The Interplay of Mitochondrial Bioenergetics and Dopamine Agonists as an Effective Disease-Modifying Therapy for Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurological ailment with a slower rate of advancement that is more common in older adults. The biggest risk factor for PD is getting older, and those over 60 have an exponentially higher incidence of this condition. The failure of the mitochondrial electron chain, changes in the dynamics of the mitochondria, and abnormalities in calcium and ion homeostasis are all symptoms of Parkinson's disease (PD). Increased mitochondrial reactive oxygen species (mROS) and an energy deficit are linked to these alterations. Levodopa (L-DOPA) is a medication that is typically used to treat most PD patients, but because of its negative effects, additional medications have been created utilizing L-DOPA as the parent molecule. Ergot and non-ergot derivatives make up most PD medications. PD is successfully managed with the use of dopamine agonists (DA). To get around the motor issues produced by L-DOPA, these dopamine derivatives can directly excite DA receptors in the postsynaptic membrane. In the past 10 years, two non-ergoline DA with strong binding properties for the dopamine D2 receptor (D2R) and a preference for the dopamine D3 receptor (D3R) subtype, ropinirole, and pramipexole (PPx) have been developed for the treatment of PD. This review covers the most recent research on the efficacy and safety of non-ergot drugs like ropinirole and PPx as supplementary therapy to DOPA for the treatment of PD.

Novel Coumarin Derivatives as Potential Urease Inhibitors for Kidney Stone Prevention and Antiulcer Therapy: From Synthesis to In Vivo Evaluation.

The presence of ammonium ions in urine, along with basic pH in the presence of urease-producing bacteria, promotes the production of struvite stones. This causes renal malfunction, which is manifested by symptoms such as fever, nausea, vomiting, and blood in the urine. The involvement of urease in stone formation makes it a good target for finding urease enzyme inhibitors, which have the potential to be developed as lead drugs against kidney stones in the future. The documented ethnopharmacology of coumarin 2-one against bacterial, fungal and viral strains encouraged us to synthesize new derivatives of coumarins by reacting aromatic aldehydes with 4-aminocoumarin. The synthesized compounds (2a to 11a) were evaluated for their antimicrobial, in vitro, and in silico properties against the urease enzyme. The study also covers in vivo determination of the synthesized compounds with respect to different types of induced ulcers. The molecular docking study along with extended MD simulations (100 ns each) and MMPBSA study confirmed the potential inhibitory candidates as evident from computed ∆Gbind (3a = -11.62 and 5a = -12.08 Kcal/mol) against the urease enzyme. The in silico analyses were augmented by an enzymatic assay, which revealed that compounds 3a and 5a had strong inhibitory action, with IC50 of 0.412 µM (64.0% inhibition) and 0.322 µM (77.7% inhibition), respectively, compared to standard (Thiourea) with 82% inhibition at 0.14 µM. Moreover, the most active compound, 5a, was further tested in vivo for antiulcer activity by different types of induced ulcers, including pyloric ligation-, ethanol-, aspirin-, and histamine-induced ulcers. Compound 5a effectively reduced gastric acidity, lipid peroxidation, and ulceration in a rat model while also inhibiting gastric ATPase activity, which makes it a promising candidate for ulcer treatment. As a result of the current research, 3a and 5a may be used as new molecules for developing potent urease inhibitors. Additionally, the compound 3a showed antibacterial activity against Staphylococcus aureus and Salmonella typhimurium, with zones of inhibition of 41 ± 0.9 mm and 35 ± 0.9 mm, respectively. Compound 7a showed antibacterial activity against Staphylococcus aureus and Salmonella typhimurium, with zones of inhibition of 30 ± 0.8 mm and 42 ± 0.8 mm, respectively. These results prove that the synthesized compounds also possess good antibacterial potential against Gram-positive and Gram-negative bacterial strains.

Three New Acrylic Acid Derivatives from Achillea mellifolium as Potential Inhibitors of Urease from Jack Bean and α-Glucosidase from Saccharomyces cerevisiae.

(1) Background: Achillea mellifolium belongs to a highly reputed family of medicinal plants, with plant extract being used as medicine in indigenous system. However, limited data is available regarding the exploitation of the medicinal potential of isolated pure compounds from this family; (2) Methods: A whole plant extract was partitioned into fractions and on the basis of biological activity, an ethyl acetate fraction was selected for isolation of pure compounds. Isolated compounds were characterized using different spectroscopic techniques. The compounds isolated from this study were tested for their medicinal potential using in-vitro enzyme assay, coupled with in-silico studies; (3) Results: Three new acrylic acid derivatives (1-3) have been isolated from the ethyl acetate fraction of Achillea mellifolium. The characterization of these compounds (1-3) was carried out using UV/Vis, FT-IR, 1D and 2D-NMR spectroscopy (1H-NMR, 13C-NMR, HMBC, NOESY) and mass spectrometry. These acrylic acid derivatives were further evaluated for their enzyme inhibition potential against urease from jack bean and α glucosidase from Saccharomyces cerevisiae, using both in-silico and in-vitro approaches. In-vitro studies showed that compound 3 has the highest inhibition against urease enzyme (IC50 =10.46 ± 0.03 µΜ), followed by compound 1 and compound 2 with percent inhibition and IC50 value of 16.87 ± 0.02 c and 13.71 ± 0.07 µΜ, respectively, compared to the standard (thiourea-IC50 = 21.5 ± 0.01 µΜ). The investigated IC50 value of compound 3 against the urease enzyme is two times lower compared to thiourea, suggesting that this compound is twice as active compared to the standard drug. On the other hand, all three compounds (1-3) revealed mild inhibition potential against α-glucosidase. In-silico molecular docking studies, in combination with MD simulations and free energy, calculations were also performed to rationalize their time evolved mode of interaction inside the active pocket. Binding energies were computed using a MMPBSA approach, and the role of individual residues to overall binding of the inhibitors inside the active pockets were also computed; (4) Conclusions: Together, these studies confirm the inhibitory potential of isolated acrylic acid derivatives against both urease and α-glucosidase enzymes; however, their inhibition potential is better for urease enzyme even when compared to the standard.

Selecting the Next Generation of Surgeons: General Surgery Program Directors and Coordinators Perspective on USMLE Changes and Holistic Approach.

INTRODUCTION: The United States Medical Licensing Examination (USMLE) was designed as a universal assessment tool for states to determine physician's medical licensure's candidacy. Recent changes in the USMLE exam have changed the way future surgical residency candidate applications will be reviewed. The survey aimed to assess the effect of changes in USMLE exams-USMLE Step 1 pass/fail, complete dissolution of USMLE clinical skills exam, and the role of holistic review in future surgical residency candidacy selection. METHODS: An anonymous online survey was created and distributed to general surgery program directors and coordinators across the USA. The survey aimed to assess attitudes toward changes to USMLE exams and the potential changes with a holistic review of candidate applications. RESULTS: The response rate was 63.7%. Most program directors and coordinators disagree with changing USMLE Step 1 to a pass/fail scoring system. The majority felt that contacts, the medical school's name, and performance in clinical electives and sub-internships would hold more significance. They also believe that a holistic review of application will decrease socioeconomic discrepancies and promote a more diverse and inclusive resident cohort. CONCLUSION: Step 2 clinical knowledge (CK) will gain more importance in future residency matches because of the change in the scoring system of Step 1. The medical school's name, personal contacts, and clinical performance in rotations will hold more significance.

Photo-inactivation of bacteria in hospital effluent via thiolated iron-doped nanoceria.

Hospital wastewater is a major contributor of disease-causing microbes and the emergence of antibiotic resistant bacteria. In this study, thiolated iron-doped nanoceria was synthesised and tested for killing of microbes from hospital effluent. These particles were designed to inhibit the efflux pumps of the bacteria found in hospital effluent with further ability to activate in visible light via iron doping thus generating tunable amount of reactive oxygen species (ROS). The quantum yield of the ROS generated by the nanoceria was 0.67 while the ROS types produced were singlet oxygen (36%), hydroxyl radical (31%) and hydroxyl ions (32%), respectively. The particles were initially synthesised through green route using Foeniculum vulgare seeds extract and were annealed at 200°C and further coated with thiolated chitosan to enhance the solubility and efflux pump inhibition. X-ray diffraction confirmed the polycrystalline nature of nanoparticles and uniform spherical shape with 30 nm size, confirmed by scanning electron microscope. The nanoparticles exhibited 100% bactericidal activity at 100 µg/mL against all the isolated bacteria. The enhanced bactericidal effect of iron-doped nanoceria could be attributed to efflux inhibition via thiolated chitosan as well as the production of ROS upon illumination in visible light, causing oxidative stress against microbes found in hospital effluent.

Perspectives on cannabis as a substitute for opioid analgesics.

With the opioid epidemic reaching new heights in the USA, it has become critical to find suitable alternatives to opioids. Cannabis, an antinociceptive, is a strong contender to help patients reduce their opioid usage. A growing literature has been examining the complex effects cannabis has on pain relief and on opioid usage; whether it is a substitute for opioids or increases their use. This review explores the studies that compare cannabis-opioid interactions and presents some challenges of cannabis research and usage. The practical clinical pharmacology of cannabis as an analgesic, including the route of administration, safety and pharmacokinetics, are discussed to address the concerns, as well as possible solutions, of cannabis as a pain reliever.

White noise as a possible therapeutic option for children with ADHD.

Attention deficit/hyperactivity disorder (ADHD) is a condition that affects many children and adults throughout the world. ADHD symptoms have been associated with changes in catecholamine release. Current therapies for ADHD have a variety of limitations that invite additional therapeutic options. White noise therapy has previously been utilized to improve sleep and aspects of cognition in a variety of patient populations. Through a proposed phenomenon called stochastic resonance, white noise may have the ability to improve symptoms in children with ADHD. Empirically, white noise therapy has been able to improve certain tasks affected by ADHD symptoms, including speech recognition and reading and writing speed. Not all tasks affected by ADHD are improved, however, and significant logistical challenges remain before this therapy could be realistically implemented. In this review, there appears to be evidence that white noise therapy could be beneficial for patients with ADHD, and therefore further research is encouraged to establish parameters for maximum therapeutic benefit.

Pharmacological effects and potential therapeutic targets of DT-13.

DT-13 is an isolated compound from Dwarf lillytruf tuber and currently among active research drugs by National Natural Science foundation of China for its several potential effects. The drug has been reported for its multiple pharmacological actions however no thorough review studies are available on it. Our present study is highlighting the pros and cons of DT-13 focusing on its potential pharmacological actions, therapeutic utilization and further exploration for novel targets. The drug possesses very low toxicity profile, quick onset and long duration of action with slow elimination that combinely makes it favorable for the clinical studies. In vivo and in vitro studies show that the drug regulates multiple cellular functions for its several pharmacological effects including, anti-adhesive effects via regulation of tissue factor and transforming growth factor; anti-migratory effects through indirect regulation of NM-IIA in the tumor microenvironment, Tissue factor, down-regulation of CCR5-CCL5 axis and MMP-2/9 inhibition; anti-metastatic effects via regulation of MMPs and tissue factor; pro-apoptotic effects by modulation of endocytosis of EGF receptor; anti-angiogenic effects via regulation of HIF-1α,ERK, Akt signalling and autophagy inducing characteristics by regulating PI3K/Akt/mTOR signalling pathway. In addition to anti-tumor activities, DT-13 has significant anti-inflammatory, cardioprotective, hepatoprotective and immunomodulating effects. Pharmaceutical dosage form and targeted drug delivery system for DT-13 has not been established yet. Moreover, DT-13, has not been studied for its action on brain, colorectal, hepatic, pancreatic, prostate and blood cancers. Similarly the effects of drug on carbohydrate and glucose metabolism is another niche yet to be explored. In some traditional therapies, crude drug from the plant is used against diabetic and neurological disorders that are not reported in scientific literature, however due to profound effects of DT-13 on blood and cerebral ischemic disorders, it is reasonable to hypothesize that there could be an association of DT-13 that require further exploration.

Three new anthraquinone derivatives isolated from Symplocos racemosa and their antibiofilm activity.

Three new alkyl substituted anthraquinone derivatives, trivially named as symploquinones A-C (Compounds 1-3) were isolated from Symplocos racemosa. The structures of these compounds were determined on the basis of extensive spectroscopic analyses (UV, IR, Mass, 1H- and 13C-NMR, and two-dimensional (2D) NMR techniques). The resulting data were also compared with the reported literature. These compounds were then subjected to antibacterial or antibiofilm testing. Compounds 1 and 3 exhibited good antibacterial activity in the concentration range of 160-83 µg·mL-1 against Streptococcus mutans, methicillin resistant Staphylococcus aureus and Proteus mirabilis. Both compounds were further screened for anti-biofilm activity, which revealed promising activities at sub-MIC concentrations. None of the compounds were found to be active against Klebsiella pneumoniae.

PHARMACOLOGICAL ACTIVITIES OF PROTOCATECHUIC ACID.

Protocatechuic acid (3,4-dihydroxybenzoic acid, PCA) is a simple phenolic acid. It is found in a large variety of edible plants and possesses various pharmacological activities. This article aims to review the modern trends in phytochemical isolation and extraction of PCA from plants and other natural resources. Moreover, this article also encompasses pharmacological and biological activities of PCA. It is well known to have anti-inflammatory, antioxidant, anti-hyperglycemia, antibacterial, anticancer, anti-ageing, anti-athro- genic, anti-tumoral, anti-asthma, antiulcer, antispasmodic and neurological properties.

Evaluation of Antioxidant, Free Radical Scavenging, and Antimicrobial Activity of Quercus incana Roxb.

Considering the indigenous utilization of Quercus incana Roxb., the present study deals with the investigation of antioxidant, free radical scavenging activity, total phenolic content, and antimicrobial activity of Q. incana Roxb. In vitro antioxidant activity of the plant fractions were determined by 1,1-diphenyl-2-picrylhydrazyl and nitric oxide scavenging method. Total phenolic contents were determined by gallic acid equivalent and antimicrobial activities were determined by agar well diffusion method. It was observed that Q. incana Roxb. showed significant antibacterial activity against Gram-positive and Gram-negative bacteria. n-Butanol fraction showed maximum activity against Micrococcus leuteus with 19 mm zone of inhibition. n-Butanol fraction of Q. incana Roxb. showed immense antifungal activity against Aspergillus niger (32 mm ± 0.55) and A. flavus (28 mm ± 0.45). Similarly n-butanol fraction showed relatively good antioxidant activity with IC50 value of 55.4 ± 0.21 µg/mL. The NO scavenging activity of ethyl acetate fraction (IC50 = 23.21 ± 0.31 µg/mL) was fairly good compared to other fractions. The current study of Q. incana Roxb. suggests the presences of synergetic action of some biological active compounds that may be present in the leaves of medicinal plant. Further studies are needed to better characterize the important active constituents responsible for the antimicrobial, antioxidant and free radical scavenging activity.

Neural substrates of executive dysfunction in fragile X-associated tremor/ataxia syndrome (FXTAS): a brain potential study.

Executive dysfunction in fragile X-associated tremor/ataxia syndrome (FXTAS) has been suggested to mediate other cognitive impairments. In the present study, event-related potentials and neuropsychological testing were combined to investigate the brain mechanisms underlying the executive dysfunction in FXTAS. Thirty-two-channel electroencephalography was recorded during an auditory "oddball" task requiring dual responses. FXTAS patients (N= 41, mean age= 62) displayed prolonged latencies of N1 and P3 and reduced amplitudes of P2 and P3, whereas their N2 measures remained within the normal range, indicating relatively preserved early-stage auditory attention but markedly impaired late-stage attention and working memory updating processes (as indexed by P3). Topographical mapping revealed a typical parietal P3 peak preceded by a prominent fronto-central P3 in normal control subjects (N= 32), whereas FXTAS patients had decreased parietal P3 amplitude and diminished fronto-central positivities with a delayed onset (∼50 ms later than controls, P < 0.002). The P3 abnormalities were associated with lower executive function test (e.g., BDS-2) scores. Smaller P3 amplitudes also correlated with increased CGG repeat length of fragile X mental retardation 1 (FMR1) gene and higher FMR1 mRNA levels. These results indicate that abnormal fronto-parietal attentional network dynamics underlie executive dysfunction, the cardinal feature of cognitive impairment in FXTAS.

Calcium channel blocking activity of Mentha longifolia L. explains its medicinal use in diarrhoea and gut spasm.

Mentha longifolia has a reputation in traditional medicine in the indications of diarrhoea and gut spasm. This study was carried out to provide a possible pharmacological basis for its medicinal use in hyperactive gut disorders. In a castor oil induced diarrhoeal model, the crude extract of Mentha longifolia (Ml.Cr), at doses of 100-1000 mg/kg, provided 31-80% protection, similar to loperamide. In isolated rabbit jejunum preparations, Ml.Cr caused inhibition of spontaneous and high K(+)-induced contractions, with respective EC50 values of 1.80 (1.34-2.24; n = 6-8) and 0.60 mg/mL (0.37-0.85; n = 6-8), which suggests spasmolytic activity, mediated possibly through calcium channel blockade (CCB). The CCB activity was further confirmed when pretreatment of the tissue with Ml.Cr (0.3-1 mg/mL) caused a rightward shift in the Ca(++) concentration-response curves (CRCs), similar to verapamil. Loperamide also inhibited spontaneous and high K(+)-induced contractions and shifted the Ca(++) CRCs to the right. Activity-directed fractionation revealed that the petroleum spirit fraction was more potent than the parent crude extract and aqueous fraction. These data indicate that the antidiarrhoeal and spasmolytic effects of the crude extract of Mentha longifolia are mediated through the presence of CCB-like constituent(s), concentrated in the petroleum spirit fraction and this study provides indirect evidence for its medicinal use in diarrhoea and spasm.

Studies on the protective effect of dietary fish oil on uranyl-nitrate-induced nephrotoxicity and oxidative damage in rat kidney.

Human and animal exposure demonstrates that uranium is nephrotoxic. However, attempts to reduce it were not found suitable for clinical use. Dietary fish oil (FO) enriched in omega-3 fatty acids reduces the severity of cardiovascular and renal diseases. Present study investigates the protective effect of FO on uranyl nitrate (UN)-induced renal damage. Rats prefed with experimental diets for 15 days, given single nephrotoxic dose of UN (0.5mg/kg body weight) intraperitoneally. After 5d of UN treatment, serum/urine parameters, enzymes of carbohydrate metabolism, brush border membrane (BBM), oxidative stress and phosphate transport were analyzed in rat kidney. UN nephrotoxicity was characterized by increased serum creatinine and blood urea nitrogen. UN increased the activity of lactate dehydrogenase and NADP-malic enzyme whereas decreased malate, isocitrate and glucose-6-phophate dehydrogenases; glucose-6-phophatase, fructose-1, 6-bisphosphatase and BBM enzyme activities. UN caused oxidant/antioxidant imbalances as reflected by increased lipid peroxidation, activities of superoxide dismutase, glutathione peroxidase and decreased catalase activity. Feeding FO alone increased activities of enzymes of glucose metabolism, BBM, oxidative stress and Pi transport. UN-elicited alterations were prevented by FO feeding. However, corn oil had no such effects and was not similarly effective. In conclusion, FO appears to protect against UN-induced nephrotoxicity by improving energy metabolism and antioxidant defense mechanism.

Studies on the protective effect of green tea against cisplatin induced nephrotoxicity.

Cisplatin (CP) an anticancer drug is known to induce nephrotoxicity, which limits its long-term clinical use. Green tea (GT), consumed since ancient times is known for its numerous health benefits. It has been shown to improve kidney functions in animal models of acute renal failure. The present study was undertaken to see whether GT can prevent CP-induced nephrotoxic and other deleterious effects. A nephrotoxic dose of CP was co-administered to control and GT-fed male Wistar rats every fifth day for 25 days. The effect of GT was determined on CP-induced alterations in various serum parameters and on enzymes of carbohydrate metabolism, brush border membrane, and antioxidant defense system in renal cortex and medulla. CP nephrotoxicity was recorded by increased serum creatinine and blood urea nitrogen. CP increased the activities of lactate dehydrogenase and acid phosphatase whereas, the activities of malate dehydrogenase, glucose-6-phosphatase, superoxide dismutase, catalase, and (32)Pi transport significantly decreased. GT consumption increased the activities of the enzymes of carbohydrate metabolism, brush border membrane, oxidative stress, and (32)Pi transport. GT ameliorated CP-induced nephrotoxic and other deleterious effects due to its intrinsic biochemical/antioxidant properties.

Protective effect of green tea extract on gentamicin-induced nephrotoxicity and oxidative damage in rat kidney.

Gentamicin (GM) is an effective aminoglycoside antibiotic against severe infections but nephrotoxicity and oxidative damage limits its long term clinical use. Various strategies were attempted to ameliorate GM nephropathy but were not found suitable for clinical practice. Green tea (GT) polyphenols have shown strong chemopreventive and chemotherapeutic effects against various pathologies. We hypothesized that GT prevents GM nephrotoxicity by virtue of its antioxidative properties. A nephrotoxic dose of GM was co-administered to control and GT-fed male Wistar rats. Serum parameters and enzymes of oxidative stress, brush border membrane (BBM), and carbohydrate metabolism were analyzed. GM increased serum creatinine, cholesterol, blood urea nitrogen (BUN), lipid peroxidation (LPO) and suppressed superoxide dismutase (SOD) and catalase activities in renal tissues. Activity of hexokinase, lactate dehydrogenase increased whereas malate dehydrogenase decreased. Gluconeogenic enzymes and glucose-6-phosphate dehydrogenase were differentially altered in the cortex and medulla. However, GT given to GM rats reduced nephrotoxicity parameters, enhanced antioxidant defense and energy metabolism. The activity of BBM enzymes and transport of Pi declined by GM whereas GT enhanced BBM enzymes and Pi transport. In conclusion, green tea ameliorates GM elicited nephrotoxicity and oxidative damage by improving antioxidant defense, tissue integrity and energy metabolism.

Studies on the protective effect of dietary fish oil on gentamicin-induced nephrotoxicity and oxidative damage in rat kidney.

Gentamicin (GM)-induced nephrotoxicity limits its long-term clinical use. Several agents/strategies were attempted to prevent GM nephrotoxicity but were not found suitable for clinical practice. Dietary fish oil (FO) retard the progression of certain types of cancers, cardiovascular and renal disorders. We aimed to evaluate protective effect of FO on GM-induced renal proximal tubular damage. The rats were pre-fed experimental diets for 10 days and then received GM (80 mg/kg body weight/day) treatment for 10 days while still on diet. Serum/urine parameters, enzymes of carbohydrate metabolism, brush border membrane (BBM), oxidative stress and phosphate transport in rat kidney were analyzed. GM nephrotoxicity was recorded by increased serum creatinine and blood urea nitrogen. GM increased the activities of lactate and glucose-6-phosphate dehydrogenases whereas decreased malate, isocitrate dehydrogenases; glucose-6 and fructose-1,6-bisphosphatases; superoxide dismutase, catalase, glutathione peroxidase and BBM enzymes. In contrast, FO alone increased enzyme activities of carbohydrate metabolism, BBM and oxidative stress. FO feeding to GM treated rats markedly enhanced resistance to GM elicited deleterious effects and prevented GM-induced decrease in 32Pi uptake across BBM. Dietary FO supplementation ameliorated GM-induced specific metabolic alterations and oxidative damage due to its intrinsic biochemical/antioxidant properties.

Influence of green tea on enzymes of carbohydrate metabolism, antioxidant defense, and plasma membrane in rat tissues.

OBJECTIVE: Green tea, consumed worldwide since ancient times, is considered beneficial to human health. We hypothesized that green tea would enhance antioxidant defenses and specific metabolic activities of rat intestine, liver, and kidney to improve their functions. METHODS: The effect of green tea given to rats in the diet or drinking water for 25 d was determined on blood chemistry and on activities of enzymes of carbohydrate metabolism, brush border membrane, and antioxidant defense. RESULTS: Serum glucose, cholesterol, phosphate, and body weight decreased, whereas the activities of lactate and malate dehydrogenases and glucose-6- and fructose 1,6-bis-phosphatases increased in the intestine and kidney but slightly changed in the liver. Activity of glucose-6-phosphate dehydrogenase profoundly increased in the renal cortex but decreased in other tissues. Lipid peroxidation increased in the intestine and renal medulla and decreased in the renal cortex and liver; catalase increased in all tissues but the medulla. Superoxide dismutase activity decreased in the intestine but increased in renal tissues. Activities of brush border membrane enzymes in general increased in the intestine and kidney. CONCLUSION: Green tea consumption resulted in enhanced enzyme activities of carbohydrate metabolism and antioxidant defenses, which may lead to improved health.