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Mitochondrial (MITO) dysfunction occurs in the failing heart and contributes to worsening of heart failure (HF). Reduced aldehyde dehydrogenase 2 (ALDH2) in left ventricular (LV) myocardium of diabetic hearts has been implicated in MITO dysfunction through accumulation of toxic aldehydes including and elevated levels of 4-hydroxy-2-nonenal (4HNE). This study examined whether dysregulation of MITO ALDH2 (mALDH2) occurs in mitochondria of the failing LV and is associated with increased levels of 4HNE.LV tissue from 7 HF and 7 normal (NL) dogs was obtained. Protein quantification of total mitochondrial ALDH2 (t-mALDH2), phosphorylated mALDH2 (p-mALDH2), total MITO protein kinase c epsilon (t-mPKCε), phosphorylated mPKCε (p-mPKCε) was performed by Western blotting, and total mALDH2 enzymatic activity was measured. Protein adducts of 4HNE-MITO and 4HNE-mALDH2 were also measured in MITO fraction by Western Blotting.Protein level of t-mALDH2 was decreased in HF compared with NL dogs (0.63 ± 0.07 vs 1.17 ± 0.08, p

Breast cancer remains a leading cause of death worldwide. The Apiaceae plant family includes many culinary spices that have been shown to have medicinal properties. Many phytochemicals exhibit potent bioactivities but often suffer from poor uptake and oral bioavailability. Bovine milk and colostrum exosomes are a compelling drug delivery platform that could address this issue; these natural nanoparticles can be loaded with hydrophilic and lipophilic small molecules and biologics, resulting in lower doses needed to inhibit cancer growth. Ethanolic extracts of eight Apiaceae spices were examined for phytochemical content and antiproliferative potential. Acid hydrolysis (AH) was employed to remove glycosides, asses its impacts on extract efficacy, and evaluate its effects on exosome loading and subsequent formulation efficacy. Antiproliferative activity was assessed through MTT assays on T-47D, MDA-MB-231, and BT-474 breast cancer cells; all extracts exhibited broad antiproliferative activity. AH enhanced the bioactivity of cumin, caraway, and fennel in T-47D cells. Celery, cumin, anise, and ajwain showed the highest activity and were assayed in exosomal formulations, which resulted in reduced doses required to inhibit cellular proliferation for all extracts except AH-cumin. Apiaceae spice extracts demonstrated antiproliferative activities that can be improved with AH and further enhanced with exosomal delivery.

Emerging viral diseases, such as Ebola, SARS, MERS, and the pathogen causing COVID-19, SARS-CoV-2, present a challenge for the development of therapeutics because of strict biosafety handling procedures and rapid mutation of their genomes. To facilitate the development of an adaptable and testable therapeutic model system, a colostrum exosome-based nanoparticle delivery system, EPM (exosome-PEI matrix), that overcomes stringent biosafety containment, was used to mimic the expression of viral proteins. This system would greatly expand the number of laboratories actively participating in the screening of potential therapeutics. EPM technology can deliver both plasmid DNA and siRNA to both simulate viral gene expression and screen potential antiviral siRNA therapeutics. Using this nanoplatform, three key SARS-CoV-2 proteins (the spike glycoprotein, nucleocapsid, and replicase) were expressed in vitro and in vivo. In vitro, several viral gene-targeting siRNAs were screened to determine knockdown efficiency, with some siRNA duplexes resulting in 80%–95% knockdown of corresponding protein expression. Moreover, in vivo experiments introducing the spike protein and nucleocapsid by EPM resulted in the production of antibodies against the viral antigen, measured up to 45 d after target delivery. Together, these findings support the efficacy of the EPM delivery system to establish a model for screening antiviral therapeutics-reduced biosafety level.

Taurine, a cysteine-derived zwitterionic sulfonic acid, is a common ingredient in energy drinks and is naturally found in fish and other seafood. In humans, taurine is produced mainly in the liver, and it can also be obtained from food. In target tissues, such as the retina, heart, and skeletal muscle, it functions as an essential antioxidant, osmolyte, and antiapoptotic agent. Taurine is also involved in energy metabolism and calcium homeostasis. Taurine plays a considerable role in bone growth and development, and high-profile reports have demonstrated the importance of its metabolism for bone health. However, these reports have not been collated for more than 10 years. Therefore, this review focuses on taurine–bone interactions and covers recently discovered aspects of taurine’s effects on osteoblastogenesis, osteoclastogenesis, bone structure, and bone pathologies (e.g., osteoporosis and fracture healing), with due attention to the taurine–cartilage relationship.

Around the world, more than 6.2 million individuals have died as a result of coronavirus disease 2019 (COVID-19). According to a recent survey conducted among immunologists, epidemiologists, and virologists, this disease is expected to become endemic. This implies that the disease could have a continuous presence and/or normal frequency in the population. Pharmacological interventions to prevent infection, as well as to treat the patients at an early phase of illness to avoid hospitalization are essential additions to the vaccines. Taurine is known to inhibit the generation of all inflammatory mediators linked to the cytokine storm. It can also protect against lung injury by suppressing increased oxidants production and promoting the resolution of the inflammatory process. Neutrophil lactoferrin degranulation stimulated by taurine may have antiviral effects against SARS-CoV-2, limiting viral replication. It is hypothesized that if taurine is administered early in the onset of COVID-19 disease, it may stop the cytokine storm from progressing, lowering morbidity and mortality.

Despite its introduction more than three decades ago, gene therapy has fallen short of its expected potential for the treatment of a broad spectrum of diseases and continues to lack widespread clinical use. The fundamental limitation in clinical translatability of this therapeutic modality has always been an effective delivery system that circumvents degradation of the therapeutic nucleic acids, ensuring they reach the intended disease target. Plasmid DNA (pDNA) for the purpose of introducing exogenous genes presents an additional challenge due to its size and potential immunogenicity. Current pDNA methods include naked pDNA accompanied by electroporation or ultrasound, liposomes, other nanoparticles, and cell-penetrating peptides, to name a few. While the topic of numerous reviews, each of these methods has its own unique set of limitations, side effects, and efficacy concerns. In this review, we highlight emerging uses of exosomes for the delivery of pDNA for gene therapy. We specifically focus on bovine milk and colostrum-derived exosomes as a nano-delivery “platform”. Milk/colostrum represents an abundant, scalable, and cost-effective natural source of exosomes that can be loaded with nucleic acids for targeted delivery to a variety of tissue types in the body. These nanoparticles can be functionalized and loaded with pDNA for the exogenous expression of genes to target a wide variety of disease phenotypes, overcoming many of the limitations of current gene therapy delivery techniques.

In this paper, we consider a survival model of a series system with random sample size, Z. Such a situation arises in competing risk analysis where the number of causes of failure is random and only the minimum of the survival times due to various causes is observed. Considering the distribution of Z as generalized Sibuya and the baseline distribution as Weibull, a Weibull-generalized Sibuya distribution is derived. The structural properties of the proposed model are studied along with the maximum likelihood estimation of the parameters. Extensive simulation studies are carried out to study the performance of the estimators. For illustration, two real data sets are analyzed and it is shown that the proposed model fits better than some of the existing models.

Complexes of curcumin with metals have shown much-improved stability, solubility, antioxidant capability, and efficacy when compared to curcumin. The present research investigates the relative bioavailability, antioxidant, and ability to inhibit inflammatory cytokine production of a curcuminoid metal chelation complex of tetrahydrocurcumin-zinc-curcuminoid termed TurmiZn. In vitro uptake assay using pig intestinal epithelial cells showed that TurmiZn has an ~3-fold increase (p ≤ 0.01) in uptake compared to curcumin and a ~2-fold increase (p ≤ 0.01) over tetrahydrocurcumin (THC). In a chicken model, an oral 1-g dose of TurmiZn showed a ~2.5-fold increase of a specific metabolite peak compared to curcumin (p = 0.004) and a ~3-fold increase compared to THC (p = 0.001). Oral doses (5 g/Kg) of TurmiZn in rats also showed the presence of curcumin and THC metabolites in plasma, indicating bioavailability across cell membranes in animals. Determination of the antioxidant activity by a 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) radical scavenging assay indicated that TurmiZn was about 13x better (p ≤ 0.0001) than curcumin and about 4X better (p ≤ 0.0001) than THC, in reducing free radicals. In vitro experiments further showed significant (p ≤ 0.01) reductions of lipopolysaccharide (LPS)-induced proinflammatory cytokines such as interleukin (IL) IL-6, IL-8, IL-15, IL-18, and tumor necrosis factor (TNF)-alpha, while showing a significant (p ≤ 0.01) increase of granulocyte-macrophage colony-stimulating factor (GM-CSF) in dog kidney cells. In vivo cytokine modulations were also observed when TurmiZn was fed for 6 weeks to newborn chickens. TurmiZn reduced IL-1 and IL-6, but significantly reduced (p ≤ 0.01) IL-10 levels while there was a concurrent significant (p = 0.02) increase in interferon gamma compared to controls. Overall, these results indicate that TurmiZn has better bioavailability and antioxidant capability than curcumin or THC and has the ability to significantly modulate cytokine levels. Thus, TurmiZn could be an excellent candidate for a novel ingredient that can be incorporated into food and supplements to help overall health during the aging process.

Taurine is a naturally occurring amino acid involved in various functions, including regulating ion channels, cell volume, and membrane stabilization. However, how this molecule orchestrates such functions is unknown, particularly the dose response in exercised muscles. Therefore, this review aimed to systematically review the dose response of taurine on both aerobic and strength exercise performance. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, relevant articles were sought on PubMed, Medline, Web of Science, and Google Scholar using related terms, including taurine, exercise performance, exercise, muscle, physical training, running, strength, endurance exercise, resistance exercise, aerobic exercise, and swimming. Ten articles were retrieved, reviewed, and subjected to systematic analysis. The following parameters were used to assess exercise performance in the selected studies: creatine kinase (CK), lactic acid dehydrogenase, carbohydrate, fat, glycerol, malondialdehyde, enzymatic antioxidants, blood pH, taurine level, and muscular strength. From the selected literature, we observed that taurine supplementation (2 g three times daily) with exercise can decrease DNA damage. Furthermore, 1 g of acute taurine administration before or after exercise can decrease lactate levels. However, acute administration of taurine (6 g) at a high dose before the start of exercise had no effect on reducing lactate level, but increased glycerol levels, suggesting that taurine could be an effective agent for prolonged activities, particularly at higher intensities. However, further studies are warranted to establish the role of taurine in fat metabolism during exercise. Finally, we observed that a low dose of taurine (0.05 g) before performing strength enhancing exercises can decrease muscular fatigue and increase enzymatic antioxidants.Systematic Review Registration:http://www.crd.york.ac.uk/PROSPERO, PROSPERO (CRD42021225243).

Abstract Diabetes is a complex condition with a variety of causes and pathophysiologies. The current single target approach has not provided ideal clinical outcomes for the treatment of the disease and its complications. Herbal medicine has been used for the management of various diseases such as diabetes over centuries. Many diabetic patients are known to use herbal medicines with antidiabetic properties in addition to their mainstream treatments, which may present both a benefit as well as potential risk to effective management of their disease. In this review we evaluate the clinical and experimental literature on herb–drug interactions in the treatment of diabetes. Pharmacokinetic and pharmacodynamic interactions between drugs and herbs are discussed, and some commonly used herbs which can interact with antidiabetic drugs summarised. Herb–drug interactions can be a double-edged sword presenting both risks (adverse drug events) and benefits (through enhancement). There is a general lack of data on herb–drug interactions. As such, more rigorous scientific research is urgently needed to guide clinical practice as well as to safeguard the wellbeing of diabetes patients.

Hyaluronic acid (also known as hyaluronan or hyaluronate) is naturally found in many tissues and fluids, but more abundantly in articular cartilage and synovial fluid (SF). Hyaluronic acid (HA) content varies widely in different joints and species. HA is a non-sulfated, naturally occurring non-protein glycosaminoglycan (GAG), with distinct physico-chemical properties, produced by synoviocytes, fibroblasts, and chondrocytes. HA has an important role in the biomechanics of normal SF, where it is partially responsible for lubrication and viscoelasticity of the SF. The concentration of HA and its molecular weight (MW) decline as osteoarthritis (OA) progresses with aging. For that reason, HA has been used for more than four decades in the treatment of OA in dogs, horses and humans. HA produces anti-arthritic effects via multiple mechanisms involving receptors, enzymes and other metabolic pathways. HA is also used in the treatment of ophthalmic, dermal, burns, wound repair, and other health conditions. The MW of HA appears to play a critical role in the formulation of the products used in the treatment of diseases. This review provides a mechanism-based rationale for the use of HA in some disease conditions with special reference to OA.

This paper deals with a general bivariate correlated frailty model. This includes the multiplicative as well as the additive frailty effect. The association parameter is studied for the shared as well as the general correlated model. The results for the gamma, the inverse Gaussian and the stable frailty models are derived.

Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed.

Aim : To evaluate the efficacy of modified temporalis muscle transfer (TMT) by silicone sling for the management of paralytic lagophthalmos. Settings and Design: Prospective interventional study. Materials and Methods : Ten patients of lagophthalmos due to facial palsy underwent modified TMT using silicone sling. The patients were followed-up for a period of 3 months. Palpebral aperture in primary gaze and during eye closure were assessed both pre- and postoperatively along with problems associated with lagophthalmos like exposure keratopathy and lacrimation. Statistical Analysis : Paired t-test was applied to measure the statistical outcome. Results : Eight patients achieved full correction of lagophthalmos with no lid gap on closing the eye. The mean (standard deviation (SD)) lid gap on eye closure was 7.7 (0.86) mm preoperatively, 0.5 (0.47) mm at 1 st postoperative day, and 0.7 (0.75) mm at 3 rd month. There was a reduction in mean lid gap on eye closure of 7 mm at 3 months (P < 0.0001) which is highly significant. The mean (SD) vertical interpalpebral distance during primary gaze was 12.05 (1.12) mm preoperatively, 10 (0.94) mm at 1 st postoperative day, and 10.35 (1.08) mm at 3 rd month. There was a reduction in mean vertical inter palpebral distance of 1.7 mm at 3 months (P = 0.001) which is significant. Exposure keratitis decreased in five out of six patients at 3 months. Conclusion : Modified TMT by silicone sling is a useful procedure with lesser morbidity and good outcomes for the treatment of paralytic lagophthalmos due to long standing facial palsy.

A new delivery method via polymeric implants was used for continuous exposure to PCBs. Female Sprague-Dawley rats received subcutaneous polymeric implants containing PCB126 (0.15% load), PCB153 (5% load), or both, for up to 45 d and release kinetics and tissue distribution were measured. PCB153 tissue levels on day 15 were readily detected in lung, liver, mammary and serum, with highest levels in the mammary tissue. PCB126 was detected only in liver and mammary tissues. However, a completely different pharmacokinetics was observed on co-exposure of PCB153 and PCB126, with a 1.8-fold higher levels of PCB153 in the liver whereas a 1.7-fold lower levels in the mammary tissue. PCB126 and PCB153 caused an increase in expression of key PCB-inducible enzymes, CYP 1A1/2 and 2B1/2, respectively. Serum and liver activities of the antioxidant enzymes, PON1 and PON3, and AhR transcription were also significantly increased by PCB126. 32P-postlabeling for polar and lipophilic DNA-adducts showed significant quantitative differences: PCB126 increased 8-oxodG, an oxidative DNA lesion, in liver and lung tissues. Adduct levels in the liver remained upregulated up to 45 d, while some lung DNA adducts declined. This is the first demonstration that continuous low-dose exposure to PCBs via implants can produce sustained tissue levels leading to the accumulation of DNA-adducts in target tissue and induction of indicator enzymes. Collectively, these data demonstrate that this exposure model is a promising tool for long-term exposure studies.