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Abstract Background Wound healing represents a complex biological process, critically important in clinical practice due to its direct implication in a patient’s recovery and quality of life. Conservative wound management frequently falls short in providing an ideal environment for the optimal tissue regeneration, often resulting in extended healing periods and elevated risk of infection and other complications. The emerging biomaterials, particularly hydrogels, have shown substantial promise in addressing these challenges by offering properties such as biocompatibility, biodegradability, and the ability to cure wound environment. Recent advancements have highlighted the therapeutic potential of integrating cell-derived conditioned medium (CM) into hydrogel matrices. Cell-derived CM represents a rich array of bioactive molecules, demonstrating significant efficacy in modulating cellular activities crucial for wound healing, including cellular proliferation, migration, and angiogenesis. Methods The methodology of this review adheres to the standards set by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. The review includes a selection of studies published within the last five years, focusing on in vivo experiments involving various types of skin injuries treated with topically applied hydrogels loaded with CM (H-CM). The search strategy refers to the PICO framework and includes the assessment of study quality by CAMARADES tool. Results The systematic review represents a detailed evaluation of H-CM dressings wound healing efficiency based on the experimental results of cell-based assays and animal wound models. The study targets to reveal wound healing capacity of H-CM dressings, and provides a comparative data analysis, limitations of methods and discussions of H-CM role in advancing the wound healing therapy. Conclusions The data presented demonstrate that H-CM is a promising material for advanced wound healing and regenerative medicine. These dressings possess proved in vitro/in vivo efficacy that highlights their strong clinical potential and paves the way to further investigations of H-CM formulations within clinical trials.

Objective: The spliced form of X-box binding protein 1 (XBP1s) is a key transcription factor in the unfolded proteinresponse (UPR), an adaptive mechanism for cell survival. Many studies demonstrated the induced expression ofXBP1s in various cancers, including hepatocellular carcinoma (HCC). Such upregulated expression is linked to anenhancement of cell proliferation, migration, and improvement of the survival rate. In this study, we aimed to assess thetherapeutic potential of targeting XBP1s, by specific decoy oligodeoxynucleotide (ODN) and evaluated the cancerousphenotypes in Huh-7 cells.Materials and Methods: In this experimental study, we transfected Huh-7 cells with XBP1s decoy oligonucleotide(ODN). Subsequently, we assess some cellular features, including viability, migration capacity, proliferation potential,and apoptosis. Therefore, various techniques included wound healing test, BrdU, and annexin/PI assays. Additionally,the colony formation capacity was evaluated. The mRNA expression levels of BAX, BCL-2, c-MYC, CCND1, MMP-9,CDH1, and CD133 were quantified by the reverse transcription-quantitative polymerase chain reaction (RT-qPCR).Results: Transfection of Huh-7 cells by XBP1s decoy ODN led to significant down-regulation of c-Myc, CCND1,MMP-9, BCL-2 and CD133 and up-regulation of CDH1 and BAX transcriptional expressions in comparison with thevehicle group. Our results also demonstrated that transfection of XBP1s-decoy reduced HCC cell viability, proliferation,migration capacity as well as colonization ability in comparison with the vehicle group.Conclusion: These findings proposed the potential application of XBP1s-decoy ODN to reduce cancerous phenotypessuch as cell proliferation, cell migration and apoptosis induction in the Huh-7 cell line. More experiments on other celllines and primary cells could validate our results.

Nanotechnology, defined as engineering at the nanometer scale, involves developing materials or systems to perform a systematic arrangement for various platforms in biomedical applications. This study presents possible applications of carbon-based nanomaterials in regenerative biomedicine, drug delivery, and cancerous conditions. We highlight significant advancements in carbon nanotubes-based nanotechnology, with an emphasis on carbon nanotubes, which accelerate various regenerative therapies in the liver, nervous system, heart, vascular system, and bone tissue engineering. Using carbon nanomaterials to deliver drugs precisely to their site of action is also one area of interest, attracting the attention of researchers and giving great hope for carbon nanomaterials’ widespread use in medicine. Moreover, green nanotechnology was introduced as an innovative and noninvasive discipline in carbon-based nanomaterials for human biomedicine. It can solve the problem of using dangerous and toxic chemical nanoscale materials.

Objective: Kienböck disease is a rare condition characterized by severe pain and restricted wrist movement. Variouspalliative methods have been proposed as therapeutic strategies for alleviating symptoms. Mesenchymal stromal cell transplantationhas been suggested as an innovative and promising approach due to its potential for inducing regeneration andimmunomodulation in the necrotic tissue. This study aims to evaluate the safety of autologous bone marrow derivedmesenchymal stromal cells (BM-MSCs) transplantation after core decompression in Kienböck disease.Materials and Methods: In this phase I of an open-label clinical trial, three patients (one female and two males) withstage 2 Kienböck disease underwent autologous BM-MSCs transplantation following lunate core decompression. Thepatients were followed up for six months to assess safety as well as secondary clinical outcomes, including pain level,range of motion (ROM), and functional disability.Results: Safety of BM-MSCs injection following the core decompression was evaluated by recording post-treatmentcomplications during the six-month follow-up. No adverse events (AEs) or severe AEs (SAEs) were reported, indicatingthat BM-MSCs injection after core decompression is a safe intervention. All patients showed a remarkable reductionin visual analog scale (VAS) scores and "Disabilities of the Arm, Shoulder, and Hand" (DASH) questionnaire scores,suggesting the therapeutic potential of this intervention. Moreover, an increase in the ROM indicated that BM-MSCstransplantation can improve wrist functionality. Additionally, radiographic assessments before and after cell infusiondemonstrated a reduction in lunate sclerosis after six months of follow-up.Conclusion: The transplantation of autologous BM-MSCs following lunate core decompression seems to be a safeclinical intervention and may lead to pain relief in patients with Kienböck disease. Furthermore, this procedure may helpprevent disease progression during the follow-up period (registration number: NCT02646007).

Objective(s): Skin aging is a degenerative process that can be induced by UV irradiation. UV radiation can produce reactive oxidate stress which causes premature aging. This study aims to examine the antiaging potential of secretome gel (SC) from human Wharton Jelly Mesenchymal Stem Cells (hWJ-MSCs) in a UVB-induced mice model. Materials and Methods: The secretome was obtained from hWJ-MSCs and made in gel form. Male mice were radiated by UVB for 15 min twice daily for 14 days. The gel was topically applied to the mice’s dorsal skin. Two treatments of secretome gel: secretome 1 is applied once and secretome 2 is applied twice daily after UVB radiation. TGF-β1, IL-10, and IL-18 gene expression was determined using RT-PCR. Hematoxylin Eosin staining was used to observe the inflammation and collagen density of skin tissue. An immunohistochemistry assay was used to analyze the protein expression of P53, COL4A1, MMP-2, and MMP-13. The data were statistically analyzed using the ANOVA test followed by the Tukey post hoc test (P

Abstract Background Burn-related injuries are a major global health issue, causing 180,000 deaths per year. Early debridement of necrotic tissue in association with a split-thickness skin graft is usually administered for some of the 2nd- and 3rd-degree injuries. However, this approach can be complicated by factors such as a lack of proper donor sites. Artificial skin substitutes have attracted much attention for burn-related injuries. Keratinocyte sheets are one of the skin substitutes that their safety and efficacy have been reported by previous studies. Methods Two consecutive clinical trials were designed, one of them is phase I, a non-randomized, open-label trial with 5 patients, and phase II is a randomized and open-label trial with 35 patients. A total number of 40 patients diagnosed with 2nd-degree burn injury will receive allogenic keratinocyte sheet transplantation. The safety and efficacy of allogeneic skin graft with autograft skin transplantation and conventional treatments, including Vaseline dressing and topical antibiotic, will be compared in different wounds of a single patient in phase II. After the transplantation, patients will be followed up on days 3, 7, 10, 14, 21, and 28. In the 3rd and 6th months after the transplantation scar, a wound closure assessment will be conducted based on the Vancouver Scar Scale and the Patient and Observer Scar Assessment Scale. Discussion This study will explain the design and rationale of a cellular-based skin substitute for the first time in Iran. In addition, this work proposes this product being registered as an off-the-shelf product for burn wound management in the country. Trial registration Iranian Registry of Clinical Trials (IRCT) IRCT20080728001031N31, 2022-04-23 for phase I and IRCT20080728001031N36, 2024-03-15 for phase II.

Non-alcoholic fatty liver disease (NAFLD) is a high-prevalence and progressive disorder. Due to lack of reliable in vitro models to recapitulate the consecutive phases, the exact pathogenesis mechanism of this disease and approved therapeutic medications have not been revealed yet. It has been proven that the interplay between multiple hepatic cell types and liver extracellular matrix (ECM) are critical in NAFLD initiation and progression. Herein, a liver microtissue (LMT) consisting of Huh-7, THP-1, and LX-2 cell lines and human umbilical vein endothelial cells (HUVEC), which could be substituted for the main hepatic cells (hepatocyte, Kupffer, stellate, and sinusoidal endothelium, respectively), encapsulated in liver derived ECM-Alginate composite, was bioengineered. When the microtissues were treated with free fatty acids (FFAs) including Oleic acid (6.6×10−4M) and Palmitic acid (3.3×10−4M), they displayed the key features of NAFLD, including similar pattern of transcripts for genes involved in lipid metabolism, inflammation, insulin-resistance, and fibrosis, as well as pro-inflammatory and pro-fibrotic cytokines’ secretions and intracellular lipid accumulation. Continuing FFAs supplementation, we demonstrated that the NAFLD phenomenon was established on day 3 and progressed to the initial fibrosis stage by day 8. Furthermore, this model was stable until day 12 post FFAs withdrawal on day 3. Moreover, administration of an anti-steatotic drug candidate, Liraglutide (15 μM), on the NAFLD microtissues significantly ameliorated the NAFLD phenomenon. Overall, we bioengineered a drug-responsive, cost-benefit liver microtissues which can simulate the initiation and progression of NAFLD. It is expected that this platform could potentially be used for studying molecular pathogenesis of NAFLD and high-throughput drug screening.

Background In spite of the observed immunomodulatory properties of different sex hormones on Multiple Sclerosis (MS) in different investigations, to date, there has been no study to systematically review the documents to add more powerful data to the field. Objectives Therefore, in this paper we aim to systematically review clinical and randomized controlled trials (RCT) assessing the effect of sex hormone therapies on individuals with MS. Design A comprehensive search of electronic databases including PubMed, EMBASE, and Scopus was conducted. Clinical trials and RCTs that assessed the impact of sex hormones on individuals with MS were selected and included in the systematic review. Data sources and methods In the final phase of the search strategy, 9 papers reached the criteria for entering in the systematic review. Two independent reviewers extracted the relevant data from each article according to the standardized data extraction form. Two reviewers also assessed the quality of each study independently using PEDro scale. Results We categorized three different classifications of outcomes including clinical, MRI, and immune system findings and put each measured outcome in the category which matched best. Conclusion In conclusion, the existed investigations on the effect of sex hormones on inflammatory and neurodegenerative components of MS are promising particularly in relapsing-remitting MS (RRMS).

Inflammatory bowel disease comprising Crohn's disease and ulcerative colitis presents with periods of flares and remission. Many reports have identified different dysregulated miRNAs in patients with IBD. Finding new biomarkers in IBD patients can help to launch a novel non-invasive approach for diagnosis and prognosis for patients with UC and CD. This study aimed to evaluate the plasma expression pattern of the miRNAs panel in IBD patients compared to healthy individuals. 73 plasma samples were included; 58 patients with IBD (33 individuals in flare and 25 in remission phase) and 15 healthy controls were enrolled in the study. The miRNA expression was measured by qRT-PCR using miScript SYBR Green PCR Kit (QIAGEN). Our results showed the expression level of miR-16-5P was significantly increased in the active phase compared to the inactive phase (P=0.0138) and in CD patients compared to UC patients (P=0.0216). There was a significant difference in the expression of miR-29a in Crohn's patients compared to healthy subjects (P=0.04). Measuring the expression of mir-106a; a significant increase was observed compared to healthy individuals (P=0.03) and patients with CD (P=0.0143) in proportion of UC patients’ group. The miR-126 expression significantly increased in patients with active disease compared to patients in the inactive phase (P=0.0413) and healthy controls (P=0.0492). This study showed evidence for differential expression levels of plasma panel of miR-16, miR-29a, miR-106a, and miR-126 in IBD patients compare to healthy individuals. We illustrate that miRNAs in plasma correlate with disease activity and can be used as a practical and non-invasive biomarker for early diagnosis and monitoring of the treatment protocol.

Kidney-liver crosstalk plays a crucial role in normal and certain pathological conditions. In pathologic states, bothrenal-induced liver damage and liver-induced kidney diseases may happen through these kidney-liver interactions.This bidirectional crosstalk takes place through the systemic conditions that mutually influence both the liver andkidneys. Ischemia and reperfusion, cytokine release and pro-inflammatory signaling pathways, metabolic acidosis,oxidative stress, and altered enzyme activity and metabolic pathways establish the base of this interaction betweenthe kidneys and liver. In these concomitant kidney-liver diseases, the survival rates strongly correlate with earlyintervention and treatment of organ dysfunction. Proper care of a nephrologist and hepatologist and the identificationof pathological conditions using biomarkers at early stages are necessary to prevent the complications induced by thiscomplex and potentially vicious cycle. Therefore, understanding the characteristics of this crosstalk is essential forbetter management. In this review, we discussed the available literature concerning the detrimental effects of kidneyfailure on liver functions and liver-induced kidney diseases.

Recent achievements in reproductive biomedicine have led to a revolution in infertility treatment. A comprehensive understandingof the current status of reproductive medicine is necessary for the development of a forward-looking plan byhealth policymakers, based on fundamental requirements. This study is a systematic review of the Scopus database toassess reproductive biomedicine publications within Iran and compared to the rest of the world from 1990 to 2020. Thedata were categorized by geographical distribution across five continents. National data were assessed in comparisonwith the world and with neighboring countries. Finally, prominent national research institutes in the field of reproductivebiomedicine in Iran were identified, and their contributions to the field highlighted. Of the five continents, the highestnumber of publications and citations is from Europe (36% publications and 41.5% citations). Corresponding numbers forthe other continents are 32 and 33% for America, and 26 and 18.4% for Asia respectively. The remaining publications andcitations were from Australia (3.8 and 4.1%) and Africa (2.6 and 3.1%). In a national analysis, the highest-ranking institutesin reproductive biomedicine are in Tehran province (50.9% of all Iranian publications), Shiraz (8.8%), Yazd (7.8%),Isfahan (7.1%), and Tabriz (6.9%). More specifically, Tehran University of Medical Science (15.9%), the Royan Institute(12.2%), Shahid Beheshti Medical University (10.1%), Shahid Sadoughi University of Medical Sciences (6.9%), andTarbiat Modares University (6.7%) account for more than 50% of all Iranian scientific publications. In recent decades,reproductive biomedical research has grown significantly in Iran. Reviewing publications in this field helps health policydecision makers to monitor the direction of research and adjust investment in the treatment of infertility. In addition, it isnecessary to expand and organize inter-organizational and international collaborations to improve the research, gain thebenefits of different experiences, and engage in international multicenter studies.

Enforcing a well-differentiated state on cells requires tumor suppressor p53 activation as a key player in apoptosis induction and well differentiation. In addition, recent investigations showed a significant correlation between poorly differentiated status and higher expression of NANOG. Inducing the expression of NANOG and decreasing p53 level switch the status of liver cancer cells from well differentiated to poorly status. In this review, we highlighted p53 and NANOG cross-talk in hepatocellular carcinoma (HCC) which is regulated through mitophagy and makes it a novel molecular target to attenuate cancerous phenotype in the management of this tumor.

CD4+ CD25+ FOXP3+ T regulatory cells (Tregs) are a subset of the immunomodulatory cell population that can inhibit both innate and adaptive immunity by various regulatory mechanisms. In hepatic microenvironment, proliferation, plasticity, migration, and function of Tregs are interrelated to the remaining immune cells and their secreted cytokines and chemokines. In normal conditions, Tregs protect the liver from inflammatory and auto-immune responses, while disruption of this crosstalk between Tregs and other immune cells may result in the progression of chronic liver diseases and the development of hepatic malignancy. In this review, we analyze the deviance of this protective nature of Tregs in response to chronic inflammation and its involvement in inducing liver fibrosis, cirrhosis, and hepatocellular carcinoma. We will also provide a detailed emphasis on the relevance of Tregs as an effective immunotherapeutic option for autoimmune diseases, liver transplantation, and chronic liver diseases including liver cancer.

Abstract Background Mesenchymal stromal cell (MSC) transplantation can improve the left ventricular ejection fraction (LVEF) after an acute myocardial infarction (AMI). Transplanted MSCs exert a paracrine effect, which might be augmented if repeated doses are administered. This study aimed to compare the effects of single versus double transplantation of Wharton’s jelly MSCs (WJ-MSCs) on LVEF post-AMI. Methods We conducted a single-blind, randomized, multicenter trial. After 3–7 days of an AMI treated successfully by primary PCI, 70 patients younger than 65 with LVEF

In the original publication [...]

The rapid development of knowledge on healthy nutrition, and hygiene practices, as well as the advent of antibioticsand vaccines, has led to increased life expectancy in the recent century. The extended lifespan has brought newchallenges for healthcare professionals, including the management of chronic degenerative diseases, malignancies,and autoimmune disorders. Advanced therapeutic medicinal products (ATMPs) have emerged as a promising frontieralongside conventional therapeutic modalities, offering innovative solutions through cell-based therapies, gene therapy,and tissue engineering. Recent years have witnessed remarkable advancements in regenerative medicine and thelaunching of innovative ATMPs. Numerous ATMPs have been registered and approved by regulatory agencies for themanagement of different diseases in 2023. The approval of groundbreaking therapies around the world has made 2023an exceptional year. Novel ATMPs and the development of artificial intelligence (AI) in 2023 will pave the way for theintegration of ATMPs and advanced technologies in personalized medicine, early diagnosis, and targeted treatments.

Objective: Macrophages are multifunctional immune cells widely used in immunological research. While autologousmacrophages have been widely used in several biomedical applications, allogeneic macrophages have alsodemonstrated similar or even superior therapeutic potential. The umbilical cord blood (UCB) is a well-describedsource of abundant allogenic monocytes and macrophages that is easy to collect and can be processed withoutinvasive methods. Current monocyte isolation procedures frequently result in heterogenous cell products, with limitedyields, activated cells, and high cost. This study outlines a simple isolation method that results in high yields and puremonocytes with the potential to differentiate into functional macrophages.Materials and Methods: In the experimental study, we describe a simple and efficient protocol to isolate highpuritymonocytes. After collection of human UCB samples, we used a gradient-based procedure composed of threeconsecutive gradient steps: i. Hydroxyethyl starch-based erythrocytes sedimentation, followed by ii. Mononuclearcells (MNCs) isolation by Ficoll-Hypaque gradient, and iii. Separation of monocytes from lymphocytes by a slighthyperosmolar Percoll gradient (0.573 g/ml). Then the differentiation potential of isolated monocytes to pro- and antiinflammatorymacrophages were evaluated in the presence of granulocyte colony-stimulating factor (GM-CSF) andmacrophage CSF (M-CSF), respectively. The macrophages were functionally characterized as well.Results: A high yield of monocytes after isolation (25 to 50 million) with a high purity (>95%) could be obtained fromevery 100-150 ml UCB. Isolated monocytes were defined based on their phenotype and surface markers expressionpattern. Moreover, they possess the ability to differentiate into pro- or anti-inflammatory macrophages with specificphenotypes, gene/surface protein markers, cytokine secretion patterns, T-cell interactions, and phagocytosis activity.Conclusion: Here we describe a simple and reproducible procedure for isolation of pure monocytes from UCB, whichcould be utilized to provide functional macrophages as a reliable and feasible source of allogenic macrophages forbiomedical research.

Objective: Mesenchymal stromal cells (MSCs) play immunomodulatory role in various autoimmune diseases. Previouspre-clinical and clinical studies have shown that MSCs could be a therapeutic modality for psoriasis. However, themechanisms of treatment and its possible side effects are under investigation. In this study, the safety and probableefficacy of injecting allogeneic adipose-derived mesenchymal stromal cells (ADSCs) in psoriatic patients were evaluated.Materials and Methods: In this phase I clinical study with six months of follow-up, total number of 1×106 or 3×106cells/cm2 of ADSCs were injected into the subcutaneous tissue of each plaque as a single dose in three males and twofemales (3M/2F) with a mean age of 32.8 ± 8.18. The primary outcome was safety. Changes in clinical and histologicalindexes, the number of B and T lymphocytes in local and peripheral blood, and serum levels of inflammatory cytokineswere assessed. Paired t test was used to compare variables at two time points (baseline and six months after injection)and repeated measures ANOVA test was utilized for variables at three time points in follow-up visits.Results: No major adverse effects such as burning, pain, itching, or any systemic side effects were observed followingADSCs injection, and the lesions showed slight to considerable improvement after injection. The mRNA expressionlevels of pro-inflammatory factors were reduced in the dermis of the patients after injection. The increased expressionlevel of Foxp3 transcription factor in the patient blood samples suggested modulation of inflammation after ADMSCsadministration. Six months after the intervention, no major side effects were reported, but skin thickness, erythema, andscaling of the plaques, as well as the PASI score, were decreased in majority of patients.Conclusion: Our study suggested that ADSC injection could be considered as a safe and effective therapeuticapproach for psoriatic plaques (registration number: IRCT20080728001031N24).

Objective: Surgery and chemotherapy are the most common therapeutic strategies proposed for oral squamous cellcarcinoma (OSCC). However, some of the disadvantages associated with the current methods like unwanted sideeffects and poor drug response lead the scientist to seek for novel modalities and delivery approaches to enhance theefficacy of treatments. The study aimed to assess the effectiveness of disulfiram (DSF)-loaded Niosomes on cancerousphenotypes of the OSCC cells.Materials and Methods: In this experimental study, an optimum formulation of DSF-loaded Niosomes was developedfor the treatment of OSCC cells to reduce drug doses and improve the poor stability of DSF in the OSCC environment.The design expert software was utilized to optimize the particles in terms of size, polydispersity index (PDI), andentrapment effcacy (EE).Results: Acidic pH increased the release rate of DSF from these formulations. The size, PDI, and EE of Niosomeswere more stable at 4°C compared to 25°C. The results indicated that DSF-loaded Niosomes could induce apoptosis(P=0.019) in the OSCC cells compared to the control group. Moreover, it could reduce colony formation ability(P=0.0046) and also migration capacity of OSCC cells (P=0.0015).Conclusion: Our findings indicated that the application of proper dose of DSF-loaded Niosomes (12.5 μg/ml) increasesapoptosis, decreases colony formation capacity and declines the migration ability of OSCC cells.

Abstract 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 .

Abstract Background Intra-articular injection of mesenchymal stromal cells (MSCs) with immunomodulatory features and their paracrine secretion of regenerative factors proposed a noninvasive therapeutic modality for cartilage regeneration in knee osteoarthritis (KOA). Methods Total number of 40 patients with KOA enrolled in two groups. Twenty patients received intra-articular injection of 100 × 106 allogeneic adipose-derived mesenchymal stromal cells (AD-MSCs), and 20 patients as control group received placebo (normal saline). Questionnaire-based measurements, certain serum biomarkers, and some cell surface markers were evaluated for 1 year. Magnetic resonance imaging (MRI) before and 1 year after injection was performed to measure possible changes in the articular cartilage. Results Forty patients allocated including 4 men (10%) and 36 women (90%) with average age of 56.1 ± 7.2 years in control group and 52.8 ± 7.5 years in AD-MSCs group. Four patients (two patients from AD-MSCs group and two patients from the control group) excluded during the study. Clinical outcome measures showed improvement in AD-MSCs group. Hyaluronic acid and cartilage oligomeric matrix protein levels in blood serum decreased significantly in patients who received AD-MSCs (P

Inflammatory and autoimmune diseases are among the most challenging disorders for health care professionals that require systemic immune suppression which associates with various side effects. Mesenchymal stromal cells (MSCs) are capable of regulating immune responses, mainly through paracrine effects and cell-cell contact. Since MSCs are advanced therapy medicinal products (ATMPs), they must follow Good Manufacturing Practice (GMP) regulations to ensure their safety and efficacy. In this study, we evaluated the immunomodulatory effects of GMP-compliant clinical grade MSCs obtained from four different sources (bone marrow, adipose tissue, Wharton’s Jelly, and decidua tissue) on allogeneic peripheral blood mononuclear cells (PBMCs). Our results revealed that WJ-MSCs were the most successful group in inhibiting PBMC proliferation as confirmed by BrdU analysis. Moreover, WJ-MSCs were the strongest group in enhancing the regulatory T cell population of PBMCs. WJ-MSCs also had the highest secretory profile of prostaglandin E2 (PGE-2), anti-inflammatory cytokine, while interleukin-10 (IL-10) secretion was highest in the DS-MSC group. DS-MSCs also had the lowest secretion of IL-12 and IL-17 inflammatory cytokines. Transcriptome analysis revealed that WJ-MSCs had the lowest expression of IL-6, while DS-MSCs were the most potent group in the expression of immunomodulatory factors such as hepatocyte growth factor (HGF) and transforming growth factor-β (TGF- β). Taken together, our results indicated that GMP-compliant Wharton’s Jelly and decidua-derived MSCs showed the best immunomodulatory performance considering paracrine factors.

"Theory of Forms" implies that a genuine version of creatures exists beyond the shapes in this world. Stem celltechnology has adopted developmental cues to mimic real life. However, the functionality of the lab-made cells is farfrom primary ones. Perhaps it is time to switch from analytical to systematic perspective in stem cell science. Thismay be the way to define new horizons based on the systematic perspective and convergence of science in stem cellbiology, bridging the current gap between the shadows of real knowledge in current research and reality in future.

Contribution of platelets in tissue regeneration and their possible application in regenerative medicine, which is primarilymediated via secretion of granular components following platelet activation, has been well established in the recent decades.Therefore, platelet rich plasma (PRP), as a portion of plasma with higher concentrations of platelets than the baseline level,is now an attractive therapeutic option in various medical fields mainly for tissue repair and regeneration following injuries.Burn injuries are devastating trauma with high rate of morbidities affecting several aspects of the patient’s life. They requirea long-time medical care and high costs. However, even following the best treatment procedures, post-burn scars areinevitable consequence of burn healing process. Therefore, development of new treatment modalities for both burn healingand prevention of post-burn scar establishment seems to be necessary. Regarding the well-known role of PRP in woundhealing, here we aimed to provide a comprehensive insight in the possible application of PRP as an adjuvant therapy forthe management of burn injuries and subsequent scars. In terms of the following keywords (individually or in combination),original/review articles were searched in PubMed, Scopus, and Google Scholar databases from 2009 to 2021: platelet richplasma, PRP therapy, platelet biology, platelet function, burn healing, burn scar, scar formation, burn management, woundhealing, regenerative medicine. All type of articles or book chapters in English language and relevant data were included inthis review. This review initially focused on PRP, its mechanisms of action, preparation methods, and available sources. Then,pathophysiology of burns and subsequent scars were discussed. Finally, their current conventional therapeutic modalities andimplication of PRP in their healing process were highlighted.

Non-alcoholic fatty liver disease (NAFLD) has become the world’s most common chronic liver disease. However, due to the lack of reliable in vitro NAFLD models, drug development studies have faced many limitations, and there is no food and drug administration-approved medicine for NAFLD treatment. A functional biomimetic in vitro human liver model requires an optimized natural microenvironment using appropriate cellular composition, to provide constructive cell-cell interactions, and niche-specific bio-molecules to supply crucial cues as cell-matrix interplay. Such a suitable liver model could employ appropriate and desired biochemical, mechanical, and physical properties similar to native tissue. Moreover, bioengineered three-dimensional tissues, specially microtissues and organoids, and more recently using infusion-based cultivation systems such as microfluidics can mimic natural tissue conditions and facilitate the exchange of nutrients and soluble factors to improve physiological function in the in vitro generated constructs. This review highlights the key players involved in NAFLD initiation and progression and discussed the available cells and matrices for in vitro NAFLD modeling. The strategies for optimizing the liver microenvironment to generate a powerful and biomimetic in vitro NAFLD model were described as well. Finally, the current challenges and future perospective for promotion in this subject were discussed.

Vitiligo is an auto-immune disease, causing depigmentation of skin in 0.2-1.8% of global population. Topicalcorticosteroids and calcineurin inhibitors are the only treatments with firm evidence of optimal effectiveness withconsiderable side effects. Phototherapies might not induce serious side effects, although the effectiveness of the methodis limited. Advanced therapy medicinal products (ATMPs) are emerging treatment modalities based on correction andreplacement of affected genes, damaged tissues or cells in treatment of difficult-to-treat diseases. Due to optimaleffectiveness and minimal side effects, ATMPs have recently gained much attention in order to develop new treatments.In this review, the ATMPs for treating vitiligo were along with its clinical success, affordability and cost-effectiveness.Currently, the main ATMP based products using in treatment of vitiligo are non-cultured epidermal cell, melanocytes,and hair follicle melanocytes. These products have shown promising results in the non-responding vitiligo patients.Furthermore, mesenchymal stem cells and multi-lineage differentiating stress enduring cells are other new potentialmodalities. Recently, Iranian Food and Drug Administration (IR-FDA) authorized the first cell-based product for vitiligo.This product is autologous suspension of keratinocytes and melanocytes. Although ATMPs are efficient and could becost-effective in long term, the most important obstacle is affordability of them. This could be facilitated by insurancecompanies and instalments payment programs from manufacturers.

The liver plays a crucial role in drug detoxification, and the main source of liver transplants is brain-dead patients. However, the demand for transplants exceeds the available supply, leading to controversies in selecting suitable candidates for acute liver diseases. This research aimed to differentiate mesenchymal stem cells (MSCs) into hepatocyte-like cells using galactosylated rat natural scaffolds and comparing 2-D and 3-D cell culture methods. The study involved isolating and culturing Wharton's jelly cells from the umbilical cord, examining surface markers and adipogenic differentiation potential of MSCs, and culturing mesenchymal cells on galactosylated scaffolds. The growth and proliferation of stem cells on the scaffolds were evaluated using the MTT test, and urea synthesis was measured in different culture environments. Changes in gene expression were analyzed using real-time PCR. Flow cytometry results confirmed the presence of specific surface antigens on MSCs, indicating their identity, while the absence of a specific antigen indicated their differentiation into adipocytes. The MTT test revealed higher cell attachment to galactosylated scaffolds compared to the control groups. Urea secretion was observed in differentiated cells, with the highest levels in cells cultured on galactosylated scaffolds. Gene expression analysis showed differential expression patterns for OCT-4, HNF1, ALB, AFP, and CYP genes under different conditions. The findings indicated that hepatocyte-like cells derived from 3D cultures on galactosylated scaffolds exhibited superior characteristics compared to cells in other culture conditions. These cells demonstrated enhanced proliferation, stability, and urea secretion ability. The study also supported the differentiation potential of MSCs derived from Wharton's jelly umbilical cord into liver-like cells.

Vitiligo is an autoimmune skin disorder that can significantly affect the quality of life in patients. However, currenttreatment strategies such as phototherapy, topical glucocorticosteroids, or systemic immunosuppressants canbe helpful in vitiligo management, and treatments for disease stability which is the main challenge in vitiligomanagement. Novel therapeutic modalities have made promising advances in this regard. Molecular targetedtherapy to target Janus-activated kinase (JAK) such as Tofacitinib and Ruxolitinib in addition to the cell-basedtreatments are innovative therapeutic options, which are recently used for vitiligo treatment. Transplantation ofnon-cultured melanocytes-keratinocytes have been studied in Iran and phase one data published in 2010 on 10patients that continued on 300 patients as phase three in 2018. Cell Tech Pharmed™ Co. registered and appliedthis cell-based product, ReColorCell®, as a GMP certified by Iranian Food and Drug Administration (IR-FDA). On11th December 2021, ReColorCell® officially registered as the first cell-based product in the Iranian drug list (IDL).Currently, the post-market study of this product is ongoing.

Non-clear cell renal cell carcinomas (nccRCC) are a diverse group of kidney cancers with histopathologically and genetically heterogeneous features. About 25% of renal cell carcinomas (RCCs) are nccRCC types. The management and treatment of nccRCCs are rather limited, and the data are often estimated from studies in the more common clear cell renal cell carcinoma (ccRCC). Each subtype has its own distinctive biological and therapeutic profile. Our knowledge of the underlying biological features of nccRCC has directed and continues to shape the use of novel therapy targeting the main signaling pathways and leading to improved overall survival (OS) of the patients. This review discusses the characteristic molecular features of the major types of nccRCC and current cell-based and animal models for studying them. In the following, we highlighted major signaling pathways and therapeutic approaches for nccRCC patients.

Abstract Background Results from recent clinical trials on bone marrow mononuclear cell (BM-MNC) transplantation show that this intervention can help reduce the incidence of heart failure (HF) after acute myocardial infarction (AMI). However, no study has evaluated the effect of the transplantation of mesenchymal stem cells (MSCs) on a clinical endpoint such as HF. Methods This single-blinded, randomized, multicenter trial aims to establish whether the intracoronary infusion of umbilical cord-derived Wharton’s jelly MSCs (WJ-MSCs) helps prevent HF development after AMI. The study will enroll 390 patients 3 to 7 days following AMI. Only patients aged below 65 years with impaired LV function (LVEF < 40%) will be included. They will be randomized (2:1 ratio) to either receive standard care or a single intracoronary infusion of 107 WJ-MSCs. The primary outcome of this study is the assessment of HF development during long-term follow-up (3 years). Discussion Data will be collected until Nov 2024. Thereafter, the analysis will be conducted. Results are expected to be ready by Dec 2024. We will prepare and submit the related manuscript following the CONSORT guidelines. This study will help determine whether or not the infusion of intracoronary WJ-MSCs in patients with AMI will reduce the incidence of AMI-induced HF. Trial registration ClinicalTrials.gov NCT05043610 , Registered on 14 September 2021 - retrospectively registered.

Exosomes are small extracellular vesicles with sizes ranging from 30–150 nanometers that contain proteins, lipids, mRNAs, microRNAs, and double-stranded DNA derived from the cells of origin. Exosomes can be taken up by target cells, acting as a means of cell-to-cell communication. The discovery of these vesicles in body fluids and their participation in cell communication has led to major breakthroughs in diagnosis, prognosis, and treatment of several conditions (e.g., cancer). However, conventional isolation and evaluation of exosomes and their microRNA content suffers from high cost, lengthy processes, difficult standardization, low purity, and poor yield. The emergence of microfluidics devices with increased efficiency in sieving, trapping, and immunological separation of small volumes could provide improved detection and monitoring of exosomes involved in cancer. Microfluidics techniques hold promise for advances in development of diagnostic and prognostic devices. This review covers ongoing research on microfluidics devices for detection of microRNAs and exosomes as biomarkers and their translation to point-of-care and clinical applications.

Hepatocellular carcinoma (HCC) is the most common type of primary hepatic cancer and is among the major causes of mortality due to cancer. Due to the lack of efficient conventional therapeutic options for this cancer, particularly in advanced cases, novel treatments including immunotherapy have been considered. However, despite the encouraging clinical outcomes after implementing these innovative approaches, such as oncolytic viruses (OVs), adoptive cell therapies (ACT), immune checkpoint blockades (ICBs), and cancer vaccines, several factors have restricted their therapeutic effect. The main concern is the existence of an immunosuppressive tumor microenvironment (TME). Combination of different ICBs or ICBs plus tyrosine kinase inhibitors have shown promising results in overcoming these limiting factors to some extent. Combination of programmed cell death ligand-1 (PD-L1) antibody Atezolizumab and vascular endothelial growth factor (VEGF) antibody Bevacizumab has become the standard of care in the first-line therapy for untestable HCC, approved by regulatory agencies. This paper highlighted a wide overview of the direct and indirect immunotherapeutic strategies proposed for the treatment of HCC patients and the common challenges that have hindered their further clinical applications.

Objectives: Epigenetic alterations, including any change in DNA methylation pattern, could be the missing link of understanding radiation-induced genomic instability. Dapper, Dishevelled-associated antagonist of β-catenin homolog 2 (DACT2) is a tumor suppressor gene regulating Wnt/β-catenin. In hepatocellular carcinoma (HCC), DACT2 is hypermethylated, while methylation status of its promoter regulates the corresponding expression. Radionuclides have been used to reduce proliferation and induce apoptosis in cancerous cells. Epigenetic impact of radionuclides as therapeutic agents for treatment of HCC is still unknown. The aim of this study was to evaluate epigenetic impact of 188Rhenium perrhenate (188ReO4) on HCC cells.Material and Methods: In this in vitro experimental study, HepG2 and Huh7 cells were treated with 188ReO4, receiving 55 and 73 Mega Becquerel (MBq) exposures, respectively. For cell viability measurement, live/dead staining was carried out 18, 24, and 48 hours post-exposure. mRNA expression level of β-Catenin, Wnt1, DNMT1, DACT2 and WIF-1 genes were quantified by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Then, possible regulatory impact of DACT2 upregulation was investigated through evaluating methylation-specific PCR (MS-PCR).Results: Results showed that viability of both cells was reduced after treatment with 188ReO4 at three time points postexposure compared to the control groups. The qRT-PCR results showed that DACT2 mRNA level was significantly increased at 24, and 48 hours post-exposure in HepG2 cells compared to the control group, while, no significant change was observed in Huh7 cells. Methylation pattern of DACT2 promoter remained unchanged in HepG2 and Huh7 cells.Conclusion: Treatment with 188ReO4 reduced viability of HepG2 and Huh7 cells. Although DACT2 expression was increased after 188ReO4 exposure in HepG2 cells, methylation pattern of its promoter remained unchanged. This study assessed impacts of the 188 ReO4 β-irradiation on expression and induction of DACT2 epigenetic aberrations as well as the correlation of this agent with viability of cells.

Abstract This review aims at becoming a guide which will help to plan the experimental design and to choose adequate methods to assess the outcomes when testing cell-based products in the treatment of the damaged vocal folds. The requirements to preclinical trials of cell-based products remain rather hazy and dictated by the country regulations. Most parameters like the way the cells are administered, selection of the cell source, selection of a carrier, and design of in vivo studies are decided upon by each research team and may differ essentially between studies. The review covers the methodological aspects of preclinical studies such as experimental models, characterization of cell products, assessment of the study outcome using molecular, morphological and immunohistochemical analyses, as well as measuring the tissue physical properties. The unified recommendations to perform preclinical trials could significantly facilitate the translation of cell-based products into the clinical practice. Graphical abstract

Cell-based therapy and tissue engineering are promising substitutes for liver transplantation to cure end-stage liver disorders. However, the limited sources for healthy and functional cells and poor engraftment rate are main challenges to the cell-based therapy approach. On the other hand, feasibility of production and size of bioengineered tissues are primary bottlenecks in tissue engineering. Here, we induce regeneration in a rat fibrotic liver model by transplanting a natural bioengineered scaffold with a native microenvironment repopulated with autologous stem/progenitor cells. In the main experimental group, a 1 mm3 stromal derived factor-1α (SDF-1α; S) loaded scaffold from decellularized liver extracellular matrix (LEM) was transplanted (Tx) into a fibrotic liver and the endogenous stem/progenitor cells were mobilized via granulocyte colony stimulating factor (G-CSF; G) therapy. Four weeks after transplantation, changes in liver fibrosis and necrosis, efficacy of cell engraftment and differentiation, vasculogenesis, and liver function recovery were assessed in this (LEM-TxSG) group and compared to the other groups. We found significant reduction in liver fibrosis stage in the LEM-TxSG, LEM-TxS and LEM-TxG groups compared to the control (fibrotic) group. Liver necrosis grade, and alanine transaminase (ALT) and aspartate transaminase (AST) levels dramatically reduced in all experimental groups compared to the control group. However, the number of engrafted cells into the transplanted scaffold and ratio of albumin (Alb) positive cells per total incorporated cells were considerably higher in the LEM-TxSG group compared to the LEM-Tx, LEM-TxS and LEM-TxG groups. Serum Alb levels increased in the LEM-Tx, LEM-TxS, and LEM-TxG groups, and was highest in the LEM-TxSG group, which was significantly more than the fibrotic group. Small vessel formation in the LEM-TxSG group was significantly higher than the LEM-Tx and LEM-TxS groups. Totally, these findings support application of the in vivo tissue engineering approach as a possible novel therapeutic strategy for liver fibrosis.

Abstract Background Meta-analysis from previous studies have shown that treatment with mesenchymal stromal cell (MCSs) may increase the left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI) by 3.84%, and the effect is greater in those who are not aged and have developed a reduced LVEF. However, it seems that MSC transplantation does its effect through an indirect paracrine effect, and direct differentiation to the cardiomyocytes does not occur. Therefore, it can be hypothesized that this paracrine effect would be augmented if repeated doses of MSC are transplanted. This study is conducted to compare single vs. double injection of MSCs. Methods This is a single-blind, randomized, multicenter trial aiming to determine whether intracoronary infusion of double doses of umbilical cord-derived Wharton’s jelly MSCs (WJ-MSCs) improves LVEF more after AMI compared to single administration. Sixty patients 3 to 7 days after AMI will be enrolled. The patients should be under 65 years old and have a severe impairment in LV function (LVEF

Abstract Introduction The current multi-center, randomized, double-blind study was conducted among children with cerebral palsy (CP) to assess the safety and efficacy of umbilical cord blood mononuclear cell (UCB-MNC). We performed the diffusion tensor imaging to assess the changes in the white matter structure. Methods Males and females aged 4 to 14 years old with spastic CP were included. Eligible participants were allocated in 4:1 ratio to be in the experimental or control groups; respectively. Individuals who were assigned in UCB-MNC group were tested for human leukocyte antigen (HLA) and fully-matched individuals were treated with UCB-MNCs. A single dose (5 × 106 /kg) UCB-MNCs were administered via intrathecal route in experimental group. The changes in gross motor function measure (GMFM)-66 from baseline to one year after treatment were the primary endpoints. The mean changes in modified Ashworth scale (MAS), pediatric evaluation of disability inventory (PEDI), and CP quality of life (CP-QoL) were also evaluated and compared between groups. The mean changes in fractional anisotropy (FA) and mean diffusivity (MD) of corticospinal tract (CST) and posterior thalamic radiation (PTR) were the secondary endpoints. Adverse events were safety endpoint. Results There were 72 included individuals (36 cases in each group). The mean GMFM-66 scores increased in experimental group; compared to baseline (+ 9.62; 95%CI: 6.75, 12.49) and control arm (β: 7.10; 95%CI: 2.08, 12.76; Cohen’s d: 0.62) and mean MAS reduced in individuals treated with UCB-MNCs compared to the baseline (-0.87; 95%CI: -1.2, -0.54) and control group (β: -0.58; 95%CI: -1.18, -0.11; Cohen’s d: 0.36). The mean PEDI scores and mean CP-QoL scores in two domains were higher in the experimental group compared to the control. The imaging data indicated that mean FA increased and MD decreased in participants of UCB-MNC group indicating improvements in white matter structure. Lower back pain, headaches, and irritability were the most common adverse events within 24 h of treatment that were related to lumbar puncture. No side effects were observed during follow-up. Conclusions This trial showed that intrathecal injection of UCB-MNCs were safe and effective in children with CP. Trial Registration The study was registered with ClinicalTrials.gov ( NCT03795974 ).

Liver cancer is a significant contributor to the cancer burden, and its incidence rates have recently increased in almost all countries. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is the second leading cause of cancer-related deaths worldwide. Because of the late diagnosis and lack of efficient therapeutic modality for advanced stages of HCC, the death rate continues to increase by ~2–3% per year. Circulating tumor cells (CTCs) are promising tools for early diagnosis, precise prognosis, and follow-up of therapeutic responses. They can be considered to be an innovative biomarker for the early detection of tumors and targeted molecular therapy. In this review, we briefly discuss the novel materials and technologies applied for the practical isolation and detection of CTCs in HCC. Also, the clinical value of CTC detection in HCC is highlighted.

Objective: Perianal fistulas in Crohn’s disease (CD) are the main challenges in inflammatory bowel diseases (IBDs). Some of the fistulas are refractory to any therapeutic strategy. The aim of this study was to evaluate the therapeutic effects of mesenchymal stromal cells (MSCs) as a novel promising modality for the treatment of fistulizing CD. Materials and Methods: This case series clinical interventional study was conducted from 2014 to 2017 at Shariati Hospital, an IBD referral center in Tehran, Iran. Refractory adult patients with CD who had draining perianal fistulas were enrolled in this study. All patients were examined by a colorectal surgeon and the fistula imaging studies were performed by pelvic magnetic resonance imaging (MRI). After autologous bone marrow(BM) aspiration and MSCs isolation, the cells were cultured and passaged under current good manufacturing practice (cGMP) conditions. Four intra-fistula injections of cells, each containing 40×106 MSCs suspended in fibrin glue, were administered by an expert surgeon every 4 weeks. Procedure safety, feasibility and closure of the perianal fistulas at week 24 were assessed. Clinical examination and MRI findings were considered as the primary end points. Results: In total, 5 patients (2 males and 3 females) were enrolled in this study. No adverse events were observed during the six-month follow-up in these patients. Both the Crohn’s Disease Activity Index (CDAI) and Perianal Disease Activity Index (PDAI) scores decreased in all patients after cell injections and one patient achieved complete remission with closure of fistulas, discontinuation of fistula discharge, and closure of the external opening. Conclusion: Local injection of MSCs combined with fibrin glue is potentially a safe and effective therapeutic approach for complex perianal fistulas in patients with CD.

Gastrointestinal (GI) cancers, including colorectal, gastric, hepatic, esophageal, and pancreatic tumors, are responsible for large numbers of deaths around the world. Chemotherapy is the most common approach used to treat advanced GI cancer. However, chemoresistance has emerged as a critical challenge that prevents successful tumor elimination, leading to metastasis and recurrence. Chemoresistance mechanisms are complex, and many factors and pathways are involved. Among these factors, non-coding RNAs (ncRNAs) are critical regulators of GI tumor development and subsequently can induce resistance to chemotherapy. This occurs because ncRNAs can target multiple signaling pathways, affect downstream genes, and modulate proliferation, apoptosis, tumor cell migration, and autophagy. ncRNAs can also induce cancer stem cell features and affect the epithelial-mesenchymal transition. Thus, ncRNAs could possibly act as new targets in chemotherapy combinations to treat GI cancer and to predict treatment response.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with very limited treatment options. Stem cells have been raised as a new treatment modality for these patients. We have designed a single-center, prospective, open-label, and single arm clinical trial to assess the safety, feasibility, and rather efficacy of administrating allogeneic adipose-derived mesenchymal stromal cells (Ad-MSCs) in ALS patients. We enrolled 17 patients with confirmed ALS diagnosis with ALS Functional Rating Scale-Revised (ALSFRS-R) ≥24 and predicted forced vital capacity (FVC) ≥40%. Allogeneic Ad-MSCs were transplanted intravenously for all patients. Follow-ups were done at 24 hours, 2, 4, 6, and 12 months after cell infusion by checking adverse events, laboratory tests, and clinically by ALSFRS-R and FVC. Patients were also followed five years later and ALSFRS-R score was recorded in the survived individuals. There was no report of severe adverse events related to cell infusion. Two patients experienced dyspnea and chest pain 36 and 65 days after cell infusion due to pulmonary emboli. The progressive decrease in ALSFRS-R and FVC levels was recorded and three patients died in the first year. During five years follow up, despite a notable decrease in functional scores, 5 patients survived. Intravenous (IV) infusion of allogeneic Ad-MSCs in ALS patients is safe and feasible. The survival rate of the patients is more than IV autologous MSCs (Registration number: IRCT20080728001031N26).

There are a lot of data about the correlation of SARS-CoV-2 infection and hypertension (HTN), but most of themare in the increased risk of morbidity and mortality in patients with HTN. SARS-CoV-2 can interfere with host cellsthrough the renin-angiotensin system (RAS) via the angiotensin-converting enzyme 2 (ACE2) receptor. RAS activationis associated with pro-inflammatory effects through the ACE/Ang II/ Angiotensin II type 1 receptor (AT1R) pathwayor anti-inflammatory effects through ACE2/Ang1-7/Mas axis. In the current paper, we discuss the pathophysiology ofnewly diagnosed HTN and its effect on morbidity in patients with coronavirus disease 2019 (COVID-19).

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic struck global health systems with overgrowing demands in many fields of health care; yet, reproductive care, particularly pregnancy care remains a special focus of interest. Pregnancy is a major physiologic change that alters temporarily normal function of many organs, and specifically the immune system. Therefore, pregnant women are more susceptible to respiratory pathogens compared to the others. The current pandemic may have serious consequences on pregnancy whether directly or indirectly. In the present review, direct and indirect possible adverse effects of SARS-CoV-2 infection on female reproductive system by focusing on pregnancy and delivery has been discussed in details. In addition, the pregnancy consequences and whether maternal infection can affect infants were deliberated. The adverse impact of luck down and related psychological complications and obesity on pregnant women were discussed as well. Finally, the effects of SARS-CoV-2 vaccination on maternal health and pregnancy outcome was analyzed.

Coronavirus disease 2019 (COVID-19), as a severe respiratory disease, affects various tissues and organs. The specific SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), is highly expressed in male gonads. Thus, male reproductive tissues could be a potential target for virus colonization. We performed a comprehensive search in PubMed and Google Scholar to retrieve relevant articles published till 15 April 2021. The keywords used were: male fertility, male reproductive health, semen parameters, sex hormones, SARS-CoV-2, and COVID-19. Validated evidence about the adverse effects of the SARS-CoV-2 infection on the male reproductive system is limited and few studies have reported semen analysis results or presence of viral RNA in semen samples of infected men. Nevertheless, alterations in reproductive hormones such as decreased level of testosterone (T) with raised luteinizing hormone (LH) have been reported in some patients. Although the impact of SARS-CoV-2 infection on the male reproduction health remains unclear, evidence suggests that male gonads may be potentially vulnerable to SARS-CoV-2 infection. In this article, we discussed the possible impacts of COVID-19 on male gonads, sex hormones, and semen quality and suggested preventive solutions.

Pancreatic cancer (PC) is one of the leading causes of cancer mortality worldwide, and its incidence and mortality rate in several regions is higher in male patients. Although numerous efforts have been made to enhance the clinical outcomes of existing therapeutic regimens, their efficiency is still low, and drug resistance usually occurs in many patients. In addition, the exact underlying molecular basis that makes PC slightly more prevalent among males remains unknown. Providing information regarding the possible association between gender and PC tumorigenesis may offer important clues for how certain molecular cross-talks can affect PC initiation and/or progression. In this study, we used several microarray expression data to identify the common up- and downregulated genes within one specific gender, which were also specified to have binding sites for androgen and/or estrogen receptors. Using functional enrichment analysis among the others, for all the gene sets found in this study, we have shed light on the plausible importance of the androgenic effectors in tumorigenesis, such as the androgen-regulated expression of the GLI transcription factor and the potential role of testosterone in the extracellular matrix (ECM)–cell interaction, which are known for their importance in tumorigenesis. Moreover, we demonstrated that the biological process axon guidance was highlighted regarding the upregulated genes in male patients. Overall, identification of gene candidates as the possible link between gender and PC progression or survival rates may help in developing strategies to reduce the incidence of this cancer.

The liver is a vital organ responsible for metabolic and digestive functions, protein synthesis, detoxification, and numerous other necessary functions. Various acute, chronic, and neoplastic disorders affect the liver and hamper its biological functions. Most of the untreated liver diseases lead to inflammation and fibrosis which develop into cirrhosis. The human amniotic membrane (hAM), the innermost layer of the fetal placenta, is composed of multiple layers that include growth-factor rich basement membrane, epithelial and mesenchymal stromal cell layers. hAM possesses distinct beneficial anti-fibrotic, anti-inflammatory and pro-regenerative properties via the secretion of multiple potent trophic factors and/or direct differentiation into hepatic cells which place hAM-based therapies as potential therapeutic strategies for the treatment of chronic liver diseases. Decellularized hAM is also an ideal scaffold for liver tissue engineering as this biocompatible niche provides an excellent milieu for cell proliferation and hepatocytic differentiation. Therefore, the current review discusses the therapeutic potential of hAM and its derivatives in providing therapeutic solutions for liver pathologies including acute liver failure, metabolic disorders, liver fibrosis as well as its application in liver tissue engineering.

Abstract Background This study assessed the safety and efficacy of intrathecal injection of umbilical cord tissue mesenchymal stem cells (UCT-MSC) in individuals with cerebral palsy (CP). The diffusion tensor imaging (DTI) was performed to evaluate the alterations in white-matter integrity. Methods Participants (4–14 years old) with spastic CP were assigned in 1:1 ratio to receive either UCT-MSC or sham procedure. Single-dose (2 × 107) cells were administered in the experimental group. Small needle pricks to the lower back were performed in the sham-control arm. All individuals were sedated to prevent awareness. The primary endpoints were the mean changes in gross motor function measure (GMFM)-66 from baseline to 12 months after procedures. The mean changes in the modified Ashworth scale (MAS), pediatric evaluation of disability inventory (PEDI), and CP quality of life (CP-QoL) were also assessed. Secondary endpoints were the mean changes in fractional anisotropy (FA) and mean diffusivity (MD) of corticospinal tract (CST) and posterior thalamic radiation (PTR). Results There were 36 participants in each group. The mean GMFM-66 scores after 12 months of intervention were significantly higher in the UCT-MSC group compared to baseline (10.65; 95%CI 5.39, 15.91) and control (β 8.07; 95%CI 1.62, 14.52; Cohen’s d 0.92). The increase was also seen in total PEDI scores (vs baseline 8.53; 95%CI 4.98, 12.08; vs control: β 6.87; 95%CI 1.52, 12.21; Cohen’s d 0.70). The mean change in MAS scores after 12 months of cell injection reduced compared to baseline (−1.0; 95%CI −1.31, −0.69) and control (β −0.72; 95%CI −1.18, −0.26; Cohen’s d 0.76). Regarding CP-QoL, mean changes in domains including friends and family, participation in activities, and communication were higher than the control group with a large effect size. The DTI analysis in the experimental group showed that mean FA increased (CST 0.032; 95%CI 0.02, 0.03. PTR 0.024; 95%CI 0.020, 0.028) and MD decreased (CST −0.035 × 10-3; 95%CI −0.04 × 10-3, −0.02 × 10-3. PTR −0.045 × 10-3; 95%CI −0.05 × 10-3, −0.03 × 10-3); compared to baseline. The mean changes were significantly higher than the control group. Conclusions The UCT-MSC transplantation was safe and may improve the clinical and imaging outcomes. Trial registration The study was registered with ClinicalTrials.gov ( NCT03795974 ).

Angiotensin-converting enzyme II (ACE2) in association with type II transmembrane serine protease (TMPRSS2) is considered the main receptor of SARS-CoV-2. However, considering the clinical complications of COVID-19 in different organs, there is no strong association between the abundance of ACE2/TMPRSS2 co-expression and clinical features of the disease and the severity of complications. Since SARS-CoV-2 affects certain organs that lack or have low expression of ACE2/TMPRSS2, it may be possible that the virus employs other receptors for colonization and entry. Based on recent studies, glucose-regulated protein 78 (GRP78) can be a potential alternative receptor for SARS-CoV-2 entry. In this letter, supporting evidence proposed GRP78 as an alternative receptor in SARS-CoV-2 infection.

Familial hypercholesterolemia (FH) is a common monogenic disease which is associated with high serum levels of low-density lipoprotein cholesterol (LDL-C) and leads to atherosclerosis and cardiovascular disease (CVD). Early diagnosis and effective treatment strategy can significantly improve prognosis. Recently, non-coding RNAs (ncRNAs) have emerged as novel biomarkers for the diagnosis and innovative targets for therapeutics. Non-coding RNAs have essential roles in the regulation of LDL-C homeostasis, suggesting that manipulation and regulating ncRNAs could be a promising theranostic approach to ameliorate clinical complications of FH, particularly cardiovascular disease. In this review, we briefly discussed the mechanisms and pathophysiology of FH and novel therapeutic strategies for the treatment of FH. Moreover, the theranostic effects of different non-coding RNAs for the treatment and diagnosis of FH were highlighted. Finally, the advantages and disadvantages of ncRNA-based therapies vs. conventional therapies were discussed.