Comparison of extruded cell nanovesicles and exosomes in their molecular cargos and regenerative potentials

Extracellular vesicles(EVs)generated from mesenchymal stem cells(MSCs)play an essential role in modulating cell–cell communication and tissue regeneration.The clinical translation of EVs is constrained by the poor yield of EVs.Extrusion has recently become an effective technique for producing a large scale of nanovesicles(NVs).In this study,we systematically compared MSC NVs(from extrusion)and EVs(from natural secretion).Proteomics and RNA sequencing data revealed that NVs resemble MSCs more closely than EVs.Additionally,microRNAs in NVs are related to cardiac repair,fibrosis repression,angiogenesis.Lastly,intravenous delivery of MSC NVs improved heart repair and cardiac function in a mouse model of myocardial infarction.

Interleukin-18, matrix metalloproteinase-22 and -29 are independent risk factors of human coronary heart disease

Background: Coronary heart disease(CHD) is characterized by arterial wall inflammation and matrix degradation. Matrix metalloproteinase(MMP)-22 and-29 and pro-inflammatory cytokine interleukin-18(IL18) are present in human hearts. IL18 may regulate MMP-22 and-29 expression, which may correlate with CHD progression. Methods and results: Immunoblot analysis showed that IL18 induced MMP-22 expression in human aortic smooth muscle cells. The Mann Whitney test from a prospective study of 194 CHD patients and 68 non-CHD controls demonstrated higher plasma levels of IL18, MMP-22 and-29 in CHD patients than in the controls. A logistic regression test suggested that plasma IL18(odds ratio(OR)=1.131, P=0.007), MMP-22(OR=1.213, P=0.040), and MMP-29(OR=1.198, P=0.033) were independent risk factors of CHD. Pearson's correlation test showed that IL18(coefficient(r)=0.214, P=0.045; r=0.246, P=0.031) and MMP-22(r=0.273, P=0.006; r=0.286, P=0.012) were associated with the Gensini score before and after adjusting for potential confounding factors. The multivariate Pearson's correlation test showed that plasma MMP-22 levels correlated positively with high-sensitive-C-reactive protein(hs-CRP)(r=0.167, P=0.023), and MMP-29 levels correlated negatively with triglyceride(r=-0.169, P=0.018). Spearman's correlation test indicated that plasma IL18 levels associated positively with plasma MMP-22(r=0.845, P<0.001) and MMP-29(r=0.548, P<0.001). Conclusions: Our observations suggest that IL18, MMP-22 and-29 serve as biomarkers and independent risk factors of CHD. Increased systemic IL18 in CHD patients may contribute to elevated plasma MMP-22 and-29 levels in these patients.

A trifunctional contraceptive gel enhances the safety and quality of sexual intercourse

Current contraceptive methods come with a number of drawbacks,including low efficacy,in the case of commercial contraceptive gels,and a reduction in the quality of sexual intercourse,in the case of condoms.Adding pharmacologically-active agents to contraceptive gels holds the potential to improve sexual experience,and hardbor safety and hygiene.In this study,we fabricated a carbomer-based contraceptive gel consisting of three agents:tenofovir,gossypol acetate,and nitroglycerin(TGN),with pH adjusted to 4.5(to be compatible with the vagina).In vitro,the gossypol component of the contraceptive gel proved to be an effective spermicide.When the concentration of gossypol acetate was 10 mg/ml,the spermicidal ability reached 100%after 30 s.In addition,tenofovir in the gel significantly inhibited lentiviral transfection efficiency in cell-containing media.In 6 pairs of rats,the gel successfully prevented all females from conceiving after successful mating.Moreover,increased sexual frequency and enhanced erection,which were promoted by the nitroglycerin in the components,were observed in male rats that had the gel applied to their penises.This novel TGN contraceptive gel yielded a higher contraceptive success rate than that of the commercial contraceptive gel(Contragel®).In addition,it has the added benefits to prevent sexually transmitted diseases and improve male libido and erectile function during sexual intercourse.Combining three FDA-approved and marketed agents together,our trifunctional TGN gel has a great potential for further translation and commercialization.

An infusible biologically active adhesive for chemotherapy-related heart failure in elderly rats

Chemotherapy-induced cardiotoxicity with subsequent heart failure(HF)is a major cause of morbidity and mortality in cancer survivors worldwide.Chemotherapy-induced HF is exceptionally challenging as it generally manifests in patients who are typically not eligible for left ventricular device implantation or heart transplantation.To explore alternative treatment strategies for cancer survivors suffering from chemotherapy-induced HF,we developed a minimally invasive infusible cardiac stromal cell secretomes adhesive(MISA)that could be delivered locally through an endoscope-guided intrapericardial injection.To mimic the typical clinical presentation of chemotherapy-induced HF in elder patients,we established an aged rat model in which restrictive cardiomyopathy with sequential HF was induced via consecutive doxorubicin injections.In vitro,we prove that MISA not only enhanced cardiomyocytes proliferation potency and viability,but also inhibited their apoptosis.In vivo,we prove that MISA improved the ventricular contractility indexes and led to beneficial effects on histological and structural features of restrictive cardiomyopathy via promoting cardiomyocyte proliferation,angiogenesis,and mitochondrial respiration.Additionally,we also evaluated the safety and feasibility of MISA intrapericardial delivery in a healthy porcine model with an intact immune system.In general,our data indicates that MISA has a strong potential for translation into large animal models and ultimately clinical applications for chemotherapy-induced HF prior to the final option of heart transplantation.

Canine on the Couch:The New Canary in the Coal Mine for Environmental Health Research

Human health is intimately connected and tied to the health of our environment and ecosystem,with only a very small fraction of the risk for chronic diseases explained by genetics alone.Companion animals are prone to disease types that are shared with people,including cancers and endocrine disorders,reinforcing the thought that environmental factors contribute to the risks for chronic diseases.These factors include air and water pollution and the built environment.As such,there is increasing interest in pursuing research with companion animals,and specifically dogs,as sentinel species to inform comparative health assessments and identify risk factors for disease.Of the canine diseases for which environmental exposure research has been published,cancers have received the most attention.This review summarizes two main aspects of this comparative approach:(1)cancers that occur in dogs and which are similar to humans and(2)research investigating environmental exposures and health outcomes in dogs.The goal of this review is to highlight the diverse conditions in which pet dogs may provide unique perspectives and advantages to examine relationships between environmental exposures and health outcomes,with an emphasis on chemical pollution and cancer.Furthermore,this review seeks to raise awareness and stimulate discussion around the best practices for the use of companion animals as environmental health sentinels.

Advances in biomaterials and regenerative medicine for primary ovarian insufficiency therapy

Primary ovarian insufficiency(POI)is an ovarian dysfunction that affects more than 1%of women and is characterized by hormone imbalances that afflict women before the age of 40.The typical perimenopausal symptoms result from abnormal levels of sex hormones,especially estrogen.The most prevalent treatment is hormone replacement therapy(HRT),which can relieve symptoms and improve quality of life.However,HRT cannot restore ovarian functions,including secretion,ovulation,and fertility.Recently,as part of a developing field of regenerative medicine,stem cell therapy has been proposed for the treatment of POI.Thus,we recapitulate the literature focusing on the use of stem cells and biomaterials for POI treatment,and sum up the underlying mechanisms of action.A thorough understanding of the work already done can aid in the development of guidelines for future translational applications and clinical trials that aim to cure POI by using regenerative medicine and biomedical engineering strategies.

Cell and biomaterial-based approaches to uterus regeneration

Asherman’s syndrome(AS)is an endometrial disorder in which intrauterine adhesions crowd the uterine cavity and wall.The fibrotic adhesions are primarily the result of invasive uterine procedures that usually involve the insertion of surgical equipment into the uterus.This syndrome is accompanied by a number of clinical manifestations,including irregular or painful menstruation and infertility.The most prevalent treatment is hysteroscopy,which involves the physical removal of the fibrous strands.Within the last decade,however,the field has been exploring the use of cellbased therapeutics,in conjunction with biomaterials,to treat AS.This review is a recapitulation of the literature focused on cellular therapies for treating AS.

Light-triggered NO-releasing nanoparticles for treating mice with liver fibrosis

Liver fibrosis, resulting from chronic liver damage and characterized by the accumulation of extracellular matrix (ECM) proteins, is a characteristic of most types of chronic liver diseases. The activation of hepatic stellate cells (HSC) is considered an essential pathological hallmark in liver fibrosis. Although nitric oxide (NO) can effectively induce HSC apoptosis, the systemic administration of NO is ineffective and may cause severe complications such as hypotension. To overcome this limitation, nanoparticles were designed to target HSCs and release NO locally under the exposure of near infrared light (NIR). To achieve this, upconversion nanoparticle (UCNP) cores were enveloped in mesoporous silica shells (UCNP@mSiO2), which were modified with hyaluronic acid (HA-UCNP@mSiO2) and Roussin’s black salt (RBS). HA molecules recognize and bind to CD44 proteins, which are overexpressed on activated HSCs. Under exposure to a 980-nm NIR laser, the UCNP cores convert the 980-nm wavelength into ultraviolet (UV) light, which then energizes the RBS (NO donors), resulting in an efficient release of NO inside of the HSCs. Once released, NO triggers HSC apoptosis and reverses the liver fibrosis. This targeted and controlled release method provides the theoretical and experimental basis for novel therapeutic approaches to treat hepatic fibrosis.

The long non-coding RNA DANA2 positively regulates drought tolerance by recruitingERF84 to promote JMJ29-mediated histone demethylation

Tens of thousands of long non-coding RNAs have been uncovered in plants,but few of them have been comprehensively studied for their biological function and molecular mechanism of their mode of action.Here,we show that the Arabidopsis long non-coding RNA DANA2 interacts with an AP2/ERF transcription factor ERF84 in the cell nucleus and then affects the transcription of JMJ29 that encodes a Jumonji C domain-containing histone H3K9 demethylase.Both RNA sequencing(RNA-seq)and genetic analyses demonstrate that DANA2 positively regulates drought stress responses through JMJ29.JMJ29 positively regulates the expression of ERF15 and GOLS2 by modulation of H3K9me2 demethylation.Accordingly,mutation of JMJ29 causes decreased ERF15 and GOLS2 expression,resulting in impaired drought tolerance,in agreement with drought-sensitive phenotypes of dana2 and erf84 mutants.Taken together,these results demonstrate that DANA2 is a positive regulator of drought response and works jointly with the transcriptional activator ERF84 to modulate JMJ29 expression in plant response to drought.

Fungi between extremotolerance and opportunistic pathogenicity on humans

Numerous agents of infections in humans and other mammals are found among fungi that are able to survive extreme environmental conditions and to quickly adapt to novel habitats.Nevertheless,the relationship between opportunistic potential and polyextremotolerance was not yet studied systematically in fungi.Here,the link between polyextremotolerance and opportunistic pathogenicity is shown in a kingdom-wide phylogenetic analysis as a statistically significant co-occurrence of extremotolerance(e.g.osmotolerance and psychrotolerance)and opportunism at the level of fungal orders.In addition to extremotolerance,fungal opportunists share another characteristic—an apparent lack of specialised virulence traits.This is illustrated by a comparative genomic analysis of 20 dothideomycetous and eurotiomycetous black fungi.While the genomes of specialised fungal plant pathogens were significantly enriched in known virulence-associated genes that encode secreted proteases,carbohydrate active enzyme families,polyketide synthases,and non-ribosomal peptide synthetases,no such signatures were observed in human opportunists.Together the presented results have several implications.If infection of human hosts is a side effect of fungal stress tolerance and adaptability,the human body is most likely neither the preferred habitat of such species,nor important for their evolutionary success.This defines opportunism as opposed to pathogenicity,where infection is advantageous for the species’fitness.Since opportunists are generally incapable of the host-to-host transmission,any host-specific adaptations are likely to be lost with the resolution of the infection,explaining the observed lack of specialised virulence traits.In this scenario opportunistic infections should be seen as an evolutionary dead end and unlikely to lead to true pathogenicity.