Translation from Preclinical Research to Clinical Trials: Transdermal Drug Delivery for Neurodegenerative and Mental Disorders.

Neurodegenerative diseases (NDs), particularly dementia, provide significant problems to worldwide healthcare systems. The development of therapeutic materials for various diseases has a severe challenge in the form of the blood-brain barrier (BBB). Transdermal treatment has recently garnered widespread favor as an alternative method of delivering active chemicals to the brain. This approach has several advantages, including low invasiveness, self-administration, avoidance of first-pass metabolism, preservation of steady plasma concentrations, regulated release, safety, efficacy, and better patient compliance. Topics include the transdermal method for therapeutic NDs, their classification, and the mechanisms that allow the medicine to enter the bloodstream through the skin. The paper also discusses the obstacles and potential outcomes of transdermal therapy, emphasizing the benefits and drawbacks of different approaches.

Body Composition Changes Over the Menopausal Transition in Women With and Without Human Immunodeficiency Virus.

BACKGROUND: Women are at risk for weight gain during the transition to menopause, but few have examined the contribution of menopause to weight gain in women with human immunodeficiency virus (WWH). METHODS: From 2000 to 2013, participants (621 WWH; 218 without HIV [WWOH]) from the Women's Interagency HIV Study were categorized by menopausal phase using serial measures of anti-Müllerian hormone (AMH). Multivariable linear mixed models examined the association of menopausal phase with body mass index (BMI) and waist circumference (WC) trajectory, stratified by HIV status. RESULTS: In models controlled for chronologic age, the estimated effects (95% confidence interval) of menopausal phase on annual rate of BMI change across early perimenopause, late perimenopause, and menopause, respectively, compared to premenopause were -0.55% (-.80 to -.30), -0.29% (-.61 to .03), and -0.67% (-1.12 to -.20) in WWH, whereas estimated effects were 0.43% (-.01 to .87) and 0.15% (-.42 to .71) across early and late perimenopause, respectively, and -0.40% (-1.24 to .45) across menopause in WWOH. The estimated effects on rate of WC change were negative across early perimenopause (-0.21% [-.44 to .03]) and menopause (-0.12% [-.5 to .26]) and positive across late perimenopause (0.18% [-.10 to .45]) in WWH, and positive across all 3 menopausal phases in WWOH, but these effects were not statistically significant. CONCLUSIONS: In WWH, the menopausal transition was associated with BMI and WC trajectories that were mostly in a negative direction and opposite from WWOH after adjusting for age, suggesting that HIV blunts weight gain during the menopausal transition.

Advances in Hydrogel-Based Drug Delivery Systems for Parkinson's Disease.

Parkinson's disease (PD) is a common central nervous system disorder (CNS) characterized by cell loss in the substantia nigra. Severe loss of dopaminergic neurons and Lewy body formation with α-synuclein inclusions are the main neuropathological features of PD. There's currently no cure for PD, but treatments are available to help relieve the symptoms and maintain quality of life. However, the variety of clinically available therapeutic molecules is mainly limited to treating symptoms rather than halting or reversing disease progression via medical interventions. As an emerging drug carrier, hydrogels loaded with therapeutic agents and cells are attracting attention as an alternative and potentially more effective approach to managing PD. The current work highlights applications of hydrogel-based biomaterials in cell culture and disease modeling as carriers for cells, medicines, and proteins as PD therapeutic models.

The Potential Crosstalk Between the Brain and Visceral Adipose Tissue in Alzheimer's Development.

The bidirectional communication between the brain and peripheral organs have been widely documented, but the impact of visceral adipose tissue (VAT) dysfunction and its relation to structural and functional brain changes have yet to be fully elucidated. This review initially examines the clinical evidence supporting associations between the brain and VAT before visiting the roles of the autonomic nervous system, fat and glucose metabolism, neuroinflammation, and metabolites. Finally, the possible effects and potential mechanisms of the brain-VAT axis on the pathogenesis of Alzheimer's disease are discussed, providing new insights regarding future prevention and therapeutic strategies.

Lipid-Based Nanocarriers via Nose-to-Brain Pathway for Central Nervous System Disorders.

Neurodegenerative disorders are distinguished by the gradual deterioration of the nervous system's structure and function due to oxidative stress, mitochondrial dysfunction, protein misfolding, excitotoxicity, and neuroinflammation. Among these NDs, Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis characterized an increasing dysfunction and loss of neuronal structure leading to neuronal cell death. Although there is currently no drug to totally reverse the effects of NDs, such novel formulations and administration routes are developed for better management and nose-to-brain delivery is one of delivery for treating NDs. This review aimed to highlight advances in research on various lipid based nanocarriers such as liposomes, solid lipid nanoparticles, nanostructured lipid carriers, microemulsion, nanoemulsion, and cubosomes which are reported to treat and alleviate the symptoms of NDs via nose-to-brain route. The challenges during clinical translation of lipid nanocarriers from bench to bed side is also discussed.

Microneedles enable the development of skin-targeted vaccines against coronaviruses and influenza viruses.

Throughout the COVID-19 pandemic, many have seriously worried that the plus burden of seasonal influenza that might create a destructive scenario, resulting in overwhelmed healthcare capacities and onwards loss of life. Many efforts to develop a safe and efficacious vaccine to prevent infection by coronavirus and influenza, highlight the importance of vaccination to combat infectious pathogens. While vaccines are traditionally given as injections into the muscle, microneedle (MN) patches designed to precisely deliver cargos into the cutaneous microenvironment, rich in immune cells, provide a noninvasive and self-applicable vaccination approach, reducing overall costs and improving access to vaccines in places with limited supply. The current review aimed to highlight advances in research on the development of MNs-mediated cutaneous vaccine delivery. Concluding remarks and challenges on MNs-based skin immunization are also provided to contribute to the rational development of safe and effective MN-delivered vaccines against these emerging infectious diseases.

In silico and in vitro studies on the anti-cancer activity of artemetin, vitexicarpin and penduletin compounds from Vitex negundo.

Vitex negundo L. (V. negundo) is one of the important medicinal and anticancer enhancer herbs. This plant is commonly used in the preparation of traditional drugs to treat numerous diseases. Inspired by the medicinal properties of this plant, the current study aimed to investigate antiproliferative potential and the primary molecular mechanisms of the apoptotic induction against human HepG2 and MCF-7 cell lines, by pure compounds isolated from targeted fractions of V. negundo which were characterized by NMR, FTIR and HRMS analysis and identified as artemetin (FLV1), vitexicarpin (FLV2), and penduletin (FLV3) compounds. The FLV1, FLV2, and FLV3 compounds were evaluated for the antiproliferative potential against HepG2 and MCF-7 cell lines by cell viability assay and exhibited IC50 values of 2.3, 23.9 and 5.6 µM and 3.9, 25.8, and 6.4 µM, respectively. In addition, those compounds increased the level of reactive oxygen species production, induced cell death occurred via apoptosis, demonstrated by Annexin V-staining cells, contributed significantly to DNA damage, and led to the activation of caspase3/caspase8 pathways.Additionally, molecular docking was also conducted to rationalize the cancer cells inhibitory and to evaluate the ability of the FLV1, FLV2, and FLV3 compounds to be developed as good drug candidates for cancers treatment.

Identification and whole-genome characterization of a novel Porcine Circovirus 3 subtype b strain from swine populations in Vietnam.

Porcine circovirus 3 (PCV3) is a novel circovirus detected in pigs suffering from porcine dermatitis and nephropathy syndrome (PDNS), reproductive failure, and multisystemic infection. In this study, we identified PCV3 infection in aborted fetuses and reported the full-length genome sequence of a PCV3 strain identified from southern Vietnam. The complete genome of this PCV3 strain is 2000 nucleotides in length. We found that it shares 98.5-99.25% sequence identity with other reference sequences and that it clusters with the PCV3b subtype. Several specific mutated sites were found to be unique to this Vietnamese PCV3b strain, including I14M in the Rep protein and K139R, I150F, and P169T in the Cap protein. The sequence data that have been made publically available as part of this study will help investigators to better understand the molecular characteristics, genetic diversity, and evolutionary history of PCV3. Careful and in-depth investigations into the epidemiology, pathogenicity, and the evolution of this novel virus is a matter of urgent economic and agricultural interest in Vietnam.

Genetic Diversity of Porcine Circovirus Subtypes from Aborted Sow Fetuses in Vietnam.

Porcine circovirus type 3 (PCV3) is an emerging circovirus that is highly distributed among swine worldwide and associated with porcine dermatitis and nephropathy syndrome, reproductive failure, and multisystemic inflammation. Here, we investigated and characterized PCV3 from aborted fetuses in Vietnam. We found that the whole genomes of PCV3 collected in these Vietnamese pig farms share 98.4-99.45% sequence identity with reference PCV3 sequences. Several distinct mutation were identified in both the Rep protein and Cap protein of these strains. These strains were clustered into two distinct subtypes (3a1 and 3b). This study contributes to a better understanding of the molecular characteristics and genetic diversity of PCV3 in Vietnam.

Therapeutic Strategies and Nano-Drug Delivery Applications in Management of Aging Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder in which the death of brain cells causes memory loss and cognitive decline. Existing drugs only suppress symptoms or delay further deterioration but do not address the cause of the disease. In spite of screening numerous drug candidates against various molecular targets of AD, only a few candidates, such as acetylcholinesterase inhibitors, are currently utilized as an effective clinical therapy. Currently, nano-based therapies can make a difference, providing new therapeutic options by helping drugs to cross the blood-brain barrier and enter the brain more effectively. The main aim of this review was to highlight advances in research on the development of nano-based therapeutics for improved treatment of AD.

Role of Insulin Resistance in the Alzheimer's Disease Progression.

Recent studies continue to find evidence linking Type 2 diabetes (T2D) with Alzheimer's disease (AD), the most common cause of dementia, a general term for memory loss and other cognitive abilities serious enough to interfere with daily life. Insulin resistance or dysfunction of insulin signaling is a universal feature of T2D, the main culprit for altered glucose metabolism and its interdependence on cell death pathways, forming the basis of linking T2D with AD as it may exacerbate Aß accumulation, tau hyperphosphorylation and devastates glucose transportation, energy metabolism, hippocampal framework and promulgate inflammatory pathways. The current work demonstrates the basic mechanisms of the insulin resistance mediates dysregulation of bioenergetics and progress to AD as a mechanistic link between diabetes mellitus and AD. This work also aimed to provide a potential and feasible zone to succeed in the development of therapies in AD by enhanced hypometabolism and altered insulin signaling.

Type 3 Diabetes and Its Role Implications in Alzheimer's Disease.

The exact connection between Alzheimer's disease (AD) and type 2 diabetes is still in debate. However, poorly controlled blood sugar may increase the risk of developing Alzheimer's. This relationship is so strong that some have called Alzheimer's "diabetes of the brain" or "type 3 diabetes (T3D)". Given more recent studies continue to indicate evidence linking T3D with AD, this review aims to demonstrate the relationship between T3D and AD based on the fact that both the processing of amyloid-ß (Aß) precursor protein toxicity and the clearance of Aß are attributed to impaired insulin signaling, and that insulin resistance mediates the dysregulation of bioenergetics and progress to AD. Furthermore, insulin-related therapeutic strategies are suggested to succeed in the development of therapies for AD by slowing down their progressive nature or even halting their future complications.

Anti-Hepatocellular-Cancer Activity Exerted by ß-Sitosterol and ß-Sitosterol-Glucoside from Indigofera zollingeriana Miq.

Indigofera zollingeriana Miq (I. zollingeriana) is a widely grown tree in Vietnam. It is used to cure various illnesses. The purpose of this study was to investigate the chemical constituents of an I. zollingeriana extract and test its anticancer activity on hepatocellular cells (Huh7 and HepG2). The experimental results of the analysis of the bioactive compounds revealed that ß-sitosterol (ß-S) and ß-sitosterol-glucoside (ß-SG) were the main ingredients of the I. zollingeriana extract. Regarding anticancer activity, the ß-S and ß-SG of I. zollingeriana were found to exhibit cytotoxic effects against HepG2 and Huh7 cells, but not against normal human primary fibroblasts. The ß-S was able to inhibit the proliferation of HepG2 and Huh7 cells in a dose-dependent manner with half-maximal inhibitory concentration (IC50) values of 6.85 ± 0.61 µg/mL and 8.71 ± 0.21 µg/mL, respectively (p < 0.01), whereas the ß-SG IC50 values were 4.64 ± 0.48 µg/mL for HepG2 and 5.25 ± 0.14 µg/mL for Huh7 cells (p < 0.01). Remarkably, our study also indicated that ß-S and ß-SG exhibited cytotoxic activities via inducing apoptosis and activating caspase-3 and -9 in these cells. These findings demonstrated that ß-S and ß-SG from I. zollingeriana could potentially be developed into promising therapeutic agents to treat liver cancer.

Potential Antimicrobial and Anticancer Activities of an Ethanol Extract from Bouea macrophylla.

Bouea macrophylla is a tree widely grown throughout South East Asia. It is used in folk medicine for the treatment of various illnesses. The present study aimed to identify the chemical constituents and to test the antimicrobial and anticancer activities of an ethanol extract from B. macrophylla leaves. The extract exhibited excellent antibacterial properties against 9 out of 10 target microorganisms. including four Gram-negative bacteria (Escherichia coli, Shigella flexneri, Vibrio cholera, and Pseudomonas aeruginosa) and four Gram-positive bacteria (Staphylococcus aureus, Listeria monocytogenes, Enterococcus faecalis, and Bacillus cereus), as well as a fungus (Candida albicans). In addition, the extract was also tested on HeLa and human colorectal carcinoma (HCT116) cells to evaluate its cytostatic effects. The ethanol extract was able to inhibit the proliferation of HeLa and HCT116 cells, showing IC50 = 24 ± 0.8 and 28 ± 0.9 µg/mL, respectively, whereas the IC50 values of doxorubicin (standard) were 13.6 ± 1.3 and 15.8 ± 1.1 µg/mL respectively. Also, we identified various bioactive compounds in the extract such as polyphenols, flavonoids, caryophyllene, phytol, and trans-geranylgeraniol by GC-MS, which could contribute to the extract's biological activities. Therefore, our findings strongly indicate that the constituents of the B. macrophylla ethanol extract could be active against the tested bacteria and fungi as well as cancer cells. Further investigation is needed to understand the mechanisms mediating the antimicrobial and anticancer effects and identify signaling pathways that could be targeted for therapeutic application.

Development of Botulinum Toxin A-Coated Microneedles for Treating Palmar Hyperhidrosis.

Hyperhidrosis is a disorder that is characterized by the production of excess amounts of sweat. The botulinum neurotoxin A (BoNT/A) has been used to treat hyperhidrosis through multiple intradermal injections at the site of the condition. However, because of BoNT/A toxicity, it is important to precisely deliver the proper dose of the toxin to the target site. In addition, the use of a conventional hypodermic needle for multiple injections in the palm makes the approach undesirable and painful. Here, we designed a BoNT/A-coated microneedle (BoNT-MN) array and tested its efficacy as a substitute pain-free method to treat hyperhidrosis. BoNT-MNs were prepared by coating polylactic acid microneedles with a BoNT/A formulation and were found to successfully penetrate into a thick skin in vitro. The coating formulations were then tested for their stability at 4, 25, and 37 °C for 24 h. BoNT-MNs were found to be much more stable than BoNT/A in a liquid state. Additionally, we carried out in vivo experiments by treating the right paws of mice with BoNT-MNs and found that the treatment induced a significant reduction in the sweating response in the mouse foot pad. Thus, BoNT/A treatment using microneedles is beneficial and may be used as a more efficient and less painful approach to treat hyperhidrosis.

The Effect of Teaching Clinics on Prescribing Practices.

OBJECTIVE: The objective of this study was to investigate the effect of lack of continuity in a teaching clinic and to ascertain the role of supervisory attending in treatment decisions in a teaching psychiatric clinic. METHODS: A retrospective evaluation of paired consecutive visits of patients attending an education clinic was performed. RESULTS: Medication changes occurred in 56.3% of all visit pairs. Visit pairs in which the resident was unchanged had significantly more medication changes than visit pairs in which the attending was unchanged. When the resident stays the same, the number of medication changes is high and does not change significantly even if the attending is the same or different. Similarly, when the resident is different, the number of medication changes is low and does not change significantly if the attending is the same or different. CONCLUSION: Residents, not the attending physicians, are more instrumental in medication changes in patients attending an education clinic.

Right Atrial Volume is Increased in Corrected Tetralogy of Fallot and Correlates with the Incidence of Supraventricular Arrhythmia: A CMR Study.

The aim of this study was to evaluate right atrial (RA) volume in corrected Tetralogy of Fallot (cTOF) and assess its correlation with the occurrence of supraventricular (SV) arrhythmia. Cardiac magnetic resonance imaging (CMR) and 24-h Holter were performed in n = 67 consecutive cTOF patients (age 30 ± 11.3 years). The CMR protocol included standard HASTE, SSFP cine, and blood flow measurements. Correlations between arrhythmia in ECG, heart volume, and functional parameters were investigated by negative binominal regression. Patients' characteristics (mean ± SD) included mean RA volume of 49 ± 19 ml/m(2) (HASTE sequence), mean right ventricular (RV) end-diastolic volume of 98 ± 27 ml/m(2), mean pulmonary valve regurgitation fraction (PR) of 21 ± 19 %, BMI of 25 kg/m(2), and heart rate of 75/min. Twenty-eight out of 67 patients experienced SV arrhythmia including SV couplets or bigeminus or longer non-sustained SV tachycardia (SVT) episodes. RA volume index was identified as an independent risk factor for different degrees of SV arrhythmia (SV couplets/bigeminus p < 0.001, SVT p < 0.001). Further risk factors for SV arrhythmia were male gender (p = 0.023) and decreased left ventricular (LV) ejection fraction (EF) (LV EF p < 0.001). RA volume is increased in adult patients with cTOF with larger RA volumes relating to higher incidence of SV arrhythmia. SV arrhythmia also appeared more often in male patients and those with decreased LV EF. Risk stratification according to these parameters could help to optimize early prevention and adjusted individual therapy to improve patient outcome and quality of life.

Repressed TGF-ß signaling through CagA-Smad3 interaction as pathogenic mechanisms of Helicobacter pylori-associated gastritis.

Helicobacter pylori (H. pylori) infection causes chronic gastric inflammation, peptic ulceration, and gastric carcinogenesis, in which H. pylori cytotoxin-associated gene A (CagA) plays major pathogenic action. Since transforming growth factor-ß (TGF-ß) and its signaling also are principally implicated in either modulating gastric mucosal inflammatory responses or causing carcinogenesis and are attenuated after H. pylori infection, we hypothesized that dysregulated Smad signaling and repressed TGF-ß might be core pathogenic mechanism for H. pylori-associated gastritis or carcinogenesis. Until now, no precise underlying mechanism how deranged TGF-ß signaling developed after H. pylori infection relevant to various clinical manifestations remains unclear. In this study, we examined the molecular mechanism about the inhibition of TGF-ß signaling by H. pylori CagA protein. H. pylori CagA significantly suppressed TGF-ß/Smad transcriptional responses through critical inhibition of Smad3, though CagA interacted constitutively with Smad2, Smad3, and Smad4. CagA inhibited TGF-ß-induced suppression of proinflammatory chemokines, such as IL-8, CXCL1 and CXCL3, as well as TGF-ß-induced transcription of target genes. In conclusion, repressed TGF-ß signaling associated with CagA-positive H. pylori infection could be an important determinant for the outcome of H. pylori infection. Therefore, TGF-ß signaling is one of the important determinants to avoid from H. pylori CagA pathogenicity.

Making medical decisions in dependence of genetic background: estimation of the utility of DNA testing in clinical, pharmaco-epidemiological or genetic studies.

An index measuring the utility of testing a DNA marker before deciding between two alternative treatments is proposed which can be estimated from pharmaco-epidemiological case-control or cohort studies. In the case-control design, external estimates of the prevalence of the disease and of the frequency of the genetic risk variant are required for estimating the utility index. Formulas for point and interval estimates are derived. Empirical coverage probabilities of the confidence intervals were estimated under different scenarios of disease prevalence, prevalence of drug use, and population frequency of the genetic variant. To illustrate our method, we re-analyse pharmaco-epidemiological case-control data on oral contraceptive intake and venous thrombosis in carriers and non-carriers of the factor V Leiden mutation. We also re-analyse cross-sectional data from the Framingham study on a gene-diet interaction between an APOA2 polymorphism and high saturated fat intake on obesity. We conclude that the utility index may be helpful to evaluate and appraise the potential clinical and public health relevance of gene-environment interaction effects detected in genomic and candidate gene association studies and may be a valuable decision support for designing prospective studies on the clinical utility.

Natural flavonoids as potential therapeutics in the management of Alzheimer's disease: a review.

Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder which is associated with the accumulation of proteotoxic Aß peptides, and pathologically characterized by the deposition of Aß-enriched plaques and neurofibrillary tangles. Given the social and economic burden caused by the rising frequency of AD, there is an urgent need for the development of appropriate therapeutics. Natural compounds are gaining popularity as alternatives to synthetic drugs due to their neuroprotective properties and higher biocompatibility. While natural compound's therapeutic effects for AD have been recently investigated in numerous in vitro and in vivo studies, only few have developed to clinical trials. The present review aims to provide a brief overview of the therapeutic effects, new insights, and upcoming perspectives of the preclinical and clinical trials of flavonoids for the treatment of Alzheimer's disease.