Immunomodulatory potential of human clonal mesenchymal stem cells and their extracellular vesicle subpopulations in an inflammatory-mediated diabetic Rhesus monkey model.

AIMS: This study aimed to investigate the therapeutic potential of a homogenous clonal population of mesenchymal stem cells (cMSC) and their extracellular vesicles (cMSC-EV) subpopulations on isolated rat islets in vitro and in inflammatory-mediated type 1 diabetes (T1D) non-human primate models. MAIN METHODS: EV subpopulations were isolated from human bone marrow-derived cMSC supernatant by low- and high-speed ultracentrifuge (EV-20K and EV-U110K) and sucrose density gradient (EV-S110K). The EVs were characterized generally and for the level of albumin, acetylcholinesterase (AChE) activity, co-isolate apoptotic markers, and expression of CD63+/annexin V+. Rat islet-derived single cells (iSCs) proliferation was measured using a Ki-67 proliferation assay. Diabetes was induced by multiple low-dose administrations of streptozotocin in rhesus monkeys. The diabetic monkeys were divided into three groups: the cMSC group, received two injections of 1.5 × 106 cMSC/kg body weight; the EV group received two injections of EVs isolated from 1.5 × 106 cMSC/kg, and the vehicle group received phosphate-buffered saline. KEY FINDINGS: EV-S110K showed higher AChE activity, lower expression of CD63+/annexin V+, and lower apoptotic co-isolates. EV-S110K induced ß-cell proliferation in vitro in a dose-dependent manner. The administration of EV-S110K and/or cMSC in diabetic monkeys demonstrated no significant changes in general diabetic indices and ß-cell mass in the pancreas of the monkeys. Both treatments demonstrated a lowering trend in blood glucose levels and reduced pro-inflammatory cytokines. In contrast, regulatory T cells and anti-inflammatory cytokines were increased. SIGNIFICANCE: cMSC and cMSC-EV provided initial evidence to attenuate clinical symptoms in inflammatory-mediated T1D non-human primates through immunomodulation.

Clonal mesenchymal stem cell-derived extracellular vesicles improve mouse model of weight drop-induced traumatic brain injury through reducing cistauosis and apoptosis.

OBJECTIVE: Traumatic brain injury (TBI) is a major risk factor for disabilities globally with no effective treatment thus far. Recently, homogenous population of clonal mesenchymal stem cells (cMSC) and their derived extracellular vesicles (cMSC-EVs) have been proposed as a promising TBI treatment strategy. We herein investigated possible therapeutic effect of cMSC-EVs in TBI treatment and the underlying mechanisms considering cis p-tau as an early hallmark of TBI. METHODS: We examined the EVs morphology, size distribution, marker expression, and uptake. Moreover, the EVs neuroprotective effects were studied in both in-vitro and in-vivo model. We also examined the anti-cis p-tau antibody-loading characteristics of the EVs. We treated TBI mouse model with EVs; prepared from cMSC-conditioned media. TBI mice were given cMSC-EVs intravenously and their cognitive functions were analyzed two months of the treatment. We employed immunoblot analysis to study the underlying molecular mechanisms. RESULTS: We observed a profound cMSC-EVs uptake by primary cultured neurons. We found a remarkable neuroprotective effect of cMSC-EVs upon nutritional deprivation stress. Furthermore, cMSC-EVs were effectively loaded with an anti-cis p-tau antibody. There was a significant improvement in cognitive function in TBI animal models treated with cMSC-EVs compared to the saline-treated group. There was a decreased cis p-tau and cleaved caspase3 as well as increased p-PI3K in all treated animals. CONCLUSIONS: The results revealed that cMSC-EVs efficiently improved animal behaviors after TBI by reducing cistauosis and apoptosis. Moreover, the EVs can be employed as an effective strategy for antibody delivery during passive immunotherapy.

Allogenic mesenchymal stromal cells and their extracellular vesicles in COVID-19 induced ARDS: a randomized controlled trial.

BACKGROUND AND AIMS: The main causes of death in patients with severe Coronavirus disease-2019 (COVID-19) are acute respiratory distress syndrome (ARDS) and multiorgan failure caused by a severe inflammatory cascade. Novel treatment strategies, such as stem-cell-based therapy and their derivatives can be used to relieve inflammation in these cases. In this study, we aimed to evaluate the safety and efficacy of therapy using mesenchymal stromal cells (MSCs) and their derived extracellular vesicles in COVID-19 patients. MATERIALS AND METHODS: COVID-19 patients with ARDS were included in this study and allocated into two study and control groups using block randomization. While all patients received recommended treatment based on guidelines from the national advisory committee for COVID-19 pandemic, the two intervention groups received two consecutive injections of MSCs (100 × 106 cells) or one dose of MSCs (100 × 106 cells) followed by one dose of MSC-derived extracellular vesicles (EVs). Patients were assessed for safety and efficacy by evaluating clinical symptoms, laboratory parameters, and inflammatory markers at baseline and 48 h after the second intervention. RESULTS: A total number of 43 patients (the MSC alone group = 11, MSC plus EV group = 8, and control group = 24) were included in the final analysis. Mortality was reported in three patients in the MSC alone group (RR: 0.49; 95% CI 0.14-1.11; P = 0.08); zero patient in the MSC plus EV group (RR: 0.08; 95% CI 0.005-1.26; P = 0.07) and eight patients in the control group. MSC infusion was associated with a decrease in inflammatory cytokines such as IL-6 (P = 0.015), TNF-α (P = 0.034), IFN-γ (P = 0.024), and CRP (P = 0.041). CONCLUSION: MSCs and their extracellular vesicles can significantly reduce the serum levels of inflammatory markers in COVID-19 patients, with no serious adverse events. Trial registration IRCT, IRCT registration number: IRCT20200217046526N2. Registered 13th April 2020, http://www.irct.ir/trial/47073 .

Drought stress memory in a germplasm of synthetic and common wheat: antioxidant system, physiological and morphological consequences.

Plants have evolved mechanisms of adaptation to fluctuations in their environmental conditions that have been given the term "stress memory". Synthetic wheat offers new hope for breeders to restore useful genes lost during the genetic bottleneck. We aimed to test whether drought priming and seed priming could improve drought tolerance in a diverse germplasm of synthetic and common wheat under field conditions. In this research, 27 wheat genotypes (including 20 synthetics, 4 common local and 3 common exotic bread wheat) were field evaluated under four water environments. These treatments included: 1) normal condition (N), plants were irrigated when 40% of the total available soil water was depleted from the root-zone, 2) seed priming-secondary stress (SD2), only water stress was applied at anthesis when 90% of the total available soil water was depleted and seeds were planted for evaluating, 3) primary stress- secondary stress (D1D2), primary water stress was applied at jointing stage when 70% of the total available soil water was depleted then secondary water stress was applied at the anthesis stage when 90% of the total available soil water was depleted, and 4) secondary stress (D2) only water stress was applied at the anthesis when 90% of the total available soil water was depleted. Our results indicated that improved efficient enzymatic antioxidant system leads to less yield reduction in D1D2 treatment. However, the positive effects of drought priming were more pronounced in drought primed (D1D2) than seed primed treatment (SD2). Synthetic wheat genotypes had a significant superiority in terms of yield, yield components and drought tolerance compared to common wheat genotypes. Nevertheless, the response of genotypes to stress memory was very different. Drought sensitive genotypes had better response to stress memory. Superior genotypes were identified as high yield and drought tolerant genotypes which can be used for future studies.

Early Diagnosis of Alzheimer's Disease with Blood Test; Tempting but Challenging.

The increasing prevalence of Alzheimer's disease (AD) has led to a health crisis. According to official statistics, more than 55 million people globally have AD or other types of dementia, making it the sixth leading cause of death. It is still difficult to diagnose AD and there is no definitive diagnosis yet; post-mortem autopsy is still the only definite method. Moreover, clinical manifestations occur very late in the course of disease progression; therefore, profound irreversible changes have already occurred when the disease manifests. Studies have shown that in the preclinical stage of AD, changes in some biomarkers are measurable prior to any neurological damage or other symptoms. Hence, creating a reliable, fast, and affordable method capable of detecting AD in early stage has attracted the most attention. Seeking clinically applicable, inexpensive, less invasive, and much more easily accessible biomarkers for early diagnosis of AD, blood-based biomarkers (BBBs) seem to be an ideal option. This review is an inclusive report of BBBs that have been shown to be altered in the course of AD progression. The aim of this report is to provide comprehensive insight into the research status of early detection of AD based on BBBs.

Comparison of various types of lasers and transurethral resection in the treatment of bladder tumors: a systematic review and meta-analysis.

Bladder cancer is one of the most common cancers of the urinary tract. The two available treatments for this malignancy are laser and Transurethral Resection of the Bladder Tumor (TURBT). The aim of this study was to compare the different parameters of these two methods. A systematic search was performed on PubMed, Scopus and Google Scholar between 2000 and 2021. All articles related to non-muscle invasive bladder cancer (NMIBC) were extracted. All analyses were performed using R-studio statistical software version 1.0.136. In total, 11 studies that reported tumor recurrence in two methods were evaluated. A total of 626 and 742 patients were treated with laser and TURBT, respectively. Tumor recurrence, duration of operation, hospitalization and catheterization in laser therapy were significantly lower than TURBT. In addition, the incidence of complications was lower in patients treated with laser. The incidence of obturator nerve reflex, bladder perforation and postoperative bladder irrigation was significantly higher in patients treated with TURBT. Only in relation to postoperative urethral stricture, no significant difference was observed between the two treatment methods. Laser therapy compared to TURBT in patients with NMIBC has fewer complications and faster recovery. Also, the risk of tumor recurrence in laser therapy is less than TURBT.

Remdesivir-Associated Significant Bradycardia: A Report of Three Cases.

Recently, remdesivir was approved by the United States Food and Drug Administration for patients with Coronavirus disease 2019 (COVID-19). We herein describe 3 patients with COVID-19 who showed significant bradycardia and QTc prolongation after remdesivir administration. Bradycardia did not respond to atropine treatment in 2 of the patients, one of whom received theophylline and the other required a temporary pacemaker. Fortunately, the patients' heart rate and rhythm returned to normal after the discontinuation of remdesivir, albeit it lengthened their hospital stays. Careful monitoring during remdesivir infusion may decrease the risk of adverse cardiovascular side effects.

Methotrexate and Curcumin co-encapsulated PLGA nanoparticles as a potential breast cancer therapeutic system: In vitro and in vivo evaluation.

Nanoparticulate delivery systems have been noticed for chemotherapeutical delivery due to their ability in controlling the drug release and reducing the side effect. These systems could also be used to deliver two drugs or more simultaneously, inhibiting the development of resistant cancerous cells. Methotrexate (MTX), one of the most frequently used chemotherapeutic agent, and Curcumin (CUR), a natural chemopreventive compound, have shown promising results in treatment or controlling the progression of cancer. The aim of this study is to prepare and evaluate polymeric nanoparticles for co-delivery of MTX and CUR. The PLGA nanoparticles were prepared and characterized in respect of their particles size, morphology, drug encapsulation efficiencies, release patterns, cell cytotoxicity, and in vivo efficacy. Altering MTX and CUR amounts leads to particle size of 142.3 ±â€¯4.07 nm with MTX encapsulation efficiency of 71.32 ±â€¯7.8% and CUR encapsulation efficiency of 85.64 ±â€¯6.3%. These particles showed significantly higher cytotoxicity in comparison with free MTX or CUR or even their solo-loaded formulations. The in vivo results showed the synergic effect of MTX and CUR co-delivery on inhibiting the progression of breast cancer. Considering the appropriate in vitro properties of acquired nanoparticles for controlled drug delivery and the satisfactory in vivo efficacy results, it seems that the prepared formulation is a promising candidate for further in vivo studies.

Nicotinamide loaded functionalized solid lipid nanoparticles improves cognition in Alzheimer's disease animal model by reducing Tau hyperphosphorylation.

BACKGROUND: Nicotinamide is considered to be effective in halting the Alzheimer's disease progression. The body could absorb a limited amount of nicotinamide at a time, requiring multiple doses through a day. To overcome such an obstacle which reduces the patient compliance, a sustained/controlled delivery system could be useful. METHOD: Nicotinamide loaded solid lipid nanoparticles (SLN) were prepared and functionalized with polysorbate 80 (S80), phosphatidylserine (PS) or phosphatidic acid (PA). The acquired particles were characterized and evaluated in respect of their cytotoxicity, biodistribution, and in vivo effectiveness through the different routes of administration. RESULTS: The optimum sizes of 112 ± 1.6 nm, 124 ± 0.8 nm, and 137 ± 1.05 nm were acquired for S80-, PS-, and PA-functionalized SLNs, respectively. The in vitro cytotoxicity on SH-SY5Y cell line showed the safety of formulations except for S80-functionalized SLNs. Biodistribution study of SLNs has proved the benefits of functionalization in improving the brain delivery. The results of spatial and memory test, i.e. Morris water maze, and also histopathology and biochemical tests demonstrated the effectiveness of i.p. injection of PS -functionalized SLNs in improving the cognition, preserving the neuronal cells and reducing tau hyperphosphorylation in a rat model of Alzheimer's disease. CONCLUSION: The acquired PS-functionalized SLN could be a potential brain delivery system. Loaded with nicotinamide, an HDAC inhibitor, it could ameliorate the cognition impairment of rats more effectively than the conventional administration of nicotinamide, i.e. oral, in the early stage of Alzheimer's disease. Graphical abstract ᅟ.

Effect of the impregnation of carbon cloth with ethylenediaminetetraacetic acid on its adsorption capacity for the adsorption of several metal ions.

Effect of loading of C-cloth with ethylenediaminetetraacetic acid (EDTA) on the adsorption capacity for the adsorption of several metal cations was studied. The concentration of ions in the solution was monitored using atomic absorption spectrometry. The adsorption isotherm data for the cations were derived at 25 degrees C and treated according to Langmuir and Freundlich models and was found that for most of the investigated cations Langmuir model was more successful. Adsorption capacities determined from Langmuir isotherms. Loading of the adsorbent with EDTA increased the adsorption capacity for the adsorption of all of the investigation ions.