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Dendrites are tree-like structures with tiny spines specialized to receive excitatory synaptic transmission. Spino-dendritic plasticity, driven by neural activity, underlies the maintenance of neuronal connections crucial for proper circuit function. Abnormalities in dendritic morphology are frequently seen in epilepsy. However, the exact etiology or functional implications are not yet known. Therefore, to better comprehend the structure-function significance of this dendritic pathology in epilepsy, it is necessary to identify the common spino-dendritic disturbances present in both human and experimental models. Here, we describe the dendritic and spine structural profiles found across human refractory epilepsy as well as in animal models of developmental, acquired, and genetic epilepsies. [ABSTRACT FROM AUTHOR]

We have studied the nonlinear interaction between two different eigen modes in suspended carbon nanotube resonators. It was found that the mode coupling in suspended carbon nanotubes was dominated by single electron-tunneling process. For suspended carbon nanotube resonator at low temperatures using quantum dot embedded in the nanotube as detector, the interaction was found between two different eigen modes. For nanotube resonators in the coulomb blockade regime the nonlinear modal interaction was dominated by single electron tunneling as opposed to displacement induced tension. A strongly enhanced mode coupling was observed in the coulomb blockade regime which was of the order of magnitude larger than in conventional micro resonators. The obtained results found in good agreement with previously obtained results. [ABSTRACT FROM AUTHOR]

Selective Neuronal Knockout of STAT3 Function Inhibits Epilepsy Progression, Improves Cognition, and Restores Dysregulated Gene Networks in a Temporal Lobe Epilepsy Model Tipton AE, Del Angel YC, Hixson K, Carlsen J, Strode D, Busquet N, Mesches MH, Gonzalez MI, Napoli E, Russek SJ, Brooks-Kayal AR. Ann Neurol. 2023 Mar 19. doi:10.1002/ana.26644 Objective: Temporal lobe epilepsy (TLE) is a progressive disorder mediated by pathological changes in molecular cascades and hippocampal neural circuit remodeling that results in spontaneous seizures and cognitive dysfunction. Targeting these cascades may provide disease-modifying treatments for TLE patients. Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) inhibitors have emerged as potential disease-modifying therapies; a more detailed understanding of JAK/STAT participation in epileptogenic responses is required, however, to increase the therapeutic efficacy and reduce adverse effects associated with global inhibition. Methods: We developed a mouse line in which tamoxifen treatment conditionally abolishes STAT3 signaling from forebrain excitatory neurons (nSTAT3KO). Seizure frequency (continuous in vivo electroencephalography) and memory (contextual fear conditioning and motor learning) were analyzed in wild-type and nSTAT3KO mice after intrahippocampal kainate (IHKA) injection as a model of TLE. Hippocampal RNA was obtained 24 h after IHKA and subjected to deep sequencing. Results: Selective STAT3 knock-out in excitatory neurons reduced seizure progression and hippocampal memory deficits without reducing the extent of cell death or mossy fiber sprouting induced by IHKA injection. Gene expression was rescued in major networks associated with response to brain injury, neuronal plasticity, and learning and memory. We also provide the first evidence that neuronal STAT3 may directly influence brain inflammation. Interpretation: Inhibiting neuronal STAT3 signaling improved outcomes in an animal model of TLE, prevented progression of seizures and cognitive co-morbidities while rescuing pathogenic changes in gene expression of major networks associated with epileptogenesis. Specifically targeting neuronal STAT3 may be an effective disease-modifying strategy for TLE. [ABSTRACT FROM AUTHOR]

HLA‐C*17:78 differs from HLA‐C*17:03:01:03 by one nucleotide change C>T in exon 3 (GCG>GTG). [ABSTRACT FROM AUTHOR]

HLA‐A*33:33:02 differs from HLA‐A*33:33:01 by one synonymous nucleotide change C>T in exon 3 (TCC>TCT). [ABSTRACT FROM AUTHOR]

This research study deals with the development of copper nanoparticles (CN) and nano-hydroxyapatite (nHAP) infused chitosan (C) and gelatin (G) based nanocomposite scaffolds for bone tissue engineering applications. Human-origin osteoblast cells (MG-63) were seeded over the scaffolds to investigate the novel biomimetic extracellular matrix system. The scanning electron microscopy (SEM) showed an average pore size between 100–146 µm for all the C-G-nHAP-CN based scaffolds. The in-vitro degradation study showed 74–83% degradation for CN-based scaffolds. For 0.03% CN based scaffold degradation rate (84%) was very close to the control scaffold. Swelling ratio was highest for the chitosan scaffold and it was in the range between 5.25–5.93 mg/mL for other scaffolds. Compressive moduli were highest for 0.03% CN scaffold (3.32 MPa) which was relatively very high in comparison to C-G-nHAP scaffold with 2.4 MPa strength in a wet state. Stress-strain graphs also show the maximum displacement by 0.03% CN scaffold. The functional and structural analysis for the scaffolds showed the presence of nHAP in the scaffold and CN peaks within the composite structure. Differential scanning colorimetry testing showed reduced crystallinity in CN-based scaffolds with a melting temperature of 320°C. Their 2D cell behaviour in the Electrical Cell Impedance System (ECIS) study showed maximum cell spreading and growth in 0.02% CN-based scaffold. The cell-seeded composite was tested for 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT), 4,6-diamidino-2-phenylindole (DAPI), and acridine orange and propidium iodide (AOPI) assay for testing its cytocompatibility for MG-63 cell line. Cell proliferation and cell spreading was observed by SEM in all the CN-based scaffolds. Alkaline phosphatase (ALP) activity was highest in 0.03% CN scaffold with 2.0 optical density (OD) value. Alizarin Red Stain (ARS) staining was performed to support this study. It can be statistically depicted that nHAP and 0.03% CN-based scaffold could be potential biomaterial for minor to severe bone-related tissue regeneration applications. [ABSTRACT FROM AUTHOR]

β-secretase 1, one of the most important proteins, is an aspartate protease. This membrane-associated protein is used for treating Alzheimer's disease (AD). Several inhibitors have been pursued against β-secretase 1, but they still have not resulted effectively. Virtual screening based on pharmacophores has been shown to be useful for lead optimization and hit identification in the preliminary phase of developing a new drug. Here, we screen the commercially available databases to find the hits against β-secretase 1 for drug discovery against AD. Virtual screening for 200,000 compounds was done using the database from the Vitas-M Laboratory. The phase screen score was utilized to assess the screened hits. Molecular docking was performed on compounds with phase scores >1.9. According to the study, the 66H ligand of the crystal structure has the maximum performance against β-secretase 1. The redocking of the co-crystal ligand showed that the docked ligand was seamlessly united with the crystal structure. The reference complex had three hydrogen bonds with Asp93, Asp289, and Gly291; one van der Waals interaction with Gly74; and three hydrophobic interactions. After equilibration, the RMSD of the reference compound sustained a value of ~1.5 A until 30 ns and then boosted to 2.5 A. On comparison, the RMSD of the S1 complex steadily increased to ~2.5 A at 15 ns, displayed slight aberrations at approximately ~2.5-3 A until 80 ns, and then achieved steadiness toward the end of the simulation. The arrangements of proteins stayed condensed during the mockup when bonded to these complexes as stable Rg values showed. Furthermore, the MM/GBSA technique was employed to analyze both compounds' total binding free energies ^Gtotal). Our research study provides a new understanding of using 66H as anti-βsecretase 1 for drug development against AD. [ABSTRACT FROM AUTHOR]

Epilepsy is a chronic neurological disorder which affects 65 million worldwide population and characterized by recurrent seizure in epileptic patients. Recently, we reported a novel piperonylpiperazine derivative, BPPU “1-[4-(4-benzo [1,3]dioxol-5-ylmethyl-piperazin-1-yl)- phenyl]-3-phenyl-urea’’ as a potent anticonvulsant agent. BPPU has shown excellent anticonvulsant activity in various in-vivo seizure models along with good anti-depressant activity. In this report, we have deeply examined the anti-epileptogenic potential of BPPU in pentylenetetrazole (PTZ) induced kindling model and BPPU effectively reduced seizure episodes in kindled animals upto 35 days. Further, neuroprotective potential of BPPU against PTZ induced neurodegeneration has also been evaluated in hippocampus as well as cortex region by histopathological and immunohistochemical studies. Epileptic patients generally suffer from a range of cognitive impairments. Therefore, the cognition enhancing effect of BPPU was also measured by using well known social recognition test, novel object recognition test, light/dark test and open field test in kindled rat model as well as scopolamine induced memory deficit mice model. Results indicated that BPPU successfully improved cognition deficits in both models. Thus, BPPU appeared as a potent anti-epileptic agent which has also capability to improve cognition decline associated with epilepsy. [ABSTRACT FROM AUTHOR]

We report the design, synthesis and pharmacological assessment of novel benzenesulfonamide derivatives acting as effective carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. All the synthesized compounds were screened for their CA inhibitory action against four isoforms of human origin (h), i.e. hCA I, hCA II, hCA VII and hCA IX. In-vitro carbonic anhydrase inhibition studies have shown that first series, 4-(2-(4-(4-substitutedpiperazin-1-yl)benzylidene)hydrazinyl)benzenesulfonamides ( 4a- 4i ) bestowed low nanomolar range to medium nanomolar range inhibitors against hCA II and hCA VII, effectively involved in epileptogenesis. Furthermore, compounds belonging to the second series, 4-(2-(4-(4-substitutedpiperazin-yl)benzylidene)hydrazinecarbonyl)benzenesulfonamides ( 8a-8k ) showed effective inhibition against hCA VII, being less effective against other hCA isoforms. Inspiring with obtained CA inhibition results, we have chosen some of the potent hCA II and hCA VII inhibitors ( 4g, 4i and 8d ) to test their anti-convulsant efficacy in MES and sc-PTZ seizure tests in Swiss Albino male mice. In result, these compounds significantly attenuated both electrical (MES) as well as chemical (sc-PTZ) induced seizures. Next, in advance anticonvulsant tests, compound 8d displayed long duration of action in time course study and successfully attenuated MES induced seizure in mice up to 6 h after drug administration without showing neurotoxicity in rotarod test. Moreover, this compound was also found to be orally active and effectively abolished generalized tonic-clonic seizures in male Wistar rats upon oral administration, being non-toxic in sub acute toxicity studies. [ABSTRACT FROM AUTHOR]

We use large-scale molecular dynamics simulations to study aging of the velocity autocorrelation function of a force-free granular gas consisting of viscoelastic particles. We study the velocity autocorrelation function for a simplified model where the coefficient of restitution is constant for all collisions, but depends on current temperature of granular gas, it is called quasi-constant coefficient of restitution εeff. From our simulation results, it is observed that A(τw, τ) depends independently on both τ and τw. Initially, A(τw, τ) decays exponentially but later as τw increases, A(τw, τ) decays slowly due to emergence of correlations in velocity field. The explicit dependence of A(τw, τ) on τw implies that the system exhibits aging property. [ABSTRACT FROM AUTHOR]

A novel series of methylsulfonyl phenyl derivatives has been designed and synthesized to evaluate their COX-2 inhibitory activity along with anti-convulsant potential. In-vitro evaluation revealed that two compounds MTL-1 and MTL-2 appeared as most potent and selective COX-2 inhibitors in the entire series. Anti-convulsant activity of both potent COX-2 inhibitors was assessed in sc-PTZ induced seizure test and MTL-1 excellently protected animals against PTZ induced seizure at the dose of 30 mg/kg. MTL-1 also indicates long duration of action in time course study and displayed significant seizure protection up to 6 h of drug administration. Further, the anti-epileptogenic effect of MTL-1 has been examined in PTZ induced chronic model of epilepsy. The results indicated that MTL-1 had a significant anti-epileptogenic effect in PTZ kindled rats as compared to Etoricoxib (ETX) and PTZ alone treated group. Additionally, MTL-1 successfully improved cognition deficit in PTZ kindled rats, which was confirmed by social recognition, novel object recognition and light-dark chamber tests. Moreover, molecular docking and molecular simulation (MD simulation) studies were also performed to elucidate the interaction of MTL-1 with the active site of COX-2 and results showed that MTL-1 suitably binds within active site of COX-2. To investigate the safety profile of MTL-1, a sub-acute toxicity study was also performed and MTL-1 emerged as a new non-toxic chemical entity. Thus, the present investigation discovered a potent and safe COX-2 inhibitor, which is endowed with an effective anti-epileptic action. [ABSTRACT FROM AUTHOR]

Two series of novel benzenesulfonamide derivatives were synthesized and evaluated for their human carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity against four isoforms, hCA I, hCA II, hCA VII, and hCA IX. It was found that compounds of both series showed low to medium nanomolar inhibitory potential against all isoforms. Some of these derivatives displayed selective inhibition against the epileptogenesis related isoforms hCA II and VII, within the nanomolar range. These potent hCA II and VII inhibitors were evaluated as anticonvulsant agents against MES and sc-PTZ induced convulsions. These sulfonamides effectively abolished induced seizures in both models. Furthermore, time dependent seizure protection capability of the most potent compound was also evaluated. A long duration of action was displayed, with efficacy up to 6 h after drug administration. The compound appeared as an orally active anticonvulsant agent without showing neurotoxicity in a rotarod test, a nontoxic chemical profile being observed in subacute toxicity study. [ABSTRACT FROM AUTHOR]

As a full-fidelity simulation of human cells, tissues, organs, and even systems at the microscopic scale, Organ-on-a-Chip (OOC) has significant ethical advantages and development potential compared to animal experiments. The need for the design of new drug high-throughput screening platforms and the mechanistic study of human tissues/organs under pathological conditions, the evolving advances in 3D cell biology and engineering, etc., have promoted the updating of technologies in this field, such as the iteration of chip materials and 3D printing, which in turn facilitate the connection of complex multi-organs-on-chips for simulation and the further development of technology-composite new drug high-throughput screening platforms. As the most critical part of organ-on-a-chip design and practical application, verifying the success of organ model modeling, i.e., evaluating various biochemical and physical parameters in OOC devices, is crucial. Therefore, this paper provides a logical and comprehensive review and discussion of the advances in organ-on-a-chip detection and evaluation technologies from a broad perspective, covering the directions of tissue engineering scaffolds, microenvironment, single/multi-organ function, and stimulus-based evaluation, and provides a more comprehensive review of the progress in the significant organ-on-a-chip research areas in the physiological state. [ABSTRACT FROM AUTHOR]

Ultrasound has been widely investigated for food processing applications. To date studies have been mainly carried out using contact-type ultrasound systems. Recently it has been demonstrated that ultrasonic waves propagated via gases including air using non-contact ultrasound devices may also be employed to enhance various food processes with minimal impact on food quality. Airborne acoustic ultrasound has been shown to be suitable for various food and non-food applications including drying, defoaming and decontamination. This novel technology is currently being actively investigated to increase the limited knowledge on the specific mechanisms involved in airborne ultrasound assisted operations. Some of the main challenges that have hampered efficient energy transmission through air have been addressed by the development of new types of transducers. The objective of this review is to outline various potential applications of airborne ultrasound including drying, defoaming and inactivation of microorganisms. Equipment types, mechanisms and challenges encountered are also discussed. [ABSTRACT FROM AUTHOR]

We report two series of novel benzenesulfonamide derivatives acting as effective carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The synthesized compounds were tested against human (h) isoforms hCA I, hCA II, hCA VII, and hCA XII. The first series of compounds, 4-(3-(2-(4-substitued piperazin-1-yl)ethyl)ureido)benzenesulfonamides, showed low nanomolar inhibitory action against hCA II, being less effective against the other isoforms. The second series, 2-(4-substitued piperazin-1-yl)-N-(4-sulfamoylphenyl)acetamide derivatives, showed low nanomolar inhibitory activity against hCA II and hCA VII, isoforms involved in epileptogenesis. Some of these derivatives were evaluated for their anticonvulsant activity and displayed effective seizure protection against MES and scPTZ induced seizures in Swiss Albino mice. These sulfonamides were also found effective upon oral administration to Wistar rats and inhibited MES induced seizure episodes in this animal model of the disease. Some of the new compounds showed a long duration of action in the performed time course anticonvulsant studies, being nontoxic in subacute toxicity studies. [ABSTRACT FROM AUTHOR]

A novel series of donepezil based multi-functional agents “( E )-5,6-dimethoxy-2-(4-(4-substituted piperazin-1-yl)benzylidene)-2,3-dihydro-1 H -inden-1-ones” have been designed and synthesized as potential anti-Alzheimer's agents. In-vitro studies revealed that these compounds demonstrated moderate to good AChE and Aβ aggregation inhibitory activity. These derivatives are also endowed with admirable antioxidant activity. Among the entire series compounds IP-9 , IP-13 and IP-15 appeared as most active multi-functional agents and displayed marked AChE inhibitory, Aβ disaggregation and antioxidant activity. Studies indicate that IP-13 and IP-15 showed better AChE inhibitory activity than the standard drug donepezil and IP-9 , IP-13 as well as IP-15 exhibited better Aβ aggregation inhibitory activity than curcumin. These compounds ( IP-9 , IP-13 and IP-15 ) successfully diminished H 2 O 2 induced oxidative stress in SH-SY5Y cells and displayed excellent neuroprotective activity against H 2 O 2 as well as Aβ induced toxicity in SH-SY5Y cells in a concentration dependent manner. Moreover, these derivatives did not exert any significant toxicity in neuronal SH-SY5Y cells in cytotoxicity assay. To elucidate the plausible binding mode of the compounds IP-9 , IP-13 and IP-15 , molecular docking studies and molecular dynamics (MD) simulation studies were also performed and the results indicate their significant interactions with the active sites of AChE as well as Aβ 1-42 peptide. Thus, the present study evidently showed that IP-9 , IP-13 and IP-15 are potent multi-functional agents against Alzheimer's disease and might serve as promising lead candidates for anti-Alzheimer drug development. [ABSTRACT FROM AUTHOR]

New and emerging robust technologies can play an important role in ensuring a more resilient meat value chain and satisfying consumer demands and needs. This paper outlines various novel thermal and non-thermal technologies which have shown potential for meat processing applications. A number of process analytical techniques which have shown potential for rapid, real-time assessment of meat quality are also discussed. The commercial uptake and consumer acceptance of novel technologies in meat processing have been subjects of great interest over the past decade. Consumer focus group studies have shown that consumer expectations and liking for novel technologies, applicable to meat processing applications, vary significantly. This overview also highlights the necessity for meat processors to address consumer risk–benefit perceptions, knowledge and trust in order to be commercially successful in the application of novel technologies within the meat sector. [ABSTRACT FROM AUTHOR]

A series ofN-(5-methyl-isoxazol-3-yl/1,3,4-thiadiazol-2-yl)-4-(3-substitutedphenylureido) benzenesulfonamide derivatives has been designed, synthesized and screened for theirin vitrohuman carbonic anhydrase (hCA; EC 4.2.1.1) inhibition potential. These newly synthesized sulfonamide compounds were assessed against isoforms hCA I, II, VII and XII, with acetazolamide (AAZ) as a reference compound. The majority of these compounds were found quite weak inhibitor against all tested isoforms. Compound15showed a modest inhibition potency against hCA I (Ki = 73.7 μM) and hCA VII (Ki = 85.8 μM). Compounds19and25exhibited hCA II inhibition with Kivalues of 96.0 μM and 87.8 μM, respectively. The results of the present study suggest that, although the synthesized derivatives have weak inhibitory potential towards all investigated isoforms, some of them may serve as lead molecules for the further development of selective inhibitors incorporating secondary sulfonamide functionalities, a class of inhibitors for which the inhibition mechanism is poorly understood. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the efficacy of high intensity ultrasound on the fermentation profile of Lactobacillus sakei in a meat model system. Ultrasound power level (0–68.5 W) and sonication time (0–9 min) at 20 °C were assessed against the growth of L. sakei using a Microplate reader over a period of 24 h. The L. sakei growth data showed a good fit with the Gompertz model ( R 2 > 0.90; SE < 0.042). Second order polynomial models demonstrated the effect of ultrasonic power and sonication time on the specific growth rate (SGR, μ , h −1 ) and lag phase ( λ , h). A higher SGR and a shorter lag phase were observed at low power (2.99 W for 5 min) compared to control. Conversely, a decrease ( p < 0.05) in SGR with an increase in lag phase was observed with an increase in ultrasonic power level. Cell-free extracts obtained after 24 h fermentation of ultrasound treated samples showed antimicrobial activity against Staphylococcus aureus , Listeria monocytogenes , Escherichia coli and Salmonella typhimurium at lower concentrations compared to control. No significant difference ( p < 0.05) among treatments was observed for lactic acid content after a 24 h fermentation period. This study showed that both stimulation and retardation of L. sakei is possible, depending on the ultrasonic power and sonication time employed. Hence, fermentation process involving probiotics to develop functional food products can be tailored by selection of ultrasound processing parameters. [ABSTRACT FROM AUTHOR]

The objective of this study is to show the effect of complex probiotics (Lactobacillus acidophilus, 1.0×107 CFU/g; Saccharomyces cerevisae, 4.3×106 CFU/g; Bacillus subtilis 2.0×106 CFU/g) on growth rate, dry matter intake (DMI) and feed conversion ratio (FCR) of growing pigs. This study was conducted on 36 growing pigs which were randomly divided and allotted to 3 treatment groups. Dietary treatments included group-1: basal diet, group-2: basal diet+0.1% complex probiotics and group-3: basal diet+0.2% complex probiotics. During 91 days of experimental period it was observed that maximum growth and better FCR were recorded in group-3 i.e. 68.17±0.56 kg and 1.51±0.45 kg/day/pig respectively. Along with that, better FCR was also recorded in group-3 (3.02±0.03:1). On the basis of present finding it is suggested that for better growth performance in growing pigs, 0.2% of complex probiotics could be used. [ABSTRACT FROM AUTHOR]

Carbonic anhydrase IX (CAIX) is a promising target in cancer therapy especially in the case of hypoxia-induced tumors. The selective inhibition of CA isozymes is a challenging task in drug design and discovery process. Here, we performed fluorescence-binding studies and inhibition assay combined with molecular docking and molecular dynamics (MD) simulation analyses to determine the binding affinity of two synthesized triazolo-pyrimidine urea derived (TPUI and TPUII) compounds with CAIX and CAII. Fluorescence binding results are showing that molecule TPUI has an excellent binding-affinity for CAIX ( k D = 0.048 μM). The TPUII also exhibits an appreciable binding affinity ( k D = 7.52 μM) for CAIX. TPUI selectively inhibits CAIX as compared to TPUII in the 4-NPA assay. Docking studies show that TPUI is spatially well-fitted in the active site cavity of CAIX, and is involve in H-bond interactions with His94, His96, His119, Thr199 and Thr200. MD simulation studies revealed that TPUI efficiently binds to CAIX and essential active site residual interaction is consistent during the entire simulation of 40 ns. These studies suggest that TPUI appeared as novel class of CAIX inhibitor, and may be used as a lead molecule for the development of potent and selective CAIX inhibitor for the hypoxia-induced cancer therapy. [ABSTRACT FROM AUTHOR]

In an attempt to reduce the high intake of dietary salt, the processed meat industry is continuously looking for alternative solutions for salt replacement. The objective of this study was to investigate the effect of employing sonication on the diffusion of sodium salt (NaCl) and a salt replacer (SR) into pork meat. Ultrasound-assisted brining experiments were carried out using 5% NaCl or SR at power levels of 9.0 and 54.9 W cm -2 for 120 min. Samples were assessed for cooking loss, water mobility, deformation, while thermal behaviour was analysed using differential scanning calorimetry (DSC). Experimental data obtained were used to estimate the mass transfer coefficient of the brining process. The mass transfer equation was solved using the Runge-Kutta method. Results showed that the ultrasonic treatment had a low influence on the mass transfer of salt into pork samples. Only at high ultrasonic power was the mass transfer coefficient higher than the static brining. This study has improved our understanding of the effect of sonication on diffusion of NaCl and SR in pork meat and will enable a more systemic approach to future healthy meat product development. [ABSTRACT FROM AUTHOR]

• Nitrogen heterocycles as new anti-Alzheimer's (AD) agents highlighting past molecular designs. • The development of safe, low-cost and highly active therapeutic agents incorporating nitrogen-containing heterocycles against AD is an important research topic. • Success stories of nitrogen-containing heterocyclic compounds in AD drug discovery. • We propose strategies for designing and developing novel potent anti-AD small molecules that can be used as treatments for AD. Alzheimer's disease (AD) is a detrimental neurodegenerative disease that progressively worsens with time. Clinical options are limited and only provide symptomatic relief to AD patients. The search for effective anti-AD compounds is ongoing with a few already in Phase III clinical trials, yet to be approved. Heterocycles containing nitrogen are important to biological processes owing to their abundance in nature, their function as subunits of biological molecules and/or macromolecular structures, and their biological activities. The present review discusses previously used strategies, SAR, relevant in vitro and in vivo studies, and success stories of nitrogen-containing heterocyclic compounds in AD drug discovery. Also, we propose strategies for designing and developing novel potent anti-AD small molecules that can be used as treatments for AD. [ABSTRACT FROM AUTHOR]

While effects of different steroids on the gene expression and regulation are well established, it is proven that steroids can also exert rapid non-genomic actions in several tissues and cells. In most cases, these non-genomic rapid effects of steroids are actually due to intracellular mobilization of Ca 2+ - and other ions suggesting that Ca 2+ channels are involved in such effects. Transient Receptor Potential (TRP) ion channels or TRPs are the largest group of non-selective and polymodal ion channels which cause Ca 2+ -influx in response to different physical and chemical stimuli. While non-genomic actions of different steroids on different ion channels have been established to some extent, involvement of TRPs in such functions is largely unexplored. In this review, we critically analyze the literature and summarize how different steroids as well as their metabolic precursors and derivatives can exert non-genomic effects by acting on different TRPs qualitatively and/or quantitatively. Such effects have physiological repercussion on systems such as in sperm cells, immune cells, bone cells, neuronal cells and many others. Different TRPs are also endogenously expressed in diverse steroid-producing tissues and thus may have importance in steroid synthesis as well, a process which is tightly controlled by the intracellular Ca 2+ concentrations. Tissue and cell-specific expression of TRP channels are also regulated by different steroids. Understanding of the crosstalk between TRP channels and different steroids may have strong significance in physiological, endocrinological and pharmacological context and in future these compounds can also be used as potential biomedicine. [ABSTRACT FROM AUTHOR]

Consumer demands for high quality, safe, nutritious and convenient meat products has provided important insights into the development of a host of processed meat products including fermented meats. It offers unique perspectives for the application of novel functional microbial cultures and promising emerging technologies in the manufacture of fermented meats. Novel non-thermal and thermal technologies, including high pressure processing, pulsed-UV light, irradiation can be utilized for processing and decontamination of meat products to improve process efficiency, product safety and product quality and composition. Application of novel technologies and culture in the development of functional fermented meat products are discussed. [ABSTRACT FROM AUTHOR]

Thiazole is a valuable scaffold in the field of medicinal chemistry and has accounted to display a variety of biological activities. Thiazole and its derivatives have attracted continuing interest to design various novel CNS active agents. In the past few decades, thiazoles have been widely used to develop a variety of therapeutic agents against numerous CNS targets. Thiazole containing drug molecules are currently being used in treatment of various CNS disorders and a number of thiazole derivatives are also presently in clinical trials. A lot of research has been carried out on thiazole and their analogues, which has proved their efficacy to overcome several CNS disorders in rodent as well as primate models. The aim of present review is to highlights diverse CNS activities displayed by thiazole and their derivatives. SAR of this nucleus has also been well discussed. This review covers the recent updates present in literature and will surely provide a greater insight for the designing and development of potent thiazole based CNS active agents in future. [ABSTRACT FROM AUTHOR]

A series of alkyl/aryl/heteroaryl piperazine derivatives ( 37 – 54 ) were designed and synthesized as potential anticonvulsant agents. The target compounds are endowed with satisfactory physicochemical as well as pharmacokinetic properties. The synthesized compounds were screened for their in vivo anticonvulsant activity in maximal electroshock (MES) and subcutaneous pentylenetetrazole (sc-PTZ) seizure tests. Further, neurotoxicity evaluation was carried out using rotarod method. Structure activity relationship studies showed that compounds possessing aromatic group at the piperazine ring displayed potent anticonvulsant activity. Majority of the compounds showed anti-MES activity whereas compounds 39 , 41 , 42 , 43 , 44 , 50 , 52 , and 53 exhibited anticonvulsant activity in both seizure tests. All the compounds except 42 , 46 , 47 , and 50 did not show neurotoxicity. The most active derivative, 45 demonstrated potent anticonvulsant activity in MES test at the dose of 30 mg/kg (0.5 h) and 100 mg/kg (4 h) and also delivered excellent protection in sc-PTZ test (100 mg/kg) at both time intervals. Therefore, compound 45 was further assessed in PTZ-kindling model of epilepsy which is widely used model for studying epileptogenesis. This compound was effective in delaying onset of PTZ-evoked seizures at the dose of 5 mg/kg in kindled animals and significantly reduced oxidative stress better than standard drug phenobarbital (PB). In result, compound 45 emerged as a most potent and safer anticonvulsant lead molecule. [ABSTRACT FROM AUTHOR]

TRPV4 is involved in several physiological and sensory functions as well as with several diseases and genetic disorders, though the molecular mechanisms for these are unclear. In this work we have analyzed molecular evolution and structure–function relationship of TRPV4 using sequences from different species. TRPV4 has evolved during early vertebrate origin (450 million years). Synteny analysis confirms that TRPV4 has coevolved with two enzymes involved in sterol biosynthesis, namely MVK and GLTP. Cholesterol-recognizing motifs are present within highly conserved TM4–Loop4–TM5 region of TRPV4. TRPV4 is present in lipid raft where it co-localizes with Caveolin1 and Filipin. TM4–Loop4–TM5 region as well as Loop4 alone can physically interact with cholesterol, its precursor mevalonate and derivatives such as stigmasterol and aldosterone. Mobility of TRPV4-GFP depends on membrane cholesterol level. Molecular evolution of TRPV4 shared striking parallelism with the cholesterol bio-synthesis pathways at the genetic, molecular and metabolic levels. We conclude that interaction with sterols and cholesterol-dependent membrane dynamics have influence on TRPV4 function. These results may have importance on TRPV4-medaited cellular functions and pathophysiology. [ABSTRACT FROM AUTHOR]

Healthy skin protects from pathogens, water loss, ultraviolet rays, and also maintains homeostasis conditions along with sensory perceptions in normal circumstances. Skin wound healing mechanism is a multi-phased biodynamic process that ultimately triggers intercellular and intracellular mechanisms. Failure to implement the normal and effective healing process may result in chronic injuries and aberrant scarring. Chronic wounds lead to substantial rising healthcare expenditure, and innovative methods to diagnose and control severe consequences are urgently needed. Skin tissue engineering (STE) has achieved several therapeutic accomplishments during the last few decades, demonstrating tremendous development. The engineered skin substitutes provide instant coverage for extensive wounds and facilitate the prevention of microbial infections and fluid loss; furthermore, they help in fighting inflammation and allow rapid neo-tissue formation. The current review primarily focused on the wound recovery and restoration process and the current conditions of STE with various advancements and complexities associated with different strategies such as cell sources, biopolymers, innovative fabrication techniques, and growth factors delivery systems. [ABSTRACT FROM AUTHOR]

HLA‐B*40:06:01:18 differs from HLA‐B*40:06:01:02 by one nucleotide change in the 5′UTR (T > C). [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptors, progesterone receptors, and human epidermal receptors. This lack of receptors renders TNBC unsuitable for targeted-based treatment, making it the most fatal and aggressive subtype of breast cancer. TNBC has a greater relapse rate, worse prognosis, and increased metastasis rate compared to non-TNBC because of its tendency to resist apoptosis, a programmed cell death triggered by most chemotherapeutic drugs, producing anticancer efficacy. This work describes two new drugs, TPH104c, and TPH104m, that induce a non-apoptotic form of cell death in TNBC. The incubation of TNBC cells with TPH104c or TPH104m causes cellular expansion and rupture without producing apoptotic characteristics, such as nuclear fragmentation, apoptotic blebbing, or caspase activation. TPH104c and TPH104m decreased the mitochondrial protein, division regulator, and dynamin-related protein 1 (DRP1). The level of DRP1 in TNBC cells affects the magnitude of cytotoxicity produced by TPH104c and TPH104m. Apoptosis induction with taxanes or anthracyclines is the primary therapy for TNBC. Cancer cells can develop resistance to anticancer drugs, causing them to recur and metastasize. Therefore, non-apoptotic cell death inducers could be a potential treatment to circumvent apoptotic drug resistance. In this study, we discovered two novel compounds, TPH104c and TPH104m, which induced non-apoptotic cell death in TNBC cells. These lead compounds were 15- to 30-fold more selective in TNBC cell lines and significantly decreased the proliferation of TNBC cells compared to that of normal mammary epithelial cell lines. TPH104c and TPH104m induced a unique type of non-apoptotic cell death, characterized by the absence of cellular shrinkage and the absence of nuclear fragmentation and apoptotic blebs. Although TPH104c and TPH104m induced the loss of the mitochondrial membrane potential, TPH104c- and TPH104m-induced cell death did not increase the levels of cytochrome c and intracellular reactive oxygen species (ROS) and caspase activation, and cell death was not rescued by incubating cells with the pan-caspase inhibitor, carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-FMK). Furthermore, TPH104c and TPH104m significantly downregulated the expression of the mitochondrial fission protein, DRP1, and their levels determined their cytotoxic efficacy. Overall, TPH104c and TPH104m induced non-apoptotic cell death, and further determination of their cell death mechanisms will aid in the development of new potent and efficacious anticancer drugs to treat TNBC. [ABSTRACT FROM AUTHOR]

Development of new and effective scaffold continues to be an area of intense research in skin tissue engineering. The objective of this study was to study the effect of copper nanoparticles over physico-chemical properties of the chitosan and gelatin composite scaffolds for skin tissue engineering. The copper-doped scaffolds were prepared using freeze-drying method. Chitosan and gelatin were taken in varied composition with 0.01%, 0.02%, and 0.03% Cu nanoparticles. The physico-chemical properties of the copper nanoparticles and the scaffolds were analyzed using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy. Porosity of the scaffolds was measured by liquid displacement method and hemocompatibility was tested using goat blood. SEM micrographs of the scaffolds displayed the interconnected pores which ranged between 25 and 40 µm. This average pore size was later enhanced to 95 µm after the addition of copper nanoparticles. Cell viability assay was performed to ensure the growth and proliferation of the skin cells over the scaffolds. FTIR, EDS, and XRD analysis of scaffolds confirmed the presence of copper in the chitosan-based scaffolds. Porosity measurement showed the interconnectivity between pores which ranged between 65 and 88% as required for skin tissue engineering application. The degradation study of the scaffolds was done which depicted that, after the addition of copper nanoparticles with 0.03%, degradation rate was decreased. SEM and cytocompatibility assay on all scaffolds showed the cell adhesion and proliferation on the scaffolds which was not affected after addition of copper nanoparticles. Oxidative stress evaluation was done to study the effect of copper nanoparticles on the cells which showed that there was no such production of ROS in the scaffolds. Hence, scaffolds prepared after doping of copper nanoparticles show suitable physico-chemical and biological properties for skin tissue engineering application. [ABSTRACT FROM AUTHOR]

• Strategies to develop multitarget-directed ligands via in silico drug discovery. • The effects of multidirectional drugs are more favorable than those of single-target or combination treatments on drug resistance, pharmacokinetics, pharmacodynamics, safety, and cost effectiveness. • The use of multitarget drugs can increase therapeutic efficacy by targeting multiple signaling pathways and addressing complex diseases with multiple underlying causes and dominant resistance mechanisms. • The drugs can be designed to avoid off-target effects, which can lead to reduced side effects and enhanced efficacy compared to single target agents. To combat multifactorial refractory diseases, such as cancer, cardiovascular, and neurodegenerative diseases, multitarget drugs have become an emerging area of research aimed at 'synthetic lethality' (SL) relationships associated with drug-resistance mechanisms. In this review, we discuss the in silico design of dual and triple-targeted ligands, strategies by which specific 'warhead' groups are incorporated into a parent compound or scaffold with primary inhibitory activity against one target to develop one small molecule that inhibits two or three molecular targets in an effort to increase potency against multifactorial diseases. We also discuss the analytical exploration of structure–activity relationships (SARs), physicochemical properties, polypharmacology, scaffold feature extraction of US Food and Drug Administration (FDA)-approved multikinase inhibitors (MKIs), and updates regarding the clinical status of dual-targeted chemotypes. [ABSTRACT FROM AUTHOR]

Asymmetric transport of cargo across axonal branches is a field of active research. Mechanisms contributing to preferential cargo transport along specific branches in vivo in wild type neurons are poorly understood. We find that anterograde synaptic vesicles preferentially enter the synaptic branch or pause at the branch point in Caenorhabditis elegans Posterior Lateral Mechanosensory neurons. The synaptic vesicle anterograde kinesin motor UNC-104 /KIF1A regulates this vesicle behavior at the branch point. Reduced levels of functional UNC-104 cause vesicles to predominantly pause at the branch point and lose their preference for turning into the synaptic branch. SAM-4 /Myrlysin, which aids in recruitment/activation of UNC-104 on synaptic vesicles, regulates vesicle behavior at the branch point similar to UNC-104. Increasing the levels of UNC-104 increases the preference of vesicles to go straight toward the asynaptic end. This suggests that the neuron optimizes UNC-104 levels on the cargo surface to maximize the fraction of vesicles entering the branch and minimize the fraction going to the asynaptic end. [ABSTRACT FROM AUTHOR]

• Chemotherapy is the only way of treatment for helminthiasis. • Anthelmintic drug resistance has been reported for commercially available anthelmintic drugs. • Benzimidazole derivatives are commercially used as anthelmintic drug. • Structural optimization of benzimidazole nucleus can be produced important anthelmintics. • The broad-spectrum activity of benzimidazole carbamates is attributed to their ability to inhibit tubulin polymerization. Globally, helminthiasis is one of the most prevalent causes of mortality and morbidity and threatens humans and livestock. An effective anthelmintic vaccine is also lacking. As a result, nematode infections are mostly treated with chemotherapy, such as benzimidazoles, but due to drug resistance, their effectiveness is limited.This review focuses on previously synthesized benzimidazole derivatives and their structure-activity relationships related to effectiveness in treating helminthiasis. For example, structural modifications have been introduced in developing benzimidazole-based drugs for helminthiasis chemotherapy at positions 2, 5, or 6, whereas positions 4 and 7 should not be altered. For benzimidazole to be effective as an anthelmintic, it must have a free hydrogen atom at its 1-position.Using the results of this review as a guide, we have proposed designs that will allow the development of more effective and less toxic drugs for helminthiasis chemotherapy. Despite this, a better understanding of parasite biochemistry and host-parasite interactions is necessary to develop innovative lead molecules with greater efficacy. [Display omitted] [ABSTRACT FROM AUTHOR]

Purpose: There is growing interest in seeking pharmacological activation of neurolysin (Nln) for stroke treatment. Discovery of central nervous system drugs remains challenging due to the protection of the blood-brain barrier (BBB). The previously reported peptidomimetic Nln activators display unsatisfactory BBB penetration. Herein, we investigate the next generation of non-peptidomimetic Nln activators with high BBB permeability. Methods: A BBB-mimicking model was used to evaluate their in vitro BBB permeability. Protein binding, metabolic stability, and efflux assays were performed to determine their unbound fraction, half-lives in plasma and brains, and dependence of BBB transporter P-glycoprotein (P-gp). The in vivo pharmacokinetic profiles were elucidated in healthy and stroke mice. Results: Compounds KS52 and KS73 out of this generation exhibit improved peptidase activity and BBB permeability compared to the endogenous activator and previous peptidomimetic activators. They show reasonable plasma and brain protein binding, improved metabolic stability, and independence of P-gp-mediated efflux. In healthy animals, they rapidly distribute into brains and reach peak levels of 18.69% and 12.10% injected dose (ID)/ml at 10 min. After 4 h, their total brain concentrations remain 7.78 and 12.34 times higher than their A50(minimal concentration required for enhancing 50% peptidase activity). Moreover, the ipsilateral hemispheres of stroke animals show comparable uptake to the corresponding contralateral hemispheres and healthy brains. Conclusions: This study provides essential details about the pharmacokinetic properties of a new generation of potent non-peptidomimetic Nln activators with high BBB permeability and warrants the future development of these agents as potential neuroprotective pharmaceutics for stroke treatment. [ABSTRACT FROM AUTHOR]

Purpose: Value driven outcome (VDO) initiative is a value-based, patient-focused tool which utilizes a clinical outcome-based approach to optimize value of care based on clinically relevant quality indicators and costs required to achieve the care. In this study, we evaluate the impact of a VDO initiative on groin hernia repair, a commonly performed elective surgery in our hospital. Methods: A VDO initiative was implemented in 2019 to encourage elective inguinal hernia repair to be performed at a day surgery setting. A comparison of outcomes was made between hernia surgeries performed in 2019 with those in 2020 and 2021. Pre-defined criteria were used to select patients that can be operated at a day surgery setting. Patients' expectations were addressed preoperatively about day surgery procedure and postoperative recovery. Day surgery bundles were used to standardize pre- and post-surgery protocols. Pain control was optimized using a specialized local anesthesia regime. Results: A total of 263 laparoscopic hernia surgeries were performed between May 2019 and December 2021. After implementation of VDO initiative, the percentage of patients discharged within 24 h increased from 78% in year 2019 to 97% in year 2020 and 99% in year 2021. Conversion rate for day surgery to short stay decreased from 9% in year 2019 to 1% in year 2020 and 2% in year 2021. In 2019 to 2021, there were no 30-day readmission, no hernia recurrence in 90 days, no conversion to open surgery. Conclusion: VDO initiative is a promising tool to deliver better value-based care for patients undergoing endo-laparoscopic inguinal hernia repair. [ABSTRACT FROM AUTHOR]

Review: 175 refs. [ABSTRACT FROM AUTHOR]

[Display omitted] In organic chemistry, the use of deuterium exchange as a tool to study the mechanism of chemical reaction has been well explored. Since two decades, the research focus on deuterated bioactive molecules has been gaining attention for investigating the therapeutic potential of deuterium replacement in a chemical structure. Recently, Food Drug Administration (FDA) approved the first deuterium-labeled drug "deutetrabenazine", and notified the deuterated drugs as new chemical entities (NCEs). Henceforth, the deuterium substitution driven structure activity relationship, preclinical pharmacokinetics, and toxicity studies were much initiated. Deuteration of a bioactive molecule often results in improved therapeutic efficacy due to the altered pharmacokinetic profile. This review provides a conceptual framework on the importance of deuterium atom in chemical structure of a drug, and its biological value in improved physiochemical properties, pharmacokinetics, biological target interaction, diagnosis, and toxicity. In addition, this review concisely updated the recent deuteration methods, chemical stability, challenges in drug development, deuterium-based imaging in diagnosis, and selected synthetic scheme of deuterated molecules. [ABSTRACT FROM AUTHOR]

Inhibition of specific carbonic anhydrase (CA) enzymes is a validated strategy for the development of agents to target cancer. The CA isoforms IX and XII are overexpressed in various human solid tumors wherein they play a critical role in regulating extracellular tumor acidification, proliferation, and progression. A series of novel sulfonamides based on the coumarin scaffold were designed, synthesized and characterized as potent and selective CA inhibitors. Selected compounds show significant activity and selectivity over CA I and CA II to target the tumor‐associated CA IX and CA XII with high inhibition activity at the single digit nanomolar level. Twelve compounds were identified to be more potent compared with acetazolamide (AAZ) control to inhibit CA IX while one was also more potent than AAZ to inhibit CA XII. Compound 18f (Ki's = 955 nM, 515 nM, 21 nM and 5 nM for CA's I, II, IX, and XII, respectively) is highlighted as a novel CA IX and XII inhibitor for further development. [ABSTRACT FROM AUTHOR]

A series of novel 2-(4-(4-substituted piperazin-1-yl)benzylidene)-1 H -indene-1,3(2 H )-diones were designed, synthesized and appraised as multifunctional anti-Alzheimer agents. In vitro studies of compounds 27 – 38 showed that these compounds exhibit moderate to excellent AChE, BuChE and Aβ aggregation inhibitory activity. Notably, compounds 34 and 38 appeared as most active multifunctional agents in the entire series and exhibited excellent inhibition against AChE (IC 50 = 0.048 μM: 34 ; 0.036 μM: 38 ), Aβ aggregation (max% inhibition 82.2%, IC 50 = 9.2 μM: 34 ; max% inhibition 80.9%, IC 50 = 10.11 μM: 38 ) and displayed significant antioxidant potential in ORAC-FL assay. Both compounds also successfully diminished H 2 O 2 induced oxidative stress in SH-SY5Y cells. Fascinatingly, compounds 34 and 38 showed admirable neuroprotective effects against H 2 O 2 and Aβ induced toxicity in SH-SY5Y cells. Additionally, both derivatives showed no considerable toxicity in neuronal cell viability assay and represented drug likeness properties in the primarily pharmacokinetics study. All these results together, propelled out that compounds 34 and 38 might serve as promising multi-functional lead candidates for treatment of AD in the future. [ABSTRACT FROM AUTHOR]

Usage of bioreactors in the field of tissue engineering has played a significant role in enabling a controlled and reproducible change in the formation of damaged tissue on being provided with specific factors. Owing to the scarcity seen in providing sufficient donor organs for transplantation there is a huge requirement for large-scale production of artificial organs. This cannot be achieved by static culturing since it does not provide an in-vivo three-dimensional (3D) microenvironment therefore tissue engineering plays a vital role in the development of artificial tissues and organs as per the clinical demands whereas bioreactors have served a major role in providing the artificial microenvironment required by the cells to grow further into a tissue and then into an organ. By providing the specific biochemical cues and mechanoresponsive stimuli the bioreactors turn to be very effective in generating transplantable organs. Apart from performing studies in a controlled manner aimed at understanding biological and physicochemical effects, bioreactors also ensure the safe and reproducible production of tissue-engineered constructs to achieve cost-effective large-scale production. The design criteria for bioreactors to be used in tissue engineering include optimal aspect ratio, proper aeration for the cells to proliferate, and agitation with reduced shear stress. The current review summarizes important aspects like Height/Diameter ratio or aspect ratio, shear stress, mechanical stress, aeration, agitation, oxygenation, etc. related to the design of tissue bioreactors, different types of bioreactors that are in use to date, and the reported pieces of literature to yield an overview on the existing concepts. It mainly focuses on the generation of 3D tissue constructs in various reactor systems specially designed for their culture and development along with their applications. [ABSTRACT FROM AUTHOR]

A novel small molecule based on benzothiazole-piperazine has been identified as an effective multi-target-directed ligand (MTDL) against Alzheimer's disease (AD). Employing a medicinal chemistry approach, combined with molecular docking, MD simulation, and binding free energy estimation, compound 1 emerged as a potent MTDL against AD. Notably, compound 1 demonstrated efficient binding to both AChE and Aβ1–42, involving crucial molecular interactions within their active sites. It displayed a binding free energy (ΔG bind) −18.64± 0.16 and −16.10 ± 0.18 kcal/mol against AChE and Aβ1–42, respectively. In-silico findings were substantiated through rigorous in vitro and in vivo studies. In vitro analysis confirmed compound 1 (IC 50 =0.42 μM) as an effective, mixed-type, and selective AChE inhibitor, binding at both the enzyme's catalytic and peripheral anionic sites. Furthermore, compound 1 demonstrated a remarkable ability to reduce the aggregation propensity of Aβ, as evidenced by Confocal laser scanning microscopy and TEM studies. Remarkably, in vivo studies exhibited the promising therapeutic potential of compound 1. In a scopolamine-induced memory deficit mouse model of AD, compound 1 showed significantly improved spatial memory and cognition. These findings collectively underscore the potential of compound 1 as a promising therapeutic candidate for the treatment of AD. [Display omitted] • A benzothiazole-piperazine-based small molecule has been developed as an effective MTDL against AD. • Compound 1 (IC 50 =0.421 μM) was a potent, mixed-type, and selective AChE inhibitor. • Compounds 1 at 50 μM effectively reduced the aggregation propensity of Aβ by 80.708%. • Compound 1 demonstrated potent neuroprotection in cells induced with H 2 O 2 and OKA neurotoxicity. • Compound 1 showed improved spatial memory and cognition in the scopolamine-induced memory deficit mouse model of AD. [ABSTRACT FROM AUTHOR]

2-(4-Benzhydrylpiperazin-1-yl)-N-(4-sulfamoylphenyl)acetamide is an effective human carbonic anhydrase (hCA) inhibitor designed through the tail approach using the acetamide moiety as linker and the benzhydrylpiperazine group as tail. Here we report the crystal structures of this compound in complex both with the ubiquitous hCA II and the brain-associated hCA VII, showing that in agreement with the previously reported inhibition constants, the inhibitor is stabilized by a higher number of polar and hydrophobic interactions in the active site of hCA VII compared to hCA II. Results point out the conformational flexibility of the linker and the tail length as fundamental features to establish significant differences in the number of favorable enzyme/inhibitor interactions and consequently in the inhibition selectivity against the two hCA isoforms. [ABSTRACT FROM AUTHOR]

Iron-based compounds possess the capability of inducing cell death due to their reactivity with oxidant molecules, but their specificity towards cancer cells and the mechanism of action are hitherto less investigated. A Fe(salen)Cl derivative has been synthesized that remains active in monomer form. The efficacy of this compound as an anti-tumor agent has been investigated in mouse and human leukemia cell lines. Fe(salen)Cl induces cell death specifically in tumor cells and not in primary cells. Mouse and human T-cell leukemia cell lines, EL4 and Jurkat cells are found to be susceptible to Fe(salen)Cl and undergo apoptosis, but normal mouse spleen cells and human peripheral blood mononuclear cells (PBMC) remain largely unaffected by Fe(salen)Cl. Fe(salen)Cl treated tumor cells show significantly higher expression level of cytochrome c that might have triggered the cascade of reactions leading to apoptosis in cancer cells. A significant loss of mitochondrial membrane potential upon Fe(salen)Cl treatment suggests that Fe(salen)Cl induces apoptosis by disrupting mitochondrial membrane potential and homeostasis, leading to cytotoxity. We also established that apoptosis in the Fe(salen)Cl-treated tumor cells is mediated through caspase-dependent pathway. This is the first report demonstrating that Fe(salen)Cl can specifically target the tumor cells, leaving the primary cells least affected, indicating an excellent potential for this compound to emerge as a next-generation anti-tumor drug. [ABSTRACT FROM AUTHOR]

[Display omitted] Modulating peptidase neurolysin (Nln) has been identified as a potential cerebroprotective target for the development of therapeutics for ischemic stroke. Continued structure–activity relationship studies on peptidomimetic small molecule activators of Nln bearing electron-donating and electron- withdrawing functionalized phenyls are explored. Incorporation of fluorine or trifluoromethyl groups produces Nln activators with enhanced A 50 , while methoxy substitution produces derivatives with enhanced A max. Selected activators containing methoxy or trifluoromethyl substitution are selective for Nln over related peptidases and possess increased blood–brain barrier penetrability than initial hits. [ABSTRACT FROM AUTHOR]

A novel series of 4-anilinoquinazoline analogues, DW (1–10), were evaluated for anticancer efficacy in human breast cancer (BT-20) and human colorectal cancer (CRC) cell lines (HCT116, HT29, and SW620). The compound, DW-8, had the highest anticancer efficacy and selectivity in the colorectal cancer cell lines, HCT116, HT29, and SW620, with IC50 values of 8.50 ± 2.53 µM, 5.80 ± 0.92 µM, and 6.15 ± 0.37 µM, respectively, compared to the non-cancerous colon cell line, CRL1459, with an IC50 of 14.05 ± 0.37 µM. The selectivity index of DW-8 was >2-fold in colon cancer cells incubated with vehicle. We further determined the mechanisms of cell death induced by DW-8 in SW620 CRC cancer cells. DW-8 (10 and 30 µM) induced apoptosis by (1) producing cell cycle arrest at the G2 phase; (2) activating the intrinsic apoptotic pathway, as indicated by the activation of caspase-9 and the executioner caspases-3 and 7; (3) nuclear fragmentation and (4) increasing the levels of reactive oxygen species (ROS). Overall, our results suggest that DW-8 may represent a suitable lead for developing novel compounds to treat CRC. [ABSTRACT FROM AUTHOR]