Rh(II)-Catalyzed Denitrogenative Reaction of N-Sulfonyl-1,2,3-triazoles with Quinolones and Isoquinolones.

Herein, we developed an efficient approach to access biologically relevant 2-aminoquinolines and 1-aminoisoquinolines from readily available N-sulfonyl-1,2,3-triazoles and 2-quinolones or 1-isoquinolones. This transformation involves the selective O-H insertion of these derivatives onto the in situ generated Rh-azavinyl carbenes (Rh-AVC) followed by rearrangement. The reaction proceeds smoothly under operationally simple conditions and the protocol was found to be scalable.

α-Synuclein seeding activity in duodenum biopsies from Parkinson's disease patients.

Abnormal deposition of α-synuclein is a key feature and biomarker of Parkinson's disease. α-Synuclein aggregates can propagate themselves by a prion-like seeding-based mechanism within and between tissues and are hypothesized to move between the intestine and brain. α-Synuclein RT-QuIC seed amplification assays have detected Parkinson's-associated α-synuclein in multiple biospecimens including post-mortem colon samples. Here we show intra vitam detection of seeds in duodenum biopsies from 22/23 Parkinson's patients, but not in 6 healthy controls by RT-QuICR. In contrast, no tau seeding activity was detected in any of the biopsies. Our seed amplifications provide evidence that the upper intestine contains a form(s) of α-synuclein with self-propagating activity. The diagnostic sensitivity and specificity for PD in this biopsy panel were 95.7% and 100% respectively. End-point dilution analysis indicated up to 106 SD50 seeding units per mg of tissue with positivity in two contemporaneous biopsies from individual patients suggesting widespread distribution within the superior and descending parts of duodenum. Our detection of α-synuclein seeding activity in duodenum biopsies of Parkinson's disease patients suggests not only that such analyses may be useful in ante-mortem diagnosis, but also that the duodenum may be a source or a destination for pathological, self-propagating α-synuclein assemblies.

Molecular interaction of lysozyme with therapeutic drug azithromycin: Effect of sodium dodecyl sulfate on binding profile.

This paper describes an inclusive biophysical study elucidating the interaction of therapeutic drug azithromycin (Azith) with hen egg white lysozyme (HEWL). Spectroscopic and computational tools have been employed to study the interaction of Azith with HEWL at pH 7.4. The fluorescence quenching constant values (Ksv) exhibited a decrease with the increase in temperature which revealed the occurrence of static quenching mechanism between Azith and HEWL. The thermodynamic data demonstrated that hydrophobic interactions were predominantly involved in the Azith-HEWL interaction. The negative value of standard Gibbs free energy (ΔG°) stated that the Azith-HEWL complex formed via spontaneous molecular interactions. The effect of sodium dodecyl sulfate (SDS) surfactant monomers on the binding propensity of Azith with HEWL was insignificant at lower concentrations however the binding significantly decreased at increased concentrations of the former. Far-UV CD data revealed alteration in the secondary structure of HEWL in the presence of Azith and the overall HEWL conformation changed. Molecular docking results revealed that the binding of Azith with HEWL takes place through hydrophobic interactions and hydrogen bonds.

Protective effects of a polyherbal medicine, Majoon Suranjan against bisphenol-A induced genetic, oxidative and tissue damages.

Bisphenol-A (BPA) is a toxic chemical largely produced and used in polycarbonate plastics worldwide. Majoon Suranjan (MS), a polyherbal formulation, is used as an anti-inflammatory medicine against rheumatoid arthritis. The present study aimed to evaluate BPA-induced toxicity and its possible amelioration by MS. To test our hypothesis, we performed gas chromatography-mass spectrometry (GC-MS) analysis, DNA interaction studies, genotoxicity tests, oxidative stress parameters, and histopathological examinations. GC-MS profiling of MS revealed the presence of various anti-oxidant compounds. DNA interaction studies showed that both chemicals intercalate between DNA base pairs. Next, we observed BPA-induced genotoxicity and oxidative damage. The observed effects might be due to BPA-induced reactive oxygen species production. Further, BPA changed the anti-oxidant enzyme activities, increased the malondialdehyde, alanine aminotransferase, alkaline phosphatase, and total bilirubin levels, and caused gross damage to the liver and kidney. Interestingly, these effects were significantly reversed by MS. In conclusion, MS shows protective effects against BPA-induced toxicity and could be a potential alternative medicine against BPA toxicity, especially in third-world countries where BPA uses are not strictly regulated.Highlights:Bisphenol-A (BPA) induces multiple toxic effects.BPA induces genotoxicity, oxidative and tissue damage.Majoon Suranjan (MS) ameliorates the BPA induced toxic effects.GC-MS profiling show various active anti-oxidant compounds in MS.MS is anti-genotoxic, anti-oxidant, and hepato-renal protective.

Interaction of Carrier Protein with Potential Metallic Drug Candidate N-Glycoside 'GATPT': Validation by Multi-Spectroscopic and Molecular Docking Approaches.

Lysozyme is often used as a model protein to study interaction with drug molecules and to understand biological processes which help in illuminating the therapeutic effectiveness of the drug. In the present work, in vitro interaction studies of 1-{(2-hydroxyethyl)amino}-2-amino-1,2-dideoxy-d-glucose triphenyl tin (IV) (GATPT) complex with lysozyme were carried out by employing various biophysical methods such as absorption, fluorescence, and circular dichroism (CD) spectroscopies. The experimental results revealed efficient binding affinity of GATPT with lysozyme with intrinsic binding (Kb) and binding constant (K) values in the order of 105 M-1. The number of binding sites and thermodynamic parameters ΔG, ΔH, and ΔS at four different temperatures were also calculated and the interaction of GATPT with lysozyme was found to be enthalpy and entropy driven. The CD spectra revealed alterations in the population of α-helical content within the secondary structure of lysozyme in presence of GATPT complex. The morphological analysis of the complex with lysozyme and lysozyme-DNA condensates was carried out by employing confocal and SEM studies. Furthermore, the molecular docking studies confirmed the interaction of GATPT within the larger hydrophobic pocket of the lysozyme via several non-covalent interactions.

RNA-targeted Cu(II)-based potential antitumor drug entity: comprehensive structural, biological {DNA/RNA binding, cleavage, cytotoxicity} and computational studies.

Copper-based bis(hydroxy naphthaldehyde) complex with axial mono aqua-coordination was synthesized and thoroughly characterized by various spectroscopic{IR, UV-vis, EPR}, ESI-Mass and single X-ray crystallographic studies. The single X-ray crystallography of the complex revealed the square pyramidal coordination geometry with P21 space group with axial water molecule ligated to copper centre. The geometry of the complex was further validated by DFT calculations, which was in accordance with other spectroscopic studies. The binding profile of the complex with ct-DNA and tRNA was carried out by employing various biophysical (absorption, fluorescence, circular dichroism, morphological studies) and computational studies (DFT, molecular docking). The experimental results revealed efficient binding of the complex with both ct-DNA and tRNA primarily, via non-covalent interactions. The binding studies Kb and K values revealed 10-fold greater binding affinity of the complex for tRNA as compared to ct-DNA. The in silico molecular docking further validated the interaction of complex within the hydrophobic pocket of ct-DNA and tRNA. The concentration and time dependent cleavage studies of DNA and tRNA were performed by employing gel electrophoresis assay. The cytotoxic activity of the complex was performed on a panel of human cell lines viz., leukemia (K-562), pancreatic (MIA-PA-CA-2), hepatoma (Hep-G2), cervical (HeLa), and breast (MDA-MB-231) by SRB assay. The complex exhibited selectively remarkably good cytotoxic potential on leukemia (K-562), cervical (HeLa) and hepatoma (Hep-G2) cancer cell lines.Communicated by Ramaswamy H. Sarma.

Cross-Talk Between Key Players in Patients with COVID-19 and Ischemic Stroke: A Review on Neurobiological Insight of the Pandemic.

The global pandemic of novel coronavirus disease 2019 (COVID-19) has taken the entire human race by surprise and led to an unprecedented number of mortalities worldwide so far. Current clinical studies have interpreted that angiotensin-converting enzyme 2 (ACE2) is the host receptor for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). In addition, ACE2 is the major component of the renin-angiotensin system. ACE2 deteriorates angiotensin II, a peptide that is responsible for the promotion of stroke. The downregulation of ACE2 further activates an immunological cascade. Thus, researchers need to explore and examine the possible links between COVID-19 and ischemic stroke (IS). Human ACE2 expression level and pattern in various tissues might be decisive for the vulnerability, symptoms, and treatment outcomes of the SARS-CoV-2 infection. The swift increase in the knowledge of SARS-CoV-2 has given creditable evidence that SARS-CoV-2 infected patients also encounter neurological deficits. As the SARS-CoV-2 binds to ACE2, it will hamper the activity of ACE2 in providing neuroprotection, especially in the case of stroke patients. Due to the downregulation of ACE2, the inflammatory response is activated in the ischemic penumbra. The COVID-19 pandemic has affected people with various pre-existing diseases, including IS, in such a way that these patients need special care and attention for their survival. Several clinical trials are currently ongoing worldwide as well as many other projects are in different stages of conceptualization and planning to facilitate the effective management of stroke patients with COVID-19 infection.

Correction: Copper(ii) l/d-valine-(1,10-phen) complexes target human telomeric G-quadruplex motifs and promote site-specific DNA cleavage and cellular cytotoxicity.

Correction for 'Copper(ii) l/d-valine-(1,10-phen) complexes target human telomeric G-quadruplex motifs and promote site-specific DNA cleavage and cellular cytotoxicity' by Farukh Arjmand et al., Dalton Trans., 2020, 49, 9888-9899, DOI: 10.1039/d0dt01527j.

Copper(ii) l/d-valine-(1,10-phen) complexes target human telomeric G-quadruplex motifs and promote site-specific DNA cleavage and cellular cytotoxicity.

Chiral l-/d-valine-(1,10-phen)-Cu(ii) complexes that target G-quadruplex DNA were synthesized and thoroughly characterized by UV-vis, IR, EPR, ESI-MS, elemental analysis and single crystal X-ray spectroscopy. Complexes 1a and 1b crystallized in the monoclinic P21/c and C2 space groups, respectively. On the basis of Wolfe-Shimer analyses, the binding affinities of 1a and 1b with G-quadruplex telomeric DNA were determined, and 1a exhibited significantly higher binding as compared to 1b. Site selective cleavage of G4-DNA was demonstrated by employing the time-dependent PAGE assay, with 1a exhibiting a significantly higher cleavage rate from A1 to G22 (4.32 (±0.13) µM h-1) than 1b (4.29 (±0.11) µM h-1). The DNA cleavage profile demonstrated that both complexes perform non-random double-strand cleavage by following first-order kinetics (kobs = 0.9432 min-1 for 1a and kobs = 0.6574 min-1 for 1b). Molecular docking simulations were performed with both parallel and anti-parallel topologies of the quadruplex to provide a clear insight on G-quadruplex-complex interactions. Complexes 1a and 1b were found to interact strongly at the minor groove cavity of the quadruplex with preferential selectivity for the parallel vs. anti-parallel quadruplex. The cytotoxic activities of complexes 1a and 1b were evaluated on a few notably important human cancer cell lines, viz, breast (MCF-7), pancreatic strains (BxPC3, AsPC1) and liver (Huh7) by an MTT assay. Both 1a and 1b exhibited pronounced cytotoxic activity with remarkably low IC50 values (1-3 µM) for all tested cancer strains.

Enantiomeric copper based anticancer agents promoting sequence-selective cleavage of G-quadruplex telomeric DNA and non-random cleavage of plasmid DNA.

Copper-based binuclear enantiomeric complexes 1S and 1R were synthesized as anticancer chemotherapeutic agents to target G-quadruplex rich region of DNA and thoroughly characterized by various spectroscopic and single X-ray crystal diffraction studies. The structure elucidation of Schiff base ligand LS and complexes 1S & 1R, was carried out by single crystal X-ray studies which showed that ligand crystallized in the monoclinic P21/n space group while complexes 1S and 1R crystallized in triclinic space groups P1[combining macron] and P1, respectively with two copper units connected to each other via an alkoxide bridge to exhibit square planar geometry which is in good agreement with other spectroscopic studies {IR, ESI-MS, EPR and magnetic moment values}. In vitro binding studies of complexes 1S and 1R were carried out with G-quadruplex DNA and CT-DNA which showed higher binding affinity and selectivity toward quadruplex DNA over the duplex DNA. To validate the potential of complexes to act as therapeutic drug candidates, the cleavage studies of complexes 1S and 1R were carried out with G-quadruplex telomeric DNA by PAGE Gel assay which showed sequence selective cleavage of 22G4via oxidative cleavage pathway. The major cleavage sites identified were G15, T6, G8, G9, G14 for complex 1S whereas for 1R G15, G20, G21, G14 cleavage sites were observed. Furthermore, these complexes were capable of cleaving pUC19 plasmid DNA in double-stranded non-random fashion which is considered to be more potent than single-strand cleavage as a source of lethal DNA lesions. Cellular studies of 1S and 1R were performed on a panel of human cancer cell lines; Huh7, MCF7, BxPC3 and AsPC1, which displayed significant cytotoxicity and differential responses toward different cancer phenotypes.

Ropinirole induces neuroprotection following reperfusion-promoted mitochondrial dysfunction after focal cerebral ischemia in Wistar rats.

Stroke is characterized by an initial ischemia followed by a reperfusion that promotes cascade of damage referred to as primary injury. The loss of mitochondrial function after ischemia, which is characterized by oxidative stress and activation of apoptotic factors is considered to play a crucial role in the proliferation of secondary injury and subsequent brain neuronal cell death. Dopamine D2 receptor agonist, Ropinirole, has been found to promote neuroprotection in Parkinson´s disease and restless leg syndrome. The current study was designed to test its efficacy in preclinical model of stroke. Previously it has been demonstrated that Ropinirole mediates its neuroprotection via mitochondrial pathways. Assuming this, we investigated the effect of Ropinirole on mitochondrial dysfunction, we have shown the positive effect of Ropinirole administration on behavioral deficits and mitochondrial health in an ischemic stroke injury model of transient middle cerebral artery occlusion (tMCAO). Male Wistar rats underwent transient middle cerebral artery occlusion and then received the Ropinirole (10 mg and 20 mg/kg b.w.) at 6 h, 12 and 18 h post occlusion. Behavioral assessment for functional deficits included grip strength, motor coordination and gait analysis. Our findings revealed a significant improvement with Ropinirole treatment in tMCAO animals. Staining of isolated brain slices from Ropinirole-treated rats with 2, 3,5-triphenyltetrazolium chloride (TTC) showed a reduction in the infarct area in comparison to the vehicle group, indicating the presence of an increased number of viable mitochondria. Ropinirole treatment was also able to attenuate mitochondrial reactive oxygen species (ROS) production, as well as block the mitochondrial permeability transition pore (mPTP), in the tMCAO injury model. In addition, it was also able to ameliorate the altered mitochondrial membrane potential and respiration ratio in the ischemic animals, thereby suggesting that Ropinirole has a positive effect on mitochondrial bioenergetics. Ropinirole inhibited the translocation of cytochrome c from mitochondria to cytosol reduces the downstream apoptotic processes. In conclusion, these results demonstrate that Ropinirole treatment is beneficial in preserving the mitochondrial functions that are altered in cerebral ischemic injury and thus can help in defining better therapies.

Pramipexole prevents ischemic cell death via mitochondrial pathways in ischemic stroke.

A dopamine D2 receptor agonist, pramipexole, has been found to elicit neuroprotection in patients with Parkinson's disease and restless leg syndrome. Recent evidence has shown that pramipexole mediates its neuroprotection through mitochondria. Considering this, we examined the possible mitochondrial role of pramipexole in promoting neuroprotection following an ischemic stroke of rat. Male Wistar rats underwent transient middle cerebral artery occlusion (tMCAO) and then received pramipexole (0.25 mg and 1 mg/kg body weight) at 1, 6, 12 and 18 h post-occlusion. A panel of neurological tests and 2,3,5-triphenyl tetrazolium chloride (TTC) staining were performed at 24 h after the surgery. Flow cytometry was used to detect the mitochondrial membrane potential, and mitochondrial levels of reactive oxygen species (ROS) and Ca2+, respectively. Mitochondrial oxidative phosphorylation was analyzed by oxygraph (oxygen electrode). Western blotting was used to analyze the expression of various proteins such as Bax, Bcl-2 and cytochrome c Pramipexole promoted the neurological recovery as shown by the panel of neurobehavioral tests and TTC staining. Post-stroke treatment with pramipexole reduced levels of mitochondrial ROS and Ca2+ after ischemia. Pramipexole elevated the mitochondrial membrane potential and mitochondrial oxidative phosphorylation. Western blotting showed that pramipexole inhibited the transfer of cytochrome c from mitochondria to cytosol, and hence inhibited the mitochondrial permeability transition pore. Thus, our results have demonstrated that post-stroke administration of pramipexole induces the neurological recovery through mitochondrial pathways in ischemia/reperfusion injury.

Development and future prospects of selective organometallic compounds as anticancer drug candidates exhibiting novel modes of action.

Organometallic complexes have widely been used for the treatment of various diseases viz., malaria, arthritis, syphilis, pernicious anemia, tuberculosis and particular in cancers. Recent decades have witnessed an upsurging interest in the application of organometallic compounds to treat various phenotypes of cancers with multiple etiologies. The unique and exceptional properties of organometallic compounds, intermediate between classical inorganic and organic materials provide new insight in the progress of inorganic medicinal chemistry. Herein, we have selectively focused on various organometallic sandwich and half-sandwich complexes of ruthenium (Ru), titanium (Ti), gold (Au) and iron (Fe) exhibiting promising activity towards a panel of cancer cell lines and resistant cancer cell lines. These complexes exhibit novel mechanisms of drug action through incorporation of outer-sphere recognition of molecular targets and controlled activation features based on ligand substitution along with monometallic and heterometallic redox processes. Furthermore, they are usually found to be uncharged or neutral possessing metals in a low oxidation state, exhibit kinetic stability, relative lipophilicity and are amenable to a host of various chemical transformations. This review mainly sheds light on the successful advancement of organometallic complexes as anticancer drug aspirants in relation to their versatile structural chemistry and innovative mechanisms of action targeting nucleic acids, several enzymes viz; thioredoxin reductases (Thrx), EGFR, transferrin, cathepsin B, topoisomerases etc.

Melatonin Improves Behavioral and Biochemical Outcomes in a Rotenone-Induced Rat Model of Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease followed only by Alzheimer's disease and affects millions of people worldwide. Despite the plethora of preclinical and clinical studies, there is currently a paucity of therapeutic agents for PD that can promote neuroprotection. In addition, the therapeutic agents currently available only help with improvement of PD symptoms. Therefore, it is imperative to find new therapeutic avenues for PD patients to minimize the economic and social burden on the concerned families. Rotenone is a frequently used neurotoxin in developing a PD model to aid in understanding the mechanisms of neuronal death. In addition, several studies have investigated the effects of melatonin, a neurohormone that is neuroprotective in various neurological diseases due to its anti-apoptotic, anti-inflammatory, and anti-oxidative properties. Our study investigated the role of melatonin-induced tyrosine hydroxylase (TH) and sensory motor function in a rotenone rat model to determine whether melatonin had any positive effects. Our results revealed that melatonin improves motor function by upregulation of TH in striatum of the brain. In addition, melatonin inhibits the striatal degeneration as shown by histopathological analysis. Therefore, results from the current study provide evidence for melatonin as a promising candidate for effective future therapeutic strategies for PD.

Comparison of self and proxy ratings for voice handicap index and motor-related quality-of-life of individuals with Parkinson's disease.

PURPOSE: Quality-of-life (QoL) consists of health, psychological well-being and communication-related domains. Due to the heterogeneous nature of Parkinson disease (PD), it is important to examine effects of different domains including motor and cognitive performance or motor and speech performance among the same set of individuals. Existing studies indicate mixed findings due to use of different QoL measures and lack of general consensus regarding QoL components. METHOD: The present study examined self and proxy ratings for 20 individuals with PD on Voice Handicap Index (VHI) and PDQ-39 mobility to determine effects on speech and motor-related QoL, respectively. RESULT: There was good level of agreement between self and proxy ratings for PDQ-39 mobility ratings alone. In addition, no overall group differences were found for self and proxy ratings of VHI and PDQ-39 mobility ratings, thus indicating similar perceptions by individuals with PD and their communication partners for speech and motor-related changes associated with PD. Further, no significant correlations between speech and motor-related QoL were found, thereby suggesting these domains to be independent of each other. CONCLUSION: The present study indicates the need to consider both self and proxy reports to understand the impact of PD on a person's overall functioning.

Comparison of self and proxy ratings for motor performance of individuals with Parkinson disease.

The impact of Parkinson disease (PD) has been examined in recent years by comparing self-ratings by individuals with PD and proxy ratings by caregivers, communication partners, and/or health care providers. However, the existing evidence is mixed with some researchers suggesting perfect agreement between rater groups while others suggesting differences among rater groups for motor performance of individuals with PD. The current study examined self and proxy perception of performance of individuals with PD for six motor characteristics (gait, rigidity, right and left bradykinesia, rest tremors, and perception of physical effort) based on Unified Parkinson Disease Rating Scale (UPDRS) motor tasks. Participants included 20 individuals with PD, 20 communication partners, and a trained rater. The study compared perceptual ratings and corresponding UPDRS scores as well as rater group differences for perceptual motor ratings. A series of Pearson Product Moment Correlations indicated significant relationship only between self-ratings for gait and rest tremors by individuals with PD and corresponding UPDRS scores (p<.05). Further, a multivariate analysis of variance was completed to compare rater group differences. Results indicated significant overestimation of rest tremors by both individuals with PD and communication partners when compared to corresponding ratings by the trained rater. Overall, the study provided evidence for perception deficits among individuals with PD and communication partners regarding motor performance of individuals with PD. Additional studies are needed to further explore the changes in perception abilities of individuals with PD and communication partners with respect to disease duration, disease severity, and other co-morbid factors.

Presence of stop bursts and multiple bursts in individuals with Parkinson disease.

Studies have reported that individuals with Parkinson Disease (PD) have imprecise articulation of stop consonants due to either slowness of articulators or decreased closure strength. The moment of release for stop consonants, called the burst, has been previously studied in individuals with PD and in other disorders. Multiple bursts (MBs) on the same stop consonant have been reported previously in some motor speech disorders, but no studies are known to have examined MBs in individuals with PD. The current study looked at the occurrences of bursts and MBs in initial stop consonants produced by nine individuals with PD (ON and OFF medication) and nine control speakers. Individuals with PD produced fewer overall bursts compared to control participants. In terms of place of articulation, individuals with PD primarily had loss of bursts in bilabial stops. In addition, individuals with PD had more MBs than control speakers, primarily in alveolars. Finally, no dopamine-related medication effects were found for occurrences of bursts or MBs in individuals with PD. Overall, the study provided evidence for loss of bursts and presence of MBs for stop consonants produced by individuals with PD.

Risk factors of hearing impairment in Indian children: a retrospective case-file study.

A significant proportion of school children are hearing impaired and they suffer from various academic and adjustment problems. Identification of risk factors will help in containing the problems. In this context this study aims to find the causative factors of hearing impairment. Data obtained from 1000 case files indicated that mean age of detection by parents was 3.03 years. A considerable gap between the mean age of detection and availing audiological rehabilitation was observed. Prenatal diseases, exposure to X-rays during gestation, premature delivery, low birth weight, postnatal jaundice, neonatal seizures and rubella were the significant predictors of hearing impairment. Therefore, children with a history of these predictive factors should be periodically screened for hearing impairment. At a higher level, mass education programmes may include imparting information on preventive measures and early identification of these risk factors.