The Effects of Nicotine on Re-endothelialization, Inflammation, and Neoatherosclerosis After Drug-Eluting Stent Implantation in a Porcine Model.

BACKGROUND AND OBJECTIVES: Cigarette smoking is a major risk factor for atherosclerosis. Nicotine, a crucial constituent of tobacco, contributes to atherosclerosis development and progression. However, evidence of the association between nicotine and neointima formation is limited. We aimed to evaluate whether nicotine enhances neointimal hyperplasia in the native epicardial coronary arteries of pigs after percutaneous coronary intervention (PCI) with drug-eluting stents (DES). METHODS: After coronary angiography (CAG) and quantitative coronary angiography (QCA), we implanted 20 DES into 20 pigs allocated to 2 groups: no-nicotine (n=10) and nicotine (n=10) groups. Post-PCI CAG and QCA were performed immediately. Follow-up CAG, QCA, optical coherence tomography (OCT), and histopathological analyses were performed 2 months post-PCI. RESULTS: Despite intergroup similarities in the baseline QCA findings, OCT analysis showed that the nicotine group had a smaller mean stent and lumen areas, a larger mean neointimal area, greater percent area stenosis, and higher peri-strut fibrin and inflammation scores than the no-nicotine group. In immunofluorescence analysis, the nicotine group displayed higher expression of CD68 and α-smooth muscle actin but lower CD31 expression than the no-nicotine group. CONCLUSIONS: Nicotine inhibited re-endothelialization and promoted inflammation and NIH after PCI with DES in a porcine model.

Genetic Alchemy unveiled: MicroRNA-mediated gene therapy as the Artisan craft in the battlefront against hepatocellular carcinoma-a comprehensive chronicle of strategies and innovations.

Investigating therapeutic miRNAs is a rewarding endeavour for pharmaceutical companies. Since its discovery in 1993, our understanding of miRNA biology has advanced significantly. Numerous studies have emphasised the disruption of miRNA expression in various diseases, making them appealing candidates for innovative therapeutic approaches. Hepatocellular carcinoma (HCC) is a significant malignancy that poses a severe threat to human health, accounting for approximately 70%-85% of all malignant tumours. Currently, the efficacy of several HCC therapies is limited. Alterations in various biomacromolecules during HCC progression and their underlying mechanisms provide a basis for the investigation of novel and effective therapeutic approaches. MicroRNAs, also known as miRNAs, have been identified in the last 20 years and significantly impact gene expression and protein translation. This atypical expression pattern is strongly associated with the onset and progression of various malignancies. Gene therapy, a novel form of biological therapy, is a prominent research area. Therefore, miRNAs have been used in the investigation of tumour gene therapy. This review examines the mechanisms of action of miRNAs, explores the correlation between miRNAs and HCC, and investigates the use of miRNAs in HCC gene therapy.

Beyond the beat: A pioneering investigation into exercise modalities for alleviating diabetic cardiomyopathy and enhancing cardiac health.

Patients with preexisting cardiovascular disease or those at high risk for developing the condition are often offered exercise as a form of therapy. Patients with cancer who are at an increased risk for cardiovascular issues are increasingly encouraged to participate in exercise-based, interdisciplinary programs due to the positive correlation between these interventions and clinical outcomes following myocardial infarction. Diabetic cardiomyopathy (DC) is a cardiac disorder that arises due to disruptions in the homeostasis of individuals with diabetes. One of the primary reasons for mortality in individuals with diabetes is the presence of cardiac structural damage and functional abnormalities, which are the primary pathological features of DC. The aetiology of dilated cardiomyopathy is multifaceted and encompasses a range of processes, including metabolic abnormalities, impaired mitochondrial function, dysregulation of calcium ion homeostasis, excessive cardiomyocyte death, and fibrosis. In recent years, many empirical investigations have demonstrated that exercise training substantially impacts the prevention and management of diabetes. Exercise has been found to positively impact the recovery of diabetes and improve several metabolic problem characteristics associated with DC. One potential benefit of exercise is its ability to increase systolic activity, which can enhance cardiometabolic and facilitate the repair of structural damage to the heart caused by DC, leading to a direct improvement in cardiac health. In contrast, exercise has the potential to indirectly mitigate the pathological progression of DC through its ability to decrease circulating levels of sugar and fat while concurrently enhancing insulin sensitivity. A more comprehensive understanding of the molecular mechanism via exercise facilitates the restoration of DC disease must be understood. Our goal in this review was to provide helpful information and clues for developing new therapeutic techniques for motion alleviation DC by examining the molecular mechanisms involved.

Cyclam-Modified Polyethyleneimine for Simultaneous TGFß siRNA Delivery and CXCR4 Inhibition for the Treatment of CCl4-Induced Liver Fibrosis.

BACKGROUND: Liver fibrosis is a chronic liver disease with excessive production of extracellular matrix proteins, leading to cirrhosis, hepatocellular carcinoma, and death. PURPOSE: This study aimed at the development of a novel derivative of polyethyleneimine (PEI) that can effectively deliver transforming growth factor ß (TGFß) siRNA and inhibit chemokine receptor 4 (CXCR4) for TGFß silencing and CXCR4 Inhibition, respectively, to treat CCl4-induced liver fibrosis in a mouse model. METHODS: Cyclam-modified PEI (PEI-Cyclam) was synthesized by incorporating cyclam moiety into PEI by nucleophilic substitution reaction. Gel electrophoresis confirmed the PEI-Cyclam polyplex formation and stability against RNAase and serum degradation. Transmission electron microscopy and zeta sizer were employed for the morphology, particle size, and zeta potential, respectively. The gene silencing and CXCR4 targeting abilities of PEI-Cyclam polyplex were evaluated by luciferase and CXCR4 redistribution assays, respectively. The histological and immunohistochemical staining determined the anti-fibrotic activity of PEI-Cyclam polyplex. The TGFß silencing of PEI-Cyclam polyplex was authenticated by Western blotting. RESULTS: The 1H NMR of PEI-Cyclam exhibited successful incorporation of cyclam content onto PEI. The PEI-Cyclam polyplex displayed spherical morphology, positive surface charge, and stability against RNAse and serum degradation. Cyclam modification decreased the cytotoxicity and demonstrated CXCR4 antagonistic and luciferase gene silencing efficiency. PEI-Cyclam/siTGFß polyplexes decreased inflammation, collagen deposition, apoptosis, and cell proliferation, thus ameliorating liver fibrosis. Also, PEI-Cyclam/siTGFß polyplex significantly downregulated α-smooth muscle actin, TGFß, and collagen type III. CONCLUSION: Our findings validate the feasibility of using PEI-Cyclam as a siRNA delivery vector for simultaneous TGFß siRNA delivery and CXCR4 inhibition for the combined anti-fibrotic effects in a setting of CCl4-induced liver fibrosis.

The effectiveness of surgical adjunctive procedures in the acceleration of orthodontic tooth movement: A systematic review of systematic reviews and meta-analysis.

OBJECTIVE: To identify and evaluate the body of the evidence regarding the effectiveness of surgical adjunctive procedures (SAPs) in accelerating orthodontic tooth movement (OTM). DATA SOURCES: Unrestricted search of three electronic databases and manual search up to 12 June 2020 were undertaken. DATA SELECTION: All systematic reviews of randomised and non-randomised controlled trials that investigate the effectiveness of the SAPs in accelerating OTM were included. DATA EXTRACTION: Study selection and data extraction were undertaken independently and in duplicate by two reviewers. A random-effects model with a 95% confidence interval (CI) was generated for comparable outcomes. Two reviewers assessed the quality of the included studies using AMSTAR2 and GRADE. RESULTS: Fourteen systematic reviews were included; however, four systematic reviews were assessed quantitatively. Meta-analysis showed that mean difference (MD) of canine retraction rate, for the first month after SAPs, was mild (MD = 0.65 mm/month). Compared to control, micro-osteoperforations (MOPs) statistically but temporally accelerate lower canine retraction and en masse retraction by 0.25 mm/month and 0.31 mm/month, respectively. There was no significant effect (P>0.05) in terms of molar anchorage loss (MAL) between control and MOP groups. Piezocision non-significantly shortens the duration of en masse retraction (4.30 months, P>0.05), but significantly shortens incisors retraction (101.64 days, P<0.001). MAL is mild but significantly less in the piezocision group compared to the control group (MD = 0.53 mm, P=0.03). Low-level evidence showed that SAPs have no significant effect on root resorption or periodontal health; however, piezocision is associated with transient acute inflammation and noticeable scars. CONCLUSION: Low-level evidence concludes that SAPs accelerate OTMs and reduce treatment duration, but the acceleration is minor and transient. The effect on anchorage loss is variable and technique related. Side effects of SAPs are transient, but some might be aesthetically noticeable. A cost-benefit analysis of SAPs should be considered while making the treatment decision.

Functional Analysis of Peptidyl-prolyl cis-trans Isomerase from Aspergillus flavus.

Aspergillus flavus, a ubiquitous filamentous fungus found in soil, plants and other substrates has been reported not only as a pathogen for plants, but also a carcinogen producing fungus for human. Peptidyl-Prolyl Isomerase (PPIases) plays an important role in cell process such as protein secretion cell cycle control and RNA processing. However, the function of PPIase has not yet been identified in A. flavus. In this study, the PPIases gene from A. flavus named ppci1 was cloned into expression vector and the protein was expressed in prokaryotic expression system. Activity of recombinant ppci1 protein was particularly inhibited by FK506, CsA and rapamycin. 3D-Homology model of ppci1 has been constructed with the template, based on 59.7% amino acid similarity. The homologous recombination method was used to construct the single ppci1 gene deletion strain Δppci1. We found that, the ppci1 gene plays important roles in A. flavus growth, conidiation, and sclerotia formation, all of which showed reduction in Δppci1 and increased in conidiation compared with the wild-type and complementary strains in A. flavus. Furthermore, aflatoxin and peanut seeds infection assays indicated that ppci1 contributes to virulence of A. flavus. Furthermore, we evaluated the effect of PPIase inhibitors on A. flavus growth, whereby these were used to treat wild-type strains. We found that the growths were inhibited under every inhibitor. All, these results may provide valuable information for designing inhibitors in the controlling infections of A. flavus.

Identification of a nonbasic melanin hormone receptor 1 antagonist as an antiobesity clinical candidate.

Identification of MCHR1 antagonists with a preclinical safety profile to support clinical evaluation as antiobesity agents has been a challenge. Our finding that a basic moiety is not required for MCHR1 antagonists to achieve high affinity allowed us to explore structures less prone to off-target activities such as hERG inhibition. We report the SAR evolution of hydroxylated thienopyrimidinone ethers culminating in the identification of 27 (BMS-819881), which entered obesity clinical trials as the phosphate ester prodrug 35 (BMS-830216).

Treatment of unstable intraarticular fracture of distal radius: POP casting with external fixation.

OBJECTIVE: To compare radiological and functional outcome of external fixation and distraction with conservative Plaster of Paris (POP) cast for unstable intra-articular fractures of the distal radius. METHODS: The study was conducted on 60 patients with unstable intra-articular fracture of distal radius who reported to emergency or outpatient Orthopaedic Surgery department of Benazir Bhutto Hospital, Rawalpindi, between March and August 2007. They were divided into two equal groups: Group A and Group B, treated by Plaster of Paris cast, and external fixation with distraction respectively. The functional outcome in terms of freedom from pain, range of movement, grip power and deformity, and the radiological outcome of radial length, incongruity and radio-ulnar joint position were analysed at three months follow-up using a 3-point scoring scale. RESULTS: In Group A, 1 (3%) patient showed excellent result, 8 (27%) patients good results, 19 (63%) patients fair results and 2 (7%) patients poor result. In Group B, 14 (47%) patients showed excellent results, 11 (37%) patients good results, 4 (13%) patients fair results and 1 (3%) patient poor result. The outcome score of the Group B patients was significantly better compared to the Group A patients (p value < 0.05). CONCLUSION: External fixation has definite advantages over conventional Plaster of Paris cast in the treatment of unstable intra-articular fractures of distal radius.

Anterior surgical interventions in spinal tuberculosis.

OBJECTIVE: To evaluate and compare the effectiveness of the modified Hong Kong procedure performed with and without additional instrumentation, in terms of improvement in neurological and kyphotic disabilities in spinal tuberculosis. STUDY DESIGN: Quasi-experimental study. PLACE AND DURATION OF STUDY: Department of Orthopaedic Surgery, Rawalpindi General Hospital, Rawalpindi, from June 1999 to May 2006. METHODOLOGY: Sixty-two cases of tuberculosis of spine, underwent modified Hong Kong procedure. In 44 cases (group A), no instrumentation was used, while in 18 cases (group B), additional anterior instrumentation in the form of narrow Dynamic Compression Plate (DCP), fixator spinae or Moss Miami instrumentation was used. Changes in the neurological status (following Frankel classification system) and kyphotic angle (as measured on X-ray) after an average of 18 months post-operative follow-up were evaluated and also compared between the two groups using t-test. RESULTS: There were 23 males and 39 females with mean age of 31.6 +/- 17.1 years. An average neurological improvement of 1.1 +/- 0.7 Frankel grade was achieved overall, which was statistically significant (p < 0.05). There was no significant difference in degree of neurological improvement on comparing the two groups (p = 0.272). In group A patients, mean improvement in kyphotic angle of 2.8 degrees +/- 5.5 degrees was achieved. In group B patients, treated with additional instrumentation, an average 8.9 degrees +/- 7.6 degrees correction was recorded. The difference in improvement between the two groups was statistically significant (p < 0.05). CONCLUSION: Modified Hong Kong procedure alone for spinal tuberculosis (TB) was successful in producing significant neurological recovery. The addition of stabilization instruments achieved better and maintained correction of kyphosis.

N-[1-Aryl-2-(1-imidazolo)ethyl]-guanidine derivatives as potent inhibitors of the bovine mitochondrial F1F0 ATP hydrolase.

A series of substituted guanidine derivatives were prepared and evaluated as potent and selective inhibitors of mitochondrial F(1)F(0) ATP hydrolase. The initial thiourethane derived lead molecules possessed intriguing in vitro pharmacological profiles, though contained moieties considered non-drug-like. Analogue synthesis efforts led to compounds with maintained potency and superior physical properties. Small molecules in this series which potently and selectivity inhibit ATP hydrolase and not ATP synthase may have utility as cardioprotective agents.