive. In this review, we have highlighted the chondrogenic potential of MSCs, factors guiding in vitro chondrogenic differentiation, biomaterials available for cartilage repair, their current market status, and the outcomes of major clinical trials. Our search on ClinicalTrials.gov using terms "stem cell" and "osteoarthritis" yielded 83 results. An analysis of the 29 trials that have been completed revealed differences in source of MSCs (bone marrow, adipose tissue, umbilical cord etc.), cell type (autologous or allogenic), and dose administered. Moreover, only 02 out of 29 studies have reported the use of matrix for cartilage repair. From future perspective, aconsensus on choice of cells, differentiation inducers, biomaterials, and clinical settings might pave a way for concocting robust strategies to improve the clinical applicability of biomimetic neocartilage constructs.

Biogenic mediated Ag/ZnO nanocomposites for photocatalytic and antibacterial activities towards disinfection of water.

The current study reports on investigation of pure ZnO nanoparticles (NPs) and Ag/ZnO nanocomposites (NCs) in which Ag noble metal mixed at different concentration (0.5%, 1.0% and 2.0%) in the presence of Ocimum tenuiflorum (Tulsi) plant seed extract (PSE). The structural, optical, electrical and chemical properties of green synthesized NPs and NCs have been monitored using diffrent analytical techniques such as XRD, SEM, TEM, EDX, UV-Vis, FTIR, EIS and EPR. Further the antimicrobial and dye degradation activity of green synthesized pure ZnO-NPs and 0.5%, 1.0% and 2.0% Ag/ZnO-NCs had been examined. The result showed that synthesized 1.0% Ag/ZnO-NCs possessed a good photocatalytic and antimicrobial activity as compared to pure ZnO-NPs and other prepared Ag/ZnO-NCs. Based on the outcomes of reactive oxygen species (ROS) detection, the improved antimicrobial and dye degradation activities of Ag/ZnO-NCs were attributed due to more ROS formation, as Ag particles on the surface of ZnO are in support of electron transfer, which could improve ROS formation by one-electron reduction of oxygen.

Photocatalytic Activity of Green Synthesized AgCl Nanoparticles Towards E. coli Bacteria.

The present work focus on plant extracts mediated synthesis of silver chloride nanoparticles (AgCl-NPs). The AgCl-NPs were synthesized using the plant leaf extract of Origanum-majorana by one step green synthesis method. The characterization of as prepared AgCl-NPs were done by various analytical techniques such as UV-Vis spectroscopy, X-ray diffraction (XRD) and fourier transform infrared spectroscopy (FTIR). The morphology and composition of AgCl-NPs was confirmed by scanning electron microscopy analysis (SEM) and energy dispersive X-ray spectroscopy (EDX) analysis, respectively. Further, photocatalytic activity of as prepared AgCl-NPs observed by elimination of E. coli bacteria from contaminated water under solar light irradiation and it was observed that AgCl-NPs possess a good photocatalytic activity performance against E. coli bacteria.

Current Status of Stem Cell Treatment for Type I Diabetes Mellitus.

BACKGROUND: Diabetes mellitus is a major health concern in current scenario which has been found to affect people of almost all ages. The disease has huge impact on global health; therefore, alternate methods apart from insulin injection are being explored to cure diabetes. Therefore, this review mainly focuses on the current status and therapeutic potential of stem cells mainly mesenchymal stem cells (MSCs) for Type 1 diabetes mellitus in preclinical animal models as well as humans. METHODS: Current treatment for Type 1 diabetes mellitus mainly includes use of insulin which has its own limitations and also the underlying mechanism of diseases is still not explored. Therefore, alternate methods to cure diabetes are being explored. Stem cells are being investigated as an alternative therapy for treatment of various diseases including diabetes. Few preclinical studies have also been conducted using undifferentiated MSCs as well as in vitro MSCs differentiated into ß islet cells. RESULTS: These stem cell transplant studies have highlighted the benefits of MSCs, which have shown promising results. Few human trials using stem cells have also affirmed the potential of these cells in alleviating the symptoms. CONCLUSION: Stem cell transplantation may prove to be a safe and effective treatment for patients with Type 1 diabetes mellitus.

Novel synthetic analogs of diallyl disulfide triggers cell cycle arrest and apoptosis via ROS generation in MIA PaCa-2 cells.

BACKGROUND: Diallyl disulfide (DADS), a principal organosulfur component of garlic, is known for its medicinal properties including anti-cancer activity. Prior studies have demonstrated that the compounds containing Diallyl disulfide moieties exhibited diverse therapeutic potential with promising biological activities. In the present study, we have investigated the in vitro anticancer activity of Diallyl disulfide derivatives (5a-5l and 7e-7m) against human cancer cell lines. METHODS: The effect of DADS analogs on different cancer cell lines was measured through MTT assay. Cell cycle progression, apoptosis, DNA fragmentation and levels of ROS were analyzed through FACS and confocal imaging. RESULTS: Bis[3-(3-fluorophenyl)prop-2-ene]disulfide (compound 5b) was the most potent compound among the tested DADS derivatives. FACS analysis revealed that increase in ROS generation by compound 5b was accompanied by cell cycle arrest in the G2/M phase and apoptosis in MIA PaCa-2 cells. Further, the apoptosis was confirmed by TUNEL assay. Western blot analysis showed that compound 5b induces G2/M phase arrest via ROS mediated DNA-damage, which in turn, induces phosphorylation of Chk1/Cdc25c/Cdc2 pathway. Furthermore, altered levels of ROS triggers intrinsic apoptotic cascade, as evidenced by dissipated mitochondrial membrane potential (ψ), decrease in Bcl-2/Bax ratio, cytochrome c release and cleavage of procaspase-3. Scavenging of ROS by antioxidant N-acetyl-cysteine (NAC) reversed the compound 5b induced augmented intracellular ROS levels and cell death. CONCLUSION: Taken together, the anti-proliferative effects of compound 5b were attributed to intracellular ROS accumulation, which in turn, triggers apoptosis by mediating DNA damage-induced G2/M phase arrest and evoking mitochondrial apoptotic pathway in MIA PaCa-2 cells.

Rational design, synthesis and biological screening of triazine-triazolopyrimidine hybrids as multitarget anti-Alzheimer agents.

In our endeavor towards the development of potent multitarget ligands for the treatment of Alzheimer's disease, a series of triazine-triazolopyrimidine hybrids were designed, synthesized and characterized by various spectral techniques. Docking and scoring techniques were used to design the inhibitors and to display their interaction with key residues of active site. Organic synthesis relied upon convergent synthetic routes were mono and di-substituted triazines were connected with triazolopyrimidine using piperazine as a linker. In total, seventeen compounds were synthesized in which the di-substituted triazine-triazolopyrimidine derivatives 9a-d showed better acetylcholinesterase (AChE) inhibitory activity than the corresponding tri-substituted triazine-triazolopyrimidine derivatives 10a-f. Out of the disubstituted triazine-triazolopyrimidine based compounds, 9a and 9b showed encouraging inhibitory activity on AChE with IC50 values 0.065 and 0.092 µM, respectively. Interestingly, 9a and 9b also demonstrated good inhibition selectivity towards AChE over BuChE by ∼28 folds. Furthermore, kinetic analysis and molecular modeling studies showed that 9a and 9b target both catalytic active site as well as peripheral anionic site of AChE. In addition, these derivatives effectively modulated Aß self-aggregation as investigated through CD spectroscopy, ThT fluorescence assay and electron microscopy. Besides, these compounds exhibited potential antioxidants (2.15 and 2.91 trolox equivalent by ORAC assay) and metal chelating properties. In silico ADMET profiling highlighted that, these novel triazine derivatives have appropriate drug like properties and possess very low toxic effects in the primarily pharmacokinetic study. Overall, the multitarget profile exerted by these novel triazine molecules qualified them as potential anti-Alzheimer drug candidates in AD therapy.

DADS Analogues Ameliorated the Cognitive Impairments of Alzheimer-Like Rat Model Induced by Scopolamine.

The development of agents that affect two or more relevant targets has drawn considerable attention in treatment of AD. Diallyl disulfide (DADS), an active principle of garlic, has been reported to prevent APP processing by amyloidogenic pathway. Recently, we have reported a new series of DADS derivatives and our findings revealed that compound 7k and 7l could provide good templates for developing new multifunctional agents for AD treatment. Thus, the present study was constructed to investigate the neuroprotective effect of DADS analogues (7k and 7l) against Aß-induced neurotoxicity in SH-SY5Y human neuroblastoma cells and in ameliorating the cognition deficit induced by scopolamine in rat model. The results indicated that compound 7k and 7l significantly inhibited Aß1-42-induced neuronal cell death by inhibiting ROS generation. Moreover, they prevented apoptosis, in response to ROS, by restoring normal Bax/Bcl-2 ratio. Furthermore, it was observed that scopolamine-induced memory impairment was coupled by alterations in neurotransmitters, acetylcholinesterase activity and oxidative stress markers. Histological analysis revealed severe damaging effects of scopolamine on the structure of cerebral cortex and hippocampus. Administration of compounds 7k and 7l at 5 mg/kg significantly reversed scopolamine-induced behavioural, biochemical, neurochemical and histological changes in a manner comparable to standard donepezil. Together the present findings and previous studies indicate that compounds 7k and 7l have neuroprotective and cognition-enhancing effects, which makes them a promising multi-target candidate for addressing the complex nature of AD.

Synthesis and screening of triazolopyrimidine scaffold as multi-functional agents for Alzheimer's disease therapies.

In present study a series of triazolopyrimidine-quinoline and cyanopyridine-quinoline hybrids were designed, synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs). Molecular docking and scoring was utilized for the design of inhibitors. The molecules were synthesized via an easily accessible, convergent synthetic route. Three triazolopyrimidine based compounds showed nanomolar activity towards acetylcholinesterase. Among them, Ethyl 6-fluoro-4-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)quinoline-3-carboxylate (10d), strongly inhibited AChE with IC50 value of 42 nM. Furthermore compound 10d was identified as most promising compound with 12 fold selectivity against butyrylcholinesterase (BuChE). This compound displayed a composed multitargeted profile with promising inhibition of self-induced and AChE - induced Aß aggregation and antioxidant activity.

Multifunctional novel Diallyl disulfide (DADS) derivatives with ß-amyloid-reducing, cholinergic, antioxidant and metal chelating properties for the treatment of Alzheimer's disease.

A series of novel Diallyl disulfide (DADS) derivatives were designed, synthesized and evaluated as chemical agents, which target and modulate multiple facets of Alzheimer's disease (AD). The results showed that the target compounds 5a-l and 7e-m exhibited significant anti-Aß aggregation activity, considerable acetylcholinesterase (AChE) inhibition, high selectivity towards AChE over butyrylcholinesterase (BuChE), potential antioxidant and metal chelating activities. Specifically, compounds 7k and 7l exhibited highest potency towards self-induced Aß aggregation (74% and 71.4%, 25 µM) and metal chelating ability. Furthermore, compounds 7k and 7l disaggregated Aß fibrils generated by Cu(2+)-induced Aß aggregation by 80.9% and 78.5%, later confirmed by transmission electron microscope (TEM) analysis. Besides, 7k and 7l had the strongest AChE inhibitory activity with IC50 values of 0.056 µM and 0.121 µM, respectively. Furthermore, molecular modelling studies showed that these compounds were capable of binding simultaneously to catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. All the target compounds displayed moderate to excellent antioxidant activity with ORAC-FL values in the range 0.546-5.86Trolox equivalents. In addition, absorption, distribution, metabolism and excretion (ADME) profile and toxicity prediction (TOPKAT) of best compounds 7k and 7l revealed that they have drug like properties and possess very low toxic effects. Collectively, the results strongly support our assertion that these compounds could provide good templates for developing new multifunctional agents for AD treatment.

Synthesis, biological evaluation and molecular docking study of novel piperidine and piperazine derivatives as multi-targeted agents to treat Alzheimer's disease.

Development of Multi-Target Directed Ligands (MTDLs) has emerged as a promising approach for targeting complex etiology of Alzheimer's disease (AD). Following this approach, a new series of N'-(4-benzylpiperidin-/piperazin-/benzhydrylpiperazin-1-yl)alkylamine derivatives were designed, synthesized and biologically evaluated as inhibitors of cholinesterases (ChEs), amyloid-beta (Aß) self aggregation and also for their radical scavenging activity. The in vitro studies showed that the majority of synthesized derivatives strongly inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC50 values in the low-nanomolar range, and were clearly more potent than the reference compound donepezil in this regard. Among them, inhibitors 5h and 5k, strongly inhibited AChE, with IC50 value of 6.83nM and 2.13nM, respectively, and particularly, compound 5k was found to be highly selective for AChE (∼38-fold). Moreover, both kinetic analysis of AChE inhibition and the docking study suggested that 5k binds simultaneously to catalytic active site and peripheral anionic site of AChE. Besides, these compounds also exhibited greater ability to inhibit self-induced Aß1-42 aggregation at 25µM with percentage inhibition from ∼54% to 89% and specially compound 5k provided highest inhibition (88.81%). Also, the derivatives containing methoxy and hydroxy groups showed potent oxygen radical absorbance capacity (ORAC) ranging from 2.2- to 4.4-fold of the Trolox value. Furthermore, results of ADMET studies suggested that all compounds exhibited appropriate drug like properties. Taken together, these results suggest that 5k might be a promising lead compound for further AD drug development.

Protective effects of a piperazine derivative [N-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-phenyl} carbamic acid ethyl ester] against aluminium-induced neurotoxicity: insights from in silico and in vivo studies.

The cholinergic hypothesis associated with Alzheimer's disease has spurred the development of numerous structural classes of compounds with different pharmacological profiles aimed at increasing central cholinergic neurotransmission. In the present study, six synthetic piperazine derivatives D1-D6 were screened for their efficacy as acetylcholinesterase inhibitors (AChEIs) through in silico and in vitro studies. Compound D2 was found to be a potential AChEI with adequate pharmacokinetic properties, as supported by in silico study. Further, in vivo studies were designed to examine the protective effect of piperazine derivative D2 (3 and 5 mg/kg for 6 weeks) in ameliorating the alterations induced by aluminium chloride (AlCl(3)) on behavioural and neurochemical indices. Behavioural tests (Morris water maze and elevated plus maze) revealed significant alterations in the short-term memory and anxiety levels in rats treated with AlCl(3), which was further improved after D2 treatment. Further, D2 treatment attenuated the neurotoxic effects of AlCl(3) as shown by the improvement in rats performance in Water maze test and in lowering AChE activity. Besides preventing lipid peroxidation and protein damage, changes in the levels of endogenous antioxidant enzymes (GST, GPx, GR and GSH) associated with AlCl3 administration were also restored upon treatment with D2. Thus, our results support the neuroprotective potential of compound D2, thus validating its use in alleviating toxic effects of aluminium.