Background Stress-associated kinases are considered major pathological mediators in several incurable neurological disorders. Importantly, among these stress kinases, the c-Jun NH2-terminal kinase (JNK) has been linked to numerous neuropathological conditions, including oxidative stress, neuroinflammation, and brain degeneration associated with brain injuries such as ischemia/reperfusion injury. In this study, we adopted a drug repurposing/reprofiling approach to explore novel JNK3 inhibitors from FDA-approved medications to supplement existing therapeutic strategies. Materials and Methods We performed in silico docking analysis and molecular dynamics simulation to screen potential candidates from the FDA approved drug library using the standard JNK inhibitor SP600125 as a reference. After the virtual screening, dabigatran, estazolam, leucovorin, and pitavastatin were further examined in ischemic stroke using an animal rodent model of focal cerebral ischemia using transient middle cerebral artery occlusion (t-MCAO). The selected drugs were probed for neuroprotective effectiveness by measuring the infarct area (%) and neurological deficits using a 28-point composite score. Biochemical assays including ELISA and immunohistochemical experiments were performed. Results We obtained structural insights for dabigatran, estazolam, and pitavastatin binding to JNK3, revealing a significant contribution of the hydrophobic regions and significant residues of active site regions. To validate the docking results, the pharmacological effects of dabigatran, estazolam, leucovorin, and pitavastatin on MCAO were tested in parallel with the JNK inhibitor SP600125. After MCAO surgery, severe neurological deficits were detected in the MCAO group compared with the sham controls, which were significantly reversed by dabigatran, estazolam, and pitavastatin treatment. Aberrant morphological features and brain damage were observed in the ipsilateral cortex and striatum of the MCAO groups. The drugs restored the anti-oxidant enzyme activity and reduced the levels of oxidative stress-induced p-JNK and neuroinflammatory mediators such as NF-kB and TNF-ɑ in rats subjected to MCAO. Conclusion Our results demonstrated that the novel FDA-approved medications attenuate ischemic stroke-induced neuronal degeneration, possibly by inhibiting JNK3. Being FDA-approved safe medications, the use of these drugs can be clinically translated for ischemic stroke-associated brain degeneration and other neurodegenerative diseases associated with oxidative stress and neuroinflammation.

BackgroundEnterococci have emerged as more virulent and multidrug-resistant in community and hospital settings. The emergence of vancomycin resistant enterococci (VRE) in hospitals has posed a serious threat to public health. The widespread use of antibiotics to treat VRE infections has resulted in the development of resistant forms of these organisms.ObjectivesPresent study deals with the efficacy of antibiotic-nanoparticle combination against clinical isolates of VRE. This study has effectively evaluated the anti-enterococcal activity of metallic nanoparticles and their combination with antibiotics with the aim to search for new biocidal combinations.Materials and MethodsInitially, the isolates were identified by various biochemical tests and also by PCR, targeting ddl, vanA and vanB genes. Antibiotic susceptibility testing was carried out by disc diffusion method. Minimum inhibitory concentration (MIC) of both antibiotics and metal nanoparticles against VRE was done using broth dilution method. On the basis of MICs, a combination of both antibiotics and nanoparticles was used by physical mixing of antibiotics and different concentrations of nanoparticles.ResultsThe MIC of metal nanoparticles were found in the range of 0.31 - 30 mM. The combination of both antibiotics and nanoparticles has effectively reduced the MICs of ciprofloxacin from 16 - 256 μg/mL to 2 - 16 μg/mL, erythromycin 1024 - 2048 μg/mL to 128 - 512 μg/mL, methicillin 32 - 256 μg/mL to 8 - 64 μg/mL and vancomycin 2 - 512 μg/mL to 0.5 - 64 μg/mL.ConclusionsAmong the nanoparticles, ZnO was found as a potent metallic nanoparticle which effectively reduced the MIC upon combination with the antibiotics. The combination exhibited enhanced bactericidal activity against multidrug resistant clinical strains of VRE with dose dependency. Further extensive study on this aspect can prove their beneficial clinical use against resistant pathogens to combat increasing resistance to antibiotics.

The Editor and Publisher of Journal of Inflammation Research wish to retract the published article. Concerns were raised regarding the duplication of several images from Figures 9-11. Specifically, The authors responded to our queries but were unable to provide a satisfactory explanation for the duplicated images. The Editor requested for the article to be retracted and the authors were notified of this.Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction.The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as "Retracted".

High blood pressure is regarded as "the silent killer" because it often has no warning signs or symptoms. About 60% of people who have diabetes also have high blood pressure. Diabetes mellitus and metabolic syndrome are common in patients with chronic obstructive pulmonary disease (COPD) because COPD directly increases the insulin resistance. Insulin resistance commonly occurs with obesity, dyslipidaemia and hypertension. Together these make up the 'metabolic syndrome', which is a major determinant of cardiovascular morbidity and mortality. Thus; the purpose of this case study is to understand the complexity of diseases that can arise problems in treatment regimes to avoid clinical errors for optimizing the therapy plans. A 58 year old male was presented in the medical ward of semi-private hospital, Rawalpindi, Pakistan with chief complaints of acute exacerbation of COPD, uncontrolled hypertension, known carotid artery stenosis and left sided chest pain. On the basis of his medical investigation, the physician prescribed him tablet Theograde(theophylline) 350mg ½ BID(twice a day), tablet Rast (rosuvastatin) 10mg 1 × HS (at night), Tablet Lasix (furosemide) 40mg 1 × O.D (once a day), tablet Minipress (prazosin) , tablet Panadol (paracetamol) 2× TDS(three times a day), tablet Famot (famotidine) 40mg 1 × O.D, Atem (Ipratropium bromide) nebulization three times a day, Ventolin (salbuatamol) nebulization four times a day, Brufen (ibuprofen) cream, steam inhalation three times a day and Injection Leflox(levofloxacin) 500mg IV × O.D. vital signs showed temperature 99°F, respiratory rate 21 breaths/ minute, Blood pressure 150/105, pulse 86/minute and PEFR 250 L/minute. Cyanosis and edema were observed. CVS= S1+S2+ loud R2. There were certain clinical and pharmaceutical inaccuracies were noted during the treatment. Thus; a rational clinical practice needed to implement health care system. Specially; the avoidable clinical errors are required to be addressed to optimize the regimens. The need of hour is a qualified pharmacist side by side with an experienced prescriber which will help to avoid the undesired health related consequences.