Exploring different classification-dependent QSAR modelling strategies for HDAC3 inhibitors in search of meaningful structural contributors.

Histone deacetylase 3 (HDAC3), a Zn2+-dependent class I HDACs, contributes to numerous disorders such as neurodegenerative disorders, diabetes, cardiovascular disease, kidney disease and several types of cancers. Therefore, the development of novel and selective HDAC3 inhibitors might be promising to combat such diseases. Here, different classification-based molecular modelling studies such as Bayesian classification, recursive partitioning (RP), SARpy and linear discriminant analysis (LDA) were conducted on a set of HDAC3 inhibitors to pinpoint essential structural requirements contributing to HDAC3 inhibition followed by molecular docking study and molecular dynamics (MD) simulation analyses. The current study revealed the importance of hydroxamate function for Zn2+ chelation as well as hydrogen bonding interaction with Tyr298 residue. The importance of hydroxamate function for higher HDAC3 inhibition was noticed in the case of Bayesian classification, recursive partitioning and SARpy models. Also, the importance of substituted thiazole ring was revealed, whereas the presence of linear alkyl groups with carboxylic acid function, any type of ester function, benzodiazepine moiety and methoxy group in the molecular structure can be detrimental to HDAC3 inhibition. Therefore, this study can aid in the design and discovery of effective novel HDAC3 inhibitors in the future.

Exploring crucial structural attributes of quinolinyl methoxyphenyl sulphonyl-based hydroxamate derivatives as ADAM17 inhibitors through classification-dependent molecular modelling approaches.

A Disintegrin and Metalloproteinase 17 (ADAM17), a Zn2+-dependent metalloenzyme of the adamalysin family of the metzincin superfamily, is associated with various pathophysiological conditions including rheumatoid arthritis and cancer. However, no specific inhibitors have been marketed yet for ADAM17-related disorders. In this study, 94 quinolinyl methoxyphenyl sulphonyl-based hydroxamates as ADAM17 inhibitors were subjected to classification-based molecular modelling and binding pattern analysis to identify the significant structural attributes contributing to ADAM17 inhibition. The statistically validated classification-based models identified the importance of the P1' substituents such as the quinolinyl methoxyphenyl sulphonyl group of these compounds for occupying the S1' - S3' pocket of the enzyme. The quinolinyl function of these compounds was found to explore stable binding of the P1' substituents at the S1' - S3' pocket whereas the importance of the sulphonyl and the orientation of the P1' moiety also revealed stable binding. Based on the outcomes of the current study, four novel compounds of different classes were designed as promising ADAM17 inhibitors. These findings regarding the crucial structural aspects and binding patterns of ADAM17 inhibitors will aid the design and discovery of novel and effective ADAM17 inhibitors for therapeutic advancements of related diseases.

Assessing structural insights into in-house arylsulfonyl L-(+) glutamine MMP-2 inhibitors as promising anticancer agents through structure-based computational modelling approaches.

MMP-2 is potentially contributing to several cancer progressions including leukaemias. Therefore, considering MMP-2 as a promising target, novel anticancer compounds may be designed. Here, 32 in-house arylsulfonyl L-(+) glutamines were subjected to various structure-based computational modelling approaches to recognize crucial structural attributes along with the spatial orientation for higher MMP-2 inhibition. Again, the docking-based 2D-QSAR study revealed that the Coulomb energy conferred by Tyr142 and total interaction energy conferred by Ala84 was crucial for MMP-2 inhibition. Importantly, the docking-dependent CoMFA and CoMSIA study revealed the importance of favourable steric, electrostatic, and hydrophobic substituents at the terminal phenyl ring. The MD simulation study revealed a lower fluctuation in the RMSD, RMSF, and Rg values indicating stable binding interactions of MMP-2 and these molecules. Moreover, the residual hydrogen bond and their interaction analysis disclosed crucial amino acid residues responsible for forming potential hydrogen bonding for higher MMP-2 inhibition. The results can effectively aid in the design and discovery of promising small-molecule drug-like MMP-2 inhibitors with greater anticancer potential in the future.

Exploration of structural alerts and fingerprints for novel anticancer therapeutics: a robust classification-QSAR dependent structural analysis of drug-like MMP-9 inhibitors.

Among various matrix metalloproteinases (MMPs), overexpression of MMP9 has been established as a key player in a variety of cancers. Therefore, MMP9 has emerged as a promising biomolecule that may be targeted to design potent inhibitors as novel anticancer therapeutics. In this study, a large database containing 1,123 drug-like MMP-9 inhibitors was considered for robust classification-dependent fragment-based QSAR study through SARpy, Bayesian classification, and recursive partitioning analyses and were validated by both internal and external validation techniques. In a nutshell, all these classification-dependent techniques revealed some common structural alerts and sub-structural fingerprints responsible for modulating MMP-9 inhibition. These observations are in agreement with the interactions obtained from the ligand-bound co-crystal structures of MMP-9 justifying the robustness of the current study. Finally, based on these crucial structural fragments, some new lead compounds were designed and further validated by the binding mode of interaction analysis. Therefore, these findings may be beneficial in designing novel and potential MMP-9 inhibitors in the future as a weapon to combat several cancers.

Achieving Energy Efficiency and Impact of SAR in a WBAN Through Optimal Placement of the Relay Node.

Wireless Body Area Network (WBAN) is an emerging and promising specialized area in Wireless networks that deals with crucial health-related datasets. Unlike other wireless networks, as this type of network deals with medical facts, losing it is fatal. WBAN is a highly constrained network. Reducing energy consumption and enhancing lifetime are the two most important challenges of WBANs. One way to achieve these is by deploying relay nodes optimally in WBANs. Generally, a relay node is placed at the midpoint of the line joining the source and the destination (D) nodes. We show that such simplistic deployment of the relay nodes is not the optimal deployment, which can hamper the overall lifetime of WBANs. In this paper, we have investigated the best location to deploy a relay node on a human body. We assume that an adaptive decode and forward relay node (R) can move linearly between the source (S) and the destination (D) nodes. Moreover, the assumption is that a relay node can be deployed linearly and that the body part of a human is a flat surface and hard. We have investigated the most energy-efficient data payload size based on the optimally placed relay location. The impact of such a deployment on different system parameters, such as distance (d), payload (L), modulation scheme, specific absorption rate, and an end to end outage (O) are examined as well. It is observed that in every aspect optimal deployment of the relay node performs an important role to enhance the lifetime of wireless body area networks. Sometimes linear relay deployment is very difficult to implement, especially on the different body parts of the human body. To address these issues, we have examined the optimal region for the relay node based on a 3D non-linear system model. The paper provides guidance for both linear and non-linear relay deployment along with the optimal data payload size under various circumstances and also considered the impact of specific absorption rates on the human body.

Protein interactions, molecular docking, antimicrobial and antifungal studies of terpyridine ligands.

Resistance to antibiotics/antibacterials/antifungals in pathogenic microbes has been developing over the past few decades and has recently become a commonplace public-health peril. Thus, alternative nontoxic potent antibiotic agents are covertly needed to control antibiotic-resistant outbreaks. In an effort to combat the challenges posed by the co-occurrence of multidrug resistance, two terpyridine ligands 4'-(4-N,N'-dimethylaminophenyl)-2,2':6',2″-terpyridine (L1) and 4'-(4-tolyl)-2,2':6',2″-terpyridine (L2) have been designed, prepared and confirmed their structure by spectral studies. Thereafter, antimicrobial assay was performed against gram positive and negative bacterial strains along with fungal strains. Both compounds L1 and L2 exhibited remarkable inhibitory activities against bacteria, Escherichia coli and Staphylococcus aureus at MIC values 6.25 and 3.125 µg/ml, respectively. In addition, in silico molecular docking studies were ascertained with bacterial DNA gyrase and fungal demethylase. Furthermore, both L1 and L2 could bind Bovine Serum Albumin (BSA) protein and binding interaction has been studied with the help of UV-Visible and fluorescence spectroscopy. While fluorescence of BSA unperturbed in the presence of L2, an addition of L1 to the solution of BSA resulted significant quenching. The binding constant calculations at different temperature confirmed that the fluorescence quenching between BSA and L1 is predominantly static in nature. The toxicity of L1 and L2 was checked using Drosophila melanogaster. The toxicity analysis suggest both the dyes are non-cytotoxic in nature.Communicated by Ramaswamy H. Sarma.

Lattice dynamics across the ferroelastic phase transition in Ba2ZnTeO6: a Raman and first-principles study.

Structural phase transitions drive several unconventional phenomena including some illustrious ferroic attributes which are relevant for technological advancements. On this note, we have investigated the ferroelastic structural transition of perovskite-type trigonal Ba2ZnTeO6 across Tc ∼ 150 K. With the help of Raman spectroscopy and density-functional theory (DFT)-based calculations, we report new intriguing observations associated with the phase transition in Ba2ZnTeO6. We observed the presence of a central peak (quasi-elastic Rayleigh profile), huge softening in the soft mode, hysteretic phonon behavior, and signatures of coexistent phases. The existence of a central peak in Ba2ZnTeO6 is manifested by a sharp rise in the intensity of the Rayleigh profile concomitant with the huge damping (or softening) of the soft mode (at ∼31 cm-1) near Tc, shedding light on the lattice dynamics during the phase transition. This is further corroborated by our phonon calculations that show that the soft mode (Eg) in the high-symmetry structure involving TeO6 octahedral rotation (with Ba and Zn translation) condenses into Ag and Bg modes in the C2/m low-symmetry phase. While most of the phonon bands split below Tc confirming the phase transition, we observed thermal hysteretic behavior of phonon modes, which signifies the first-order nature of the transition and the presence of coexisting phases as corroborated by our temperature-dependent X-ray diffraction and specific heat measurements.

Robust classification-based molecular modelling of diverse chemical entities as potential SARS-CoV-2 3CLpro inhibitors: theoretical justification in light of experimental evidences.

COVID-19 is the most unanticipated incidence of 2020 affecting the human population worldwide. Currently, it is utmost important to produce novel small molecule anti-SARS-CoV-2 drugs urgently that can save human lives globally. Based on the earlier SARS-CoV and MERS-CoV infection along with the general characters of coronaviral replication, a number of drug molecules have been proposed. However, one of the major limitations is the lack of experimental observations with different drug molecules. In this article, 70 diverse chemicals having experimental SARS-CoV-2 3CLproinhibitory activity were accounted for robust classification-based QSAR analysis statistically validated with 4 different methodologies to recognize the crucial structural features responsible for imparting the activity. Results obtained from all these methodologies supported and validated each other. Important observations obtained from these analyses were also justified with the ligand-bound crystal structure of SARS-CoV-2 3CLpro enzyme. Our results suggest that molecules should contain a 2-oxopyrrolidine scaffold as well as a methylene (hydroxy) sulphonic acid warhead in proper orientation to achieve higher inhibitory potency against SARS-CoV-2 3CLpro. Outcomes of our study may be able to design and discover highly effective SARS-CoV-2 3CLpro inhibitors as potential anticoronaviral therapy to crusade against COVID-19.

Electronic structure and magnetic behaviors of exfoliated MoS2 nanosheets.

The correlation of electronic structure and magnetic behaviors of layered molybdenum disulfide (MoS2) nanosheets, mechanically exfoliated from pristine hexagonal crystal (2H-MoS2) have been studied. Raman spectra show the energy difference (ΔE) between two Raman peaks A 1g and [Formula: see text] was about 20.2 cm-1, indicating the formation of mono-/bi-layered MoS 2 nanosheets as obtained after mechanical exfoliation from pristine 2H-MoS 2 . The absence of the reflection peak (0 0 2) in x-ray diffraction patterns confirms the formation of few-layered and mono-/bi-layered MoS 2 nanosheets with reduced thickness. Mo 3d and S 2p  XPS core level peaks shifted to higher energy with the reduction of the number of layers in exfoliated MoS2. As the number of layers decreased, valence band maximum position increased from 1.11 eV (pristine MoS2) to 1.57 eV (mono-/bi-layered MoS 2 nanosheets), whereas the surface work function (Ф) reduced from 4.85 eV (pristine MoS2) to 4.47 eV (mono-/bi-layered MoS2 nanosheets), as observed from UPS (He-I) measurements. UPS (He-II) spectra, as well as VB-PES spectra of mono-/bi-layered MoS 2 nanosheets, exhibits an enhanced valence band density of states (DOS) of S 3p -derived states near Fermi level (E f). Mo L II-edge and S K-edge x-ray absorption near edge structure spectra of mono-/bi-layered MoS 2 nanosheets show the splitting of different peaks that cause a noticeable change in their band structure. Magnetic M-H hysteresis loops measurement clearly demonstrates the increase of room temperature ferromagnetism from pristine to mono-/bi-layer MoS2, due to the existence of defects ('S'-vacancies or defects at the grain boundaries region) and the increase of DOS.

Reduction in polyamine catabolism leads to spermine-mediated airway epithelial injury and induces asthma features.

BACKGROUND: Airway epithelial injury is a crucial component of acute and severe asthma pathogenesis and a promising target for treatment of refractory asthma. However, the underlying mechanism of epithelial injury remains poorly explored. Although high levels of polyamines, mainly spermine, have been found in asthma and comorbidity, their role in airway epithelial injury and the cause of their altered levels in asthma have not been explored. METHODS: We measured key polyamine metabolic enzymes in lung samples from normal and asthmatic subjects and in mice with OVA-induced allergic airway inflammation (AAI). Polyamine metabolism was modulated using pharmacologic/genetic modulators. Epithelial stress and apoptosis were measured by TSLP levels and TUNEL assay, respectively. RESULTS: We found loss of the polyamine catabolic enzymes spermidine/spermine-N (1)-acetyltransferase-1 (SAT1) and spermine oxidase (SMOX) predominantly in bronchial epithelial cells (BECs) of human asthmatic lung samples and mice with AAI. In naïve mice, SAT1 or SMOX knockdown led to airway hyper-responsiveness, remodeling, and BEC apoptosis. Conversely, in mice with AAI, overexpression of either SAT1 or SMOX alleviated asthmatic features and reduced TSLP levels and BEC apoptosis. Similarly, while pharmacological induction of SAT1 and SMOX using the polyamine analogue bis(ethyl)norspermine (BENSPM) alleviated asthmatic features with reduced TSLP levels and BEC apoptosis, pharmacological inhibition of these enzymes using BERENIL or MDL72527, respectively, worsened them. Spermine accumulation in lungs correlated with BEC apoptosis, and spermine treatment caused apoptosis of human BEAS-2B cells in vitro. CONCLUSIONS: Spermine induces BEC injury. Induction of polyamine catabolism may represent a novel therapeutic approach for asthma via reversing BEC stress.

Choroidal metastases as the initial presentation of lung cancer: A rare scenario.

Clinical reports of symptomatic intraocular metastasis as the initial presentation of lung cancer are rare. We report the case of a 49-year-old female patient who presented with loss of vision due to choroidal metastases as the initial manifestation of her disseminated lung cancer. This particular patient was referred to us from ophthalmology department as a case of choroidal metastases from unknown primary. Detailed evaluation at our department helped detect the primary to be a nonsmall cell carcinoma of the right lung, which had multiple distant metastases.

Emergence of co-production of plasmid-mediated AmpC beta-lactamase and ESBL in cefoxitin-resistant uropathogenic Escherichia coli.

Plasmid-mediated AmpC (pAmpC) and ESBL co-production was detected in Escherichia coli a major etiologic agent of urinary tract infection. Isolates resistant to cefoxitin by CLSI methodology were tested for pAmpC beta-lactamase using phenylboronic acid and ESBLs by combined disk diffusion method. pAmpC/ESBL genes were characterized by PCR and sequencing. Transconjugation experiments were done to study the transfer of pAmpC and ESBL production from clinical isolates as donor to E. coli J53 AziR as recipient. Incompatibility groups of transmissible plasmids were classified by PCR-based replicon typing (PBRT). Among 148 urine culture positive isolates, E. coli was reported in 39.86 % (59/148), with 93.22 % (55/59) of cefoxitin resistance. pAmpC production was detected in 25, with varied distribution of blaCMY-2 and blaDHA-1type genes alone (n = 13 and 7 respectively) or in combination (n = 5). ESBL co-production was observed in 88 % (22/25) of pAmpC producing isolates with predominance of blaTEM (n = 20). Twenty-three transconjugants showed transmission of pAmpC-and ESBL-resistant genes with co-carriage of blaCMY-2 and blaTEM (n = 15) in plasmids of IncF type (n = 9) being predominant, followed by IncI1 (n = 4) and IncH1 (n = 2) in combination. All clinical isolates were clonally diverse. Resistance against different beta-lactams in uropathogenic E. coli has been an emerging concern in resource- poor countries such as India. Knowledge on the occurrence of AmpC beta-lactamases and ESBL amongst this pathogen and its transmission dynamics may aid in hospital infection control.

Microencapsulation of a putative probiotic Enterobacter species, C6-6, to protect rainbow trout, Oncorhynchus mykiss (Walbaum), against bacterial coldwater disease.

Flavobacterium psychrophilum is the causative agent of bacterial coldwater disease (BCWD), which has a major impact on salmonid aquaculture globally. An Enterobacter species, C6-6, isolated from the gut of rainbow trout, Oncorhynchus mykiss (Walbaum), has been identified as a potential probiotic species providing protection against BCWD. This study examined the effects of alginate microencapsulation on the protective efficacy of C6-6 against BCWD in vivo when administered to rainbow trout fry orally or by intraperitoneal (IP) injection. Viable C6-6 bacteria were microencapsulated successfully, and this process (microencapsulation) did not significantly deteriorate its protective properties as compared to the administration of non-microencapsulated C6-6 bacteria. Both oral and IP delivery of C6-6 achieved significantly better protection than control treatments that did not contain C6-6 bacteria. The highest relative percent survival (RPS) resulted from IP delivery (71.4%) and was significantly greater than the highest oral RPS (38.6%). Successful intestinal colonization was not critical to protective effects of C6-6. The study showed that C6-6 administration, with or without encapsulation, was a viable choice for protecting fry from BCWD especially when administered intraperitoneally.

Nuclear matrix binding protein SMAR1 regulates T-cell differentiation and allergic airway disease.

Asthma is a complex airway allergic disease involving the interplay of various cell types, cytokines, and transcriptional factors. Though many factors contribute to disease etiology, the molecular control of disease phenotype and responsiveness is not well understood. Here we report an essential role of the matrix attachment region (MAR)-binding protein SMAR1 in regulating immune response during allergic airway disease. Conditional knockout of SMAR1 in T cells rendered the mice resistant to eosinophilic airway inflammation against ovalbumin (OVA) allergen with low immunoglobulin E (IgE) and interleukin-5 (IL-5) levels. Moreover, a lower IgE/IgG2a ratio and higher interferon-γ (IFN-γ) response suggested aberrant skewing of T-cell differentiation toward type 1 helper T cell (Th1) response. We show that SMAR1 functions as a negative regulator of Th1 and Th17 differentiation by interacting with two potential and similar MAR regions present on the promoters of T-bet and IL-17. Thus, we present SMAR1 as a regulator of T-cell differentiation that favors the establishment of Th2 cells by modulating Th1 and Th17 responses.

Photophysical investigations on effective and selective complexation of a designed monoporhyrin with C60 and C70 in solution.

The present paper reports spectroscopic and theoretical insights on ground state complexation of a designed monoporphyrin, 1, with C60 and C70 in toluene. The central interest of the present investigations is the selectivity in binding constant (K) of the fullerene-1 complexes in solution. The ground state interaction between fullerenes and 1 is first evidenced from UV-Vis measurements. Steady state fluorescence experiment reveals efficient quenching of the excited singlet state of 1 in presence of both C60 and C70. Average K values, viz., K(av), for the complexes of C60 and C70 with 1 are determined to be 1620 and 30330 dm(3) mol(-1), respectively. The magnitude of K(av) suggests that 1 preferentially binds C70 in comparison to C60. Time resolved emission measurements establish that C70-1 complex is stabilized much more in comparison to C60-1 system in terms of charge separation process. Ab initio calculations in vacuo substantiate the strong binding between C70 and 1 in terms of heat of formation values of the respective complex, and at the same time, determine the orientation of bound guest (here C70) with the molecular plane of 1.

Histone deacetylase 3 as a novel therapeutic target in multiple myeloma.

Histone deacetylases (HDACs) represent novel molecular targets for the treatment of various types of cancers, including multiple myeloma (MM). Many HDAC inhibitors have already shown remarkable antitumor activities in the preclinical setting; however, their clinical utility is limited because of unfavorable toxicities associated with their broad range HDAC inhibitory effects. Isoform-selective HDAC inhibition may allow for MM cytotoxicity without attendant side effects. In this study, we demonstrated that HDAC3 knockdown and a small-molecule HDAC3 inhibitor BG45 trigger significant MM cell growth inhibition via apoptosis, evidenced by caspase and poly (ADP-ribose) polymerase cleavage. Importantly, HDAC3 inhibition downregulates phosphorylation (tyrosine 705 and serine 727) of signal transducers and activators of transcription 3 (STAT3). Neither interleukin-6 nor bone marrow stromal cells overcome this inhibitory effect of HDAC3 inhibition on phospho-STAT3 and MM cell growth. Moreover, HDAC3 inhibition also triggers hyperacetylation of STAT3, suggesting crosstalk signaling between phosphorylation and acetylation of STAT3. Importantly, inhibition of HDAC3, but not HDAC1 or 2, significantly enhances bortezomib-induced cytotoxicity. Finally, we confirm that BG45 alone and in combination with bortezomib trigger significant tumor growth inhibition in vivo in a murine xenograft model of human MM. Our results indicate that HDAC3 represents a promising therapeutic target, and validate a prototype novel HDAC3 inhibitor BG45 in MM.

Long distance directional growth of dopaminergic axons along pathways of netrin-1 and GDNF.

Different experimental and clinical strategies have been used to promote survival of transplanted embryonic ventral mesencephalic (VM) neurons. However, few studies have focused on the long-distance growth of dopaminergic axons from VM transplants. The aim of this study is to identify some of the growth and guidance factors that support directed long-distance growth of dopaminergic axons from VM transplants. Lentivirus encoding either glial cell line-derived neurotrophic factor (GDNF) or netrin-1, or a combination of lenti-GDNF with either lenti-GDNF family receptor α1 (GFRα-1) or lenti-netrin-1 was injected to form a gradient along the corpus callosum. Two weeks later, a piece of embryonic day 14 VM tissue was transplanted into the corpus callosum adjacent to the low end of the gradient. Results showed that tyrosine hydroxylase (TH(+)) axons grew a very short distance from the VM transplants in control groups, with few axons reaching the midline. In GDNF or netrin-1 expressing groups, more TH(+) axons grew out of transplants and reached the midline. Pathways co-expressing GDNF with either GFRα-1 or netrin-1 showed significantly increased axonal outgrowth. Interestingly, only the GDNF/netrin-1 combination resulted in the majority of axons reaching the distal target (80%), whereas along the GDNF/GFRα-1 pathway only 20% of the axons leaving the transplant reached the distal target. This technique of long-distance axon guidance may prove to be a useful strategy in reconstructing damaged neuronal circuits, such as the nigrostriatal pathway in Parkinson's disease.

Comparative evaluation of fosinopril and herbal drug Dioscorea bulbifera in patients of diabetic nephropathy.

Worldwide, diabetic nephropathy is one of the leading causes of end-stage renal failure. This hospital-based single-center prospective open-label randomized case-control interventional study was performed to evaluate and compare the native drug Dioscorea bulbifera with fosinopril in the management of diabetic nephropathy. Patients with diabetic nephropathy with proteinuria >500 mg/day or albuminuria >300 mg/ day, S Cr ≤2.5 mg/dL and hypertension controlled with a single drug were included into the study and were divided into three groups according to the interventional drugs that they were given; group A (n = 46) on fosinopril (5-40 mg/day), group B (n = 45) on Dioscorea bulbifera (500 mg BD) and group C (n = 46) on neither of these drugs. All necessary laboratory investigations needed to assess the effect of both the drugs were carried out. Patients were followed-up for six months. The study included 137 patients (M:F 2.61:1) with an age range of 19-76 years. At the sixth-month follow-up, a significant decrease in the systolic blood pressure was noted in all three groups whereas the diastolic blood pressure decreased significantly only in group B. There was significantly better control of both systolic and diastolic blood pressures in group B than in the other groups. Although fasting blood sugar was poorly controlled in the initial visit in all three groups, there was a significant decrease at the sixth-month follow-up in all three groups. Moreover, the decrease was significantly more pronounced in group B than in the other two groups. Low-density lipoprotein decreased significantly only in group B. Proteinuria, serum transforming growth factor-ß, interleukin-6 (IL-6) and C-reactive protein decreased in both group A and group B, more so in the latter, but the differences between the groups were not statistically significant. Importantly, proteinuria and serum IL-6 showed an increasing trend in group C. It can be concluded that Dioscorea bulbifera was more effective than fosinopril in controlling blood pressure, glycemia, cholesterolemia and inflammatory state in diabetic nephropathy. Both agents decreased proteinuria. However, creatinine clearance significantly decreased with both the drugs, more so with Dioscera, and thus further evaluation with a larger trial is needed.

A comparative pharmacokinetic study of a fixed dose combination for essential hypertensive patients: a randomized crossover study in healthy human volunteers.

BACKGROUND: This study was aimed to investigate the relative bioavailability of fixed-dose-combination (FDC) product of amlodipine, telmisartan and hydrochlorothiazide with individual marketed products in healthy male volunteers. Control of blood pressure with fixed dose combination of the above drugs acting through different mechanism have a benefit of convenient dosing in terms of compliance, lower the dose and subsequently reduce the side effects. METHODS: The authors investigated the relative bioavailability under a fasting state of the 3 drugs in a randomized, open-label, 2-treatment, 2-period, 2-sequence, crossover bioequivalence study with a washout period of 21 days. Plasma concentration of the analytes were assayed in timed samples with a simple, highly sensitive and rapid validated method using HPLC coupled to tandem mass spectrometry that had a lower limit of quantification of 1 ng/mL for all the 3 components. RESULTS: Test and reference formulations gave a mean Cmax of 5.234±0.914 ng/mL and 4.991±0.563 ng/mL, 108.839±13.601 ng/mL and 114.783±12.315 ng/mL and 97.814±10.779 ng/mL and 93.731±10.018 ng/mL for amlodipine, telmisartan and hydrochlorothiazide respectively. The AUC0-t of amlodipine, telmisartan and hydrochlorothiazide was 161.484 ng.h/mL, 1 917.644 ng.h/mL and 822.847 ng.h/mL for test formulation and 162.108 ng.h/mL, 2 014.764 ng.h/mL and 829.323 ng.h/mL for reference in the fasting state. CONCLUSION: The 90% confidence intervals for the test/reference ratio of the pharmacokinetic parameters in fasting state (mean Cmax, AUC0-t, and AUC0-∞) were within the acceptable range of 80.00-125.00. Thus, these findings clearly indicate that the FDC product is bioequivalent with the individual marketed products in terms of rate and extent of drug absorption and is well tolerated with no significant adverse reactions.

Computational classification of mitochondrial shapes reflects stress and redox state.

Dynamic variations in mitochondrial shape have been related to function. However, tools to automatically classify and enumerate mitochondrial shapes are lacking, as are systematic studies exploring the relationship of such shapes to mitochondrial stress. Here we show that during increased generation of mitochondrial reactive oxygen species (mtROS), mitochondria change their shape from tubular to donut or blob forms, which can be computationally quantified. Imaging of cells treated with rotenone or antimycin, showed time and dose-dependent conversion of tubular forms to donut-shaped mitochondria followed by appearance of blob forms. Time-lapse images showed reversible transitions from tubular to donut shapes and unidirectional transitions between donut and blob shapes. Blobs were the predominant sources of mtROS and appeared to be related to mitochondrial-calcium influx. Mitochondrial shape change could be prevented by either pretreatment with antioxidants like N-acetyl cysteine or inhibition of the mitochondrial calcium uniporter. This work represents a novel approach towards relating mitochondrial shape to function, through integration of cellular markers and a novel shape classification algorithm.