Exosomes are nanoscale extracellular vesicles released by diverse cell types, serving essential functions in intercellular communication and physiological processes. These vesicles have garnered considerable interest in recent years for their potential as drug delivery systems, attributed to their natural origin, minimal immunogenicity, high biocompatibility, and capacity to traverse biological barriers, including the blood-brain barrier. Exosomes can be obtained from diverse biological fluids, rendering them accessible and versatile vehicles for therapeutic medicines. This study emphasizes the burgeoning significance of exosomes in drug administration, concentrating on their benefits, including improved stability, target selectivity, and the capacity to encapsulate various biomolecules, such as proteins, nucleic acids, and small molecules. Notwithstanding their potential applications, other problems remain, including as effective drug loading, industrial scalability, and the standardization of isolation methodologies. Overcoming these hurdles via new research is essential for fully harnessing the promise of exosomes in therapeutic applications, especially in the treatment of intricate diseases like cancer and neurological disorders.

Objectives: This study aims to evaluate the efficacy and safety of oral supplementation with hydrolyzed collagen peptides (HCP) type I and type III (CollaSel PRO®) in reducing joint pain and stiffness and improving physical function in patients with osteoarthritis (OA). Methods: In this randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov Identifier: NCT05369780; approved by the Institutional Review Board), 160 adult patients with OA (mean age 52.4 ± 4.3 years; 111 females, 49 males) were randomly assigned to receive either 10 g/day of CollaSel PRO® (n = 80) or placebo (maltodextrin, n = 80) for 8 weeks. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was used to evaluate knee and hip joints, and the American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scale (AOFAS-AHFS) was used for ankle joints. Assessments were conducted at baseline and at weeks 1, 4, and 8. Results: In the CollaSel PRO® group, a significant decrease in WOMAC scores (mean ± SD 50.5 ± 17.0, 40.7 ± 16.9 and 33.8 ± 16.5 vs. 53.7 ± 16.9, respectively, p < 0.001 for each) and significant increase in AOFAS-AHFS scores (64.2 ± 13.1, 73.6 ± 12.3 and 80.8 ± 9.9 vs. 61.8 ± 13.9, respectively, p < 0.001 for each) were noted at weeks 1, 4, and 8 compared to the baseline scores. WOMAC scores were significantly lower in comparing HCP and placebo, and AOFAS-AHFS scores were higher in the HCP group compared to the placebo group at weeks 4 and 8 (all p < 0.001). Conclusions: CollaSel PRO® appears to be a safe and effective option for the symptomatic management of osteoarthritis. It significantly improved joint pain, stiffness, and physical function in multiple joints. These improvements are not only statistically significant but also clinically meaningful, supporting the need for longer-term evaluation.

Antisense oligonucleotides (ASOs) are short, synthetic, single-stranded deoxynucleotide sequences composed of phosphate backbone-connected sugar rings. Designing of those strands is based on Watson-Crick hydrogen bonding mechanism. Thanks to rapidly advancing medicine and technology, evolving of the gene therapy area and ASO approaches gain attention. Considering the genetic basis of diseases, it is promising that gene therapy approaches offer more specific and effective options compared to conventional treatments. The objective of this review is to explain the mechanism of ASOs and discuss the characteristics and safety profiles of therapeutic agents in this field. Pharmacovigilance for gene therapy products is complex, requiring accurate assessment of benefit-risk balance and evaluation of adverse effects.

A common pathological hallmark of neurodegenerative disorders is neuronal cell death, accompanied by neuroinflammation and oxidative stress. The vasoactive intestinal peptide (VIP) is a pleiotropic peptide that combines neuroprotective and immunomodulatory actions. The gene therapy field shows long-term promise for treating a wide range of neurodegenerative diseases (ND). In this study, we aimed to investigate the in vitro efficacy of transduction of microglia using lentiviral gene therapy vectors encoding VIP (LentiVIP). Additionally, we tested the protective effects of the secretome derived from LentiVIP-infected “immortalized human” microglia HMC3 cells, and cells treated with Synthetic VIP (SynVIP), against toxin-induced neurodegeneration. First, LentiVIP, which stably expresses VIP, was generated and purified. VIP secretion in microglial conditioned media (MG CM) for LentiVIP-infected HMC3 microglia cells was confirmed. Microglia cells were activated with lipopolysaccharide, and groups were formed as follows: 1) Control, 2) SynVIP-treated, or 3) LentiVIP-transduced. These MG CM were applied on an in vitro neurodegenerative model formed by differentiated (d)- SH-SY5Y cells. Then, cell survival analysis and apoptotic nuclear staining, besides measurement of oxidative/inflammatory parameters in CM of cells were performed. Activated MG CM reduced survival rates of both control and toxin-applied (d)- SH-SY5Y cells, whereas LentiVIP-infected MG CM and SynVIP-treated ones exhibited better survival rates. These findings were supported by apoptotic nuclear evaluations of (d)- SH-SY5Y cells, alongside oxidative/inflammatory parameters in their CM. LentiVIP seems worthy of further studies for the treatment of ND because of the potential of gene therapy to treat diseases effectively with a single injection.

Scabies, caused by the Sarcoptes scabiei var hominis mite burrowing into the skin, is a highly contagious disease characterized by intense nocturnal itching. Its global impact is considerable, affecting more than 200 million individuals annually and posing significant challenges to healthcare systems worldwide. Transmission occurs primarily through direct skin-to-skin contact, contributing to its widespread prevalence and emergence as a substantial public health concern affecting large populations. This review presents consensus-based clinical practice guidelines for diagnosing and managing scabies, developed through the fuzzy Delphi method by dermatology, parasitology, pediatrics, pharmacology, and public health experts. The presence of burrows containing adult female mites, their eggs, and excreta is the diagnostic hallmark of scabies. Definitive diagnosis typically involves direct microscopic examination of skin scrapings obtained from these burrows, although dermoscopy has become a diagnostic tool in clinical practice. Treatment modalities encompass topical agents, such as permethrin, balsam of Peru, precipitated sulfur, and benzyl benzoate. In cases where topical therapy proves inadequate or in instances of crusted scabies, oral ivermectin is recommended as a systemic treatment option. This comprehensive approach addresses the diagnostic and therapeutic challenges associated with scabies, optimizing patient care, and management outcomes.

Background: This study aimed to evaluate the efficacy and safety of oral hydrolyzed collagen peptide (HCP) in healthy females by assessing the skin parameters via biophysical and skin imaging techniques. Methods: 112 females were randomly assigned to receive either HCP (n = 57; 10 g CollaSel Pro®) or placebo (n = 55; 10 g maltodextrin) daily for eight weeks. The contribution of HCP to skin elasticity, hydration, and roughness was investigated against a placebo, while the facial soft tissue sagging (RMS) and safety data were also recorded. Results: HCP was associated with significant improvements in skin elasticity (p = 0.009), skin hydration (p ranged from 0.003 to <0.001), and skin roughness (p ranged from 0.002 to <0.001). In the HCP vs. the placebo group, week eight values for skin elasticity (43.0 (7.4) vs. 40.3 (3.3) mPa, p = 0.017), skin hydration (65.8 (18.9) vs. 53.1 (14.9) g/m3, p < 0.001) and skin roughness (40.2 (20.4) vs. 24.9 (20.9) g/m3, p < 0.001) were significantly higher. In the HCP group, week 8 RMS values were significantly lower than baseline values (1.02 (0.21) vs. 1.10 (0.21) mm, p = 0.012). Conclusions: CollaSel Pro® HCP can be considered a well-tolerated, safe product that effectively improves dermal health and the appearance of sagging and ameliorates the signs of the aging process.

Introduction: Coronavirus diseases-2019 (COVID-19) have been ongoing for more than two years. Despite the scientific research conducted in this process, there is still no widely accepted definitive treatment for the disease. For treating COVID-19, using antiviral agents previously used for the treatment of other RNA-virus infections has been seen as a fast way to a solution, and favipiravir is one of the leading agents. This prospective, multicenter, observational study was designed to investigate the safety of favipiravir in 500 patients treated with favipravir for favipravir. Methods: This study was conducted as a multicenter prospective study. Eight different sites from four cities participated, and 500 patients were included in the study. Follow-up of laboratory parameters, adverse events (AEs), and amelioration of fever, dyspnea, and cough symptoms of the patients was recorded in a case report form. Results: A total of 475 patients from eight centers completed the study. A total of 401 AEs were reported in 206 (51.4%) patients, which were mild-to-moderate in the majority of cases. Serious AEs occurred in 5 patients and death occurred in 4 patients. From the first to the last measurement, serum alanine aminotransferase levels (31.9±27.7 vs. 47.2±49.7 U/L, p<0.001) increased, whereas C-reactive protein (39.9±66.4 vs. 15.2±30.5 mg/L, p<0.001) and creatine kinase (101.7±187.7 vs. 71.9±43.5 U/L, p=0.018) levels decreased. In follow-up parameters, oxygen saturation (SpO2; 96.2±2.7 vs. 97.5±2.1%, p<0.001) and amelioration of fever (>37.8 for 6.6% on day 3, 3.2% on day 5, and 0.6% on day 10), dyspnea (for 56.4% on day 5, 62.4% on day 7, and 81.2% on day 10), and cough (46.0% on day 5, 73.0% on day 7, and 87.3% on day 10) were noted in an increasingly higher percentage of patients with continued therapy. Conclusion: The current study provides real-life data of favipiravir, which is a unique option in Turkey for treating COVID-19 patients. The results revealed that favipiravir is a well-tolerated agent with a low side-effect profile. However, it needs to be evaluated with well-designed, dose-compared, randomized controlled studies for the evaluation of efficacy.

Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and lacks hormonal and growth factor receptors commonly expressed by other types of breast cancer making it difficult to treat by conventional treatments. Although gene therapy might be a therapeutic option, delivery of genes into TNBC cells is still an obstacle. In this study, it was aimed to overcome this obstacle by folic acid (FA) conjugated polyplex formulations to targeting the folate receptor which has been reported to be overexpressed in TNBC cells. Non-covalent complexes of FA and LPEI polyplexes (FA-polyplexes) were prepared at six different ratios. After characterization studies, cytotoxicity and transfection ability were evaluated. Conjugation of FA by increasing amounts of LPEI polyplexes, increased the size from 204.1 to 469.8 nm. Their PDI values were between 0.31-0.51, and zeta potentials were positive. After treatment with polyplex formulations, cell viability was decreased significantly starting from 3:1(w/w) polymer:pDNA ratio and from 3:3:1 (w/w)FA:polyplex ratio. Cell viability decreased below 70% above the 5:1 (w/w) polymer:pDNA ratio. Addition of folic acid to polyplex formulations reversed the cytotoxicity of P3, P4 and P5 formulations. Although LV-RFP pDNA was delivered successfully into 4T1 cells by all formulations, fluorescent microscope images showed that, the optimal formulations were FA-P3 and FA-P4. This gene delivery system, generated by non-covalent conjugation of folic acid to polyplexes, increased the uptake and decreased the cytotoxicity of LPEI polyplexes. Non-covalent complexes of folic acid-LPEI polyplexes represent promising delivery systems in gene therapy, directed against cancer cells expressing folate receptors.

With the discovery of genetic factors of diseases, gene therapy has become a promising treatment option for many diseases, especially for different types of cancer, one of which is breast cancer. Triple negative breast cancer (TNBC), with the lack of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), represents the most aggressive subtype of breast tumors. Currently, there is no targeted therapy available for TNBC due to the absence of molecular targets. Signal transducer and activator of transcription 3 (STAT3) oncogene is overexpressed in TNBC and plays an important role in the tumor formation and metastasis, thus may be considered as a potential therapeutic target. Delivery of RNA interference molecules (siRNA, shRNA, miRNA) to block genes responsible for tumor development/proliferation is a promising strategy for cancer therapy. The present study aimed to develop a polyplex system for delivery of pDNA-encoded STAT3-shRNA into the 4T1 TNBC cells. Polyplexes were prepared at different polymer:pDNA (1:1, 2:1, 3:1 w/w) ratios by either branched (B1S, B2S, B3S) or linear (L1S, L2S, L3S) polyethylenimines (PEIs) and characterized in terms of particle size, polydispersity index and zeta potential. Condensation of plasmid DNA, serum stability, cytotoxicity and transfection activity of polyplexes were evaluated. Moreover, the effects of pDNA-encoded STAT3-shRNA on migration ability of TNBC cells were tested using wound healing assay. Particle sizes were 189.3 nm, 237 nm and 310.2 nm for B1, B2 and B3 polyplexes respectively and 172.8 nm, 382 nm and 441 nm for L1, L2 and L3 polyplexes respectively. Zeta potential values were B1: +11.8 mV, B2: +21.9 mV and B3: +32.7 mV and L1: +19.8 mV, L2: +23.8 mV and L3: +25.1 mV. The lowest PDI values were obtained by B1S (0.32) and B2S (0.24) polyplexes. The obtained cationic polyplexes exhibited pDNA binding and protection ability. When compared to control, L1S and L2S poyplexes did not showed cytotoxic effects. 4T1 TNBC cell migration was best inhibited by B1S and B2S polyplexes. At 72 h the remaining percentage of cell-free area compared to time zero was higher in the B2S polyplexes (70,4%), followed by the B1S polyplexes (33,3%). Opposed to this, branched PEI polymer, linear PEI polymer and linear PEI polyplexes had no inhibitor effect on cell migration ability. The mean difference between B1S and B2S (37.073%) was also highly significant. The box plot graph showed that between 0 and 72 h, the lowest migration change has been detected by B2S polypexes which has 2:1 w/w polymer:pDNA ratio. Wound healing studies revealed that migration was inhibited by delivery of pDNA-encoded STAT3-shRNA which might be a potential therapy against TNBC and branched PEI polyplexes could be considered promising polycation-mediated delivery vehicles for non-viral cancer gene therapy.

Gene therapy, recently frequently investigated, is an alternative treatment method that introduces therapeutic genes into a cancer cell or tissue to cause cell death or slow down the growth of the cancer. This treatment has various strategies such as therapeutic gene activation or silencing of unwanted or defective genes; therefore a wide variety of genes and viral or nonviral vectors are being used in studies. Gene therapy strategies in cancer can be classified as inhibition of oncogene activation, activation of tumor suppressor gene, immunotherapy, suicide gene therapy and antiangiogenic gene therapy. In this review, we explain gene therapy, gene therapy strategies in cancer, approved gene medicines for cancer treatment and future of gene therapy in cancer. Today gene therapy has not yet reached the level of replacing conventional therapies. However, with a better understanding of the mechanism of cancer to determine the right treatment and target, in the future gene therapy, used as monotherapy or in combination with another existing treatment options, is likely to be used as a new medical procedure that will make cancer a controllable disease.

Gene therapy, recently frequently investigated, is an alternative treatment method that introduces therapeutic genes into a cancer cell or tissue to cause cell death or slow down the growth of the cancer. This treatment has various strategies such as therapeutic gene activation or silencing of unwanted or defective genes; therefore a wide variety of genes and viral or nonviral vectors are being used in studies. Gene therapy strategies in cancer can be classified as inhibition of oncogene activation, activation of tumor suppressor gene, immunotherapy, suicide gene therapy and antiangiogenic gene therapy. In this review, we explain gene therapy, gene therapy strategies in cancer, approved gene medicines for cancer treatment and future of gene therapy in cancer. Today gene therapy has not yet reached the level of replacing conventional therapies. However, with a better understanding of the mechanism of cancer to determine the right treatment and target, in the future gene therapy, used as monotherapy or in combination with another existing treatment options, is likely to be used as a new medical procedure that will make cancer a controllable disease.

The suppression of oxidative-stress induced neurotoxicity by antioxidants serves as a potential preventive strategy for neurodegenerative diseases. In this study, we aimed to investigate the cell protective and antioxidant effects of masitinib and cromolyn sodium against toxin-induced neurodegeneration.First, human neuroblastoma SH-SY5Y cells were differentiated into neuron-like (d)-SH-SY5Y cells. The differentiated cells were confirmed by immuno-staining with anti-PGP9.5 antibody, a neuronal marker. Cell culture groups were formed, and a neurotoxin, 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) was applied on cells followed by masitinib and/or cromolyn sodium treatments. Survival rate of cells were detected by MTT assay. Anti-inflammatory Transforming Growth Factor-beta 1 (TGF-beta 1) and nitric oxide (NO) levels and total oxidant and antioxidant capacities (TOC and TAC) in cell conditioned media (CM) were measured. Morphological analysis and apoptotic nuclear assessment of cells were also noted.When (d)-SH-SY5Y cells were exposed to neurotoxin, cell viability rates of these cells were found to be decreased in a concentration-dependent manner. CM of toxin applied group displayed higher levels of TOC/TAC ratios and NO levels compared to control (p < 0.01). Both masitinib and cromolyn sodium protected cells from toxin-induced cell death as revealed by ameliorated rates of viability, reversed toxin-induced elevation of TOC/ TAC ratios, and decreased NO levels in their CM (p < 0.01). Combined treatment significantly reduced TOC/TAC ratios and NO levels more effectively compared to mono-treatments. Both drugs also increased TGF-beta 1 levels significantly in cell CM. When these agents were tested for therapeutic effects against toxin-induced cell degeneration, better viability results were obtained by both masitinib and cromolyn sodium treatment, with significantly better amelioration provided by combined application of these drugs (p < 0.01).This study demonstrated new findings that combined treatment with cromolyn sodium, an FDA-approved drug of asthma, and masitinib, an orally administered drug with a low toxicity, exert neuroprotective and additive therapeutic effects. We propose that combination therapy of masitinib and cromolyn sodium may represent an innovative treatment in neurodegenerative diseases. Combination therapy may be more advantageous that it enables combined application of lower doses of both drugs, providing less side effects.

Objective: The endo-opioid and endo-cannabinoid systems are important in regulating pain and have been implicated in migraine pathophysiology. Patients with frequent attacks, such as patients with chronic migraine (CM), frequently develop medication overuse headache (MOH). Not all patients with chronic headache develop MOH, the reason for which is not exactly known. We aimed to assess the involvement of these neurotransmitter systems in episodic and CM and in MOH. Materials and Methods: Patients with (episodic migraine; n=29), (CM; n=15), MOH (n=16) and 31 healthy controls were recruited and blood levels of nociceptin and anandamide (AEA) were compared between groups, as well as their levels with headache parameters. Results: AEA levels were significantly lower in the combined migraine groups compared to controls (p=0.009), but head to head comparison of the groups revealed no significant difference (p=0.062). Median nociceptin levels were found to be very high in CM (235.76 ng/l) group and very low in MOH (30.08 ng/l) group, but the difference was not statistically significant. Conclusion: Our finding of low AEA levels in migraine supports the hypothesis of a dysfunctional endocannabinoid system in migraine. Although our results failed to reveal any differences between episodic and CM, an interpretation of findings reported in the literature suggested that this low endocannabinoid inhitory tone might contribute to nociceptive facilitation resulting in maintained central sensitization and therefore sustained pain in CM. Although not significant, nociceptin levels were much higher in CM group and the lowest levels were found in MOH group. It is possible that in CM, the opioid system tries to counterbalance the endocannabinoid dysfunction and if the opioid levels fail to rise, the patient is driven to an excessive use of analgesics and MOH develops. Although we were unable to prove this hypothesis we think it would be worthwhile studying this hypothesis in a larger group of patients.

Facioscapulohumeral Muscular Dystrophy (FSHD) is in the top three list of all dystrophies with an approximate 1:8000 incidence. It is not a life-threatening disease; however, the progression of the disease extends over being wheelchair bound. Despite some drug trials continuing, including DUX4 inhibition, TGF-ß inhibition and resokine which promote healthier muscle, there is not an applicable treatment option for FSHD today. Still, there is a need for new agents to heal, stop or at least slow down muscle wasting. Current FSHD studies involving nutraceuticals as vitamin C, vitamin E, coenzyme Q10, zinc, selenium, and phytochemicals as curcumin or genistein, daidzein flavonoids provide promising treatment strategies. In this review, we present the clinical and molecular nature of FSHD and focus on nutraceuticals and phytochemicals that may alleviate FSHD. In the light of the association of impaired pathophysiological FSHD pathways with nutraceuticals and phytochemicals according to the literature, we present both studied and novel approaches that can contribute to FSHD treatment.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the zoonotic pathogen that causes the "Coronavirus Disease of 2019 (COVID-19)", and COVID-19 itself is yet to be thoroughly understood. Both the disease as well as the mechanisms by which the host interacts with the SARS-CoV-2 have not been fully enlightened. The epidemiological factors -e.g. age, sex, race-, the polymorphisms of the host proteins, the blood types and individual differences have all been in discussions about affecting the progression and the course of COVID-19 both individually and collectively, as their effects are mostly interwoven. We focused mainly on the effect of polymorphic variants of the host proteins that have been shown to take part in and/or affect the pathogenesis of COVID-19. Additionally, how the procedures of diagnosing and treating COVID-19 are affected by these variants and what possible changes can be implemented are the other questions, which are sought to be answered.

Mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occur spontaneously during replication. Thousands of mutations have accumulated and continue to since the emergence of the virus. As novel mutations continue appearing at the scene, naturally, new variants are increasingly observed. Since the first occurrence of the SARS-CoV-2 infection, a wide variety of drug compounds affecting the binding sites of the virus have begun to be studied. As the drug and vaccine trials are continuing, it is of utmost importance to take into consideration the SARS-CoV-2 mutations and their respective frequencies since these data could lead the way to multi-drug combinations. The lack of effective therapeutic and preventive strategies against human coronaviruses (hCoVs) necessitates research that is of interest to the clinical applications. The reason why the mutations in glycoprotein S lead to vaccine escape is related to the location of the mutation and the affinity of the protein. At the same time, it can be said that variations should occur in areas such as the receptor-binding domain (RBD), and vaccines and antiviral drugs should be formulated by targeting more than one viral protein. In this review, a literature survey in the scope of the increasing SARS-CoV-2 mutations and the viral variations is conducted. In the light of current knowledge, the various disguises of the mutant SARS-CoV-2 forms and their apparent differences from the original strain are examined as they could possibly aid in finding the most appropriate therapeutic approaches.

Pseudomonas aeruginosa, an opportunistic Gram-negative pathogen, is one of the major causes of nosocomial infections. In addition to its physiological adaptation capacity, it can develop resistance to disinfectants and antibiotics through various mechanisms. Recently, new eradication methods are gaining attention. Therefore, in this study, an LNA-2'-O-methyl hybrid antisense oligonucleotide targeting the acyl carrier protein P (acpP) gene was introduced into P. aeruginosa isolates. The design was determined through sequence analysis and prediction of the secondary structure of mRNA by software. Niosomes were used for enhancing cellular uptake. The control of the binding and transfection ability of the sequence was determined fluorometrically by labeling with 6-Fam. The effects were determined with broth microdilution method and qPCR studies. Eight different formulations were prepared. Among these, one formulation has shown to have ASO complexation ability whose composition was 312 mu l Span 80 + 69.5 mg Cholesterol+ 36.4 mg CTAB+1 ml Chloroform and 5 ml dH(2)O. Thus this formulation was determined as the delivery system for the next stages. Significant gene inhibition was detected at the six isolates. Results of this study suggested that niosomes can be used as a delivery system for cellular uptake of ASO and could eliminate bacterial growth. (C) 2021 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.