Coenzyme Q10 and vitamin E alleviate heat stress-induced mood disturbances in male mice: Modulation of inflammatory pathways and the HPA axis.

Heat stress, as an environmental stressor, can lead to temperature dysregulation and neuroinflammation, causing depression and anxiety by disrupting brain physiology and functional connectivity. This study looked at how co-enzyme Q10 (Q10) and vitamin E (Vit E), alone and together, affected heat stress-caused anxiety and depression symptoms and inflammation in male mice. Five groups were utilized in the study: control, heat stress (NS), Q10, Vit E, and the combination group (Q10+Vit E). The mice were subjected for 15 min/day to a temperature of 43°C for 14 consecutive days, followed by daily treatments for two weeks with either normal saline, Q10 (500 mg/kg), Vit E (250 mg/kg), or their combination. The forced swimming test (FST) and tail suspension test (TST) were employed to evaluate despair behavior, whereas the elevated plus maze (EPM) and open field test (OFT) were used to assess anxious behaviors. Subsequently, the animals were sacrificed, and serum corticosterone levels, protein expression of inflammasome-related proteins, and hsp70 gene expression were evaluated in the prefrontal cortex (PFC). The study revealed that treatment with Vit E and Q10, alone or together, provided anxiolytic and antidepressant effects in the heat-stress-subjected animals. Also, giving Vit E and Q10 alone or together greatly lowered serum corticosterone levels. In the PFC, they also lowered the levels of hsp70 mRNA and NF-κB, caspase 1, NLRP3, and IL-1ß proteins. It is speculated that treatment with Q10 and Vit E can attenuate heat stress-associated anxious and depressive responses by inhibiting the inflammatory pathways and modulating the hypothalamus-pituitary-adrenal axis.

Criteria, Greenhouse Gas, and Hazardous Air Pollutant Emissions Factors from Residential Cordwood and Pellet Stoves Using an Integrated Duty Cycle Test Protocol.

Air pollution from residential wood heating (RWH) presents challenges at the intersection of climate and public health. With a revised National Ambient Air Quality Standard (NAAQS, at 9 µg/m3) for particulate matter (PM) in the United States (U.S.), the Environmental Protection Agency (EPA) will likely classify new non-attainment areas due primarily to emissions from RWH. Agencies will use emissions factors (EFs) to develop attainment strategies. Many will rely on EPA modeling platforms based on data from the National Emissions Inventory (NEI). The NEI uses RWH EFs based on data from mid-1990's in-situ studies and a speciation profile from a 2001 study of fireplace emissions. The NEI does not include greenhouse gas (GHG) emissions for this sector, which plays a key role when assessing climate reduction strategies for the buildings sector. Here, we tested seven wood stoves to determine EFs, representing various vintages and control technologies, using a novel test method that reflects in-use operational settings called the Integrated Duty Cycle. The study measured multiple pollutants concurrently: criteria pollutants (particulate matter [PM], CO, and NOx), nonmethane total hydrocarbons (NMTHCs), GHGs, black carbon (eBC), brown carbon (BrC), and multiple hazardous air pollutants (HAPs). We found no significant difference in PM EFs between uncertified and non-catalytic stove technologies. RWH EF results from this study exceeded 2020 NEI RWH EFs for NMTHC and multiple HAPs. Applying our study's EFs to the 2020 NEI suggests that RWH, compared to all other sources, ranks as the 2nd largest source category of formaldehyde; the 3rd largest of benzene, 1,3-butadiene, and acrolein; and the 4th largest of Pb emissions. RWH also emits more methane compared to natural gas or oil residential heating, raising questions about substitution of wood as a climate neutral heating fuel. However, compared to uncertified stoves, pellet stove EFs (except toxic metals) were significantly lower (p < 0.01). In summary, RWH appears to be an underestimated source of PM (non-catalytic technology), methane, NMTHC, toxic metals, and other HAPs, which has important implications for climate and public health policy in the U.S. and globally.

Docosahexaenoic Acid Reduced Vascular Endothelial Cell Injury in Diabetic Rats Via the Modulation of Autophagy.

Purpose: Among varied ω-3 polyunsaturated fatty acid types, the therapeutic properties of docosahexaenoic acid (DHA) have been indicated under diabetic conditions in different cell lineages. Here, we investigated the anti-diabetic properties of DHA in rats with type 2 diabetes mellitus (D2M) focusing on autophagy-controlling factors. Methods: D2M was induced in male Wistar rats using a single dose of streptozocin (STZ) and a high-fat diet for 8 weeks. On week 2, diabetic rats received DHA 950 mg/kg/d until the end of the study. After that, rats were euthanized, and aortic and cardiac tissue samples were stained with H&E staining for histological assessment. The expression of adhesion molecules, ICAM-1 and VCAM-1, was measured in heart samples using real-time PCR analysis. Using western blotting, protein levels of BCLN1, LC3, and P62 were measured in D2M rats pre- and post-DHA treatment. Results: Data showed intracellular lipid vacuoles inside the vascular cells, and cardiomyocytes, after induction of D2M and DHA reduced intracellular lipid droplets and in situ inflammatory response. DHA can diminish increased levels of ICAM-1 in diabetic conditions (P Control vs. D2M rats=0.005) and reach near-to-control values (P Control vs. D2M rats=0.28; P D2M rats vs. D2M rats+DHA=0.033). Based on western blotting, D2M slightly increased the BCLN1 and LC3-II/I ratio without affecting P62. DHA promoted the LC3II/I ratio (P=0.303) and reduced P62 (P Control vs. D2M rats+DHA =0.0433; P D2M vs. D2M rats+DHA=0.096), leading to the completion of autophagy flux under diabetic conditions. Conclusion: DHA can reduce lipotoxicity of cardiovascular cells possibly via the activation of adaptive autophagy response in D2D rats.

Toxoplasma gondii suppress human cord blood cell differentiation to the NK cell population.

BACKGROUND: Toxoplasma gondii is an obligate intracellular protozoan parasite that can invade all mammalian cells. It is well established that natural killer (NK) cells have critical protective roles in innate immunity during infections by intracellular pathogens. In the current study, we conducted an in vitro experiment to evaluate NK cell differentiation and activation from human umbilical cord blood mononuclear cells (UCB-MNCs) after infection with T. gondii tachyzoites. METHODS: UCB-MNCs were infected by fresh tachyzoites of type I (RH) or type II (PTG) strains of T. gondii pre-expanded in mesenchymal stem cells for 2 weeks in a medium enriched with stem cell factor, Flt3, IL-2, and IL-15. Flow cytometry analysis and western blot analysis were performed to measure the CD57+, CD56+, and Granzyme A (GZMA). RESULTS: Data revealed that incubation of UCB-MNCs with NK cell differentiation medium increased the CD57+, CD56+, and GZMA. UCB-MNCs cocultured with PTG tachyzoites showed a significant reduction of CD56+ and GZMA, but nonsignificant changes, in the levels of CD56+ compared to the control UCB-MNCs (p > .05). Noteworthy, 2-week culture of UCB-MNCs with type I (RH) tachyzoites significantly suppressed CD57+, CD56+, and GZMA, showing reduction of NK cell differentiation from cord blood cells. CONCLUSION: Our findings suggest that virulent T. gondii tachyzoites with cytopathic effects inhibit NK cell activation and eliminate innate immune responses during infection, and consequently enable the parasite to continue its survival in the host body.

Melatonin reduces lung injury in type 1 diabetic mice by the modulation of autophagy.

BACKGROUND: In recent years, the role of autophagy has been highlighted in the pathogenesis of diabetes and inflammatory lung diseases. In this study, using a diabetic model of mice, we investigated the expression of autophagy-related genes in the lung tissues following melatonin administration. RESULTS: Data showed histopathological remodeling in lung tissues of the D group coincided with an elevated level of IL-6, Becline-1, LC3, and P62 compared to the control group (p < 0.05). After melatonin treatment, histopathological remodeling was improved D + Mel group. In addition, expression levels of IL-6, Becline-1, LC3, and P62 were decreased in D + Mel compared to D group (P < 0.05). Statistically significant differences were not obtained between Mel group and C group (p > 0.05). CONCLUSION: Our results showed that melatonin injection can be effective in the amelioration of lung injury in diabetic mice presumably by modulating autophagy-related genes.

Oxygen Reduction Pathway for Spinel Metal Oxides in Alkaline Media: An Experimentally Supported Ab Initio Study.

Precious-metal-free spinel oxide electrocatalysts are promising candidates for catalyzing the oxygen reduction reaction (ORR) in alkaline fuel cells. In this theory-driven study, we use joint density functional theory (JDFT) in tandem with supporting electrochemical measurements to identify a novel theoretical pathway for the ORR on cubic Co3O4 nanoparticle electrocatalysts, which aligns more closely with experimental results than previous models. The new pathway employs the cracked adsorbates *(OH)(O) and *(OH)(OH), which, through hydrogen bonding, induce spectator surface *H. This results in an onset potential closely matching experimental values, in stark contrast to the traditional ORR pathway, which keeps adsorbates intact and overestimates the onset potential by 0.7 V. Finally, we introduce electrochemical strain spectroscopy (ESS), a groundbreaking strain analysis technique. ESS combines ab initio calculations with experimental measurements to validate the proposed reaction pathways and pinpoint rate-limiting steps.

Tumor immune escape: extracellular vesicles roles and therapeutics application.

BACKGROUND: Immune escape, a process by which tumor cells evade immune surveillance, remains a challenge for cancer therapy. Tumor cells produce extracellular vesicles (EVs) that participate in immune escape by transferring bioactive molecules between cells. EVs refer to heterogeneous vesicles that participate in intercellular communication. EVs from tumor cells usually carry tumor antigens and have been considered a source of tumor antigens to induce anti-tumor immunity. However, evidence also suggests that these EVs can accelerate immune escape by carrying heat shock proteins (HSPs), programmed death-ligand 1 (PD-L1), etc. to immune cells, suppressing function and exhausting the immune cells pool. EVs are progressively being evaluated for therapeutic implementation in cancer therapies. EVs-based immunotherapies involve inhibiting EVs generation, using natural EVs, and harnessing engineering EVs. All approaches are associated with advantages and disadvantages. The EVs heterogeneity and diverse physicochemical properties are the main challenges to their clinical applications. SHORT CONCLUSION: Although EVs are criminal; they can be useful for overcoming immune escape. This review discusses the latest knowledge on EVs population and sheds light on the function of tumor-derived EVs in immune escape. It also describes EVs-based immunotherapies with a focus on engineered EVs, followed by challenges that hinder the clinical translation of EVs that are essential to be addressed in future investigations. Video Abstract.

Tumor cells-derived exosomal noncoding RNAs in cancer angiogenesis: Molecular mechanisms and prospective.

Exosomes, heterogeneous, membrane-bound nanoparticles that originated from eukaryotic cells, contribute to intracellular communication by transferring various biomolecules both on their surface and as internal cargo. One of the most significant current discussions on cancer progression is noncoding RNAs cargo of exosomes, which can regulate angiogenesis in tumor. A growing body of evidence shows that exosomes from tumor cells contain various microRNAs, long noncoding RNAs, and circular RNAs that can promote tumor progression by inducing angiogenesis. However, some noncoding RNAs may inhibit cancer angiogenesis. Targeting angiogenic noncoding RNA of exosomes may serve as a hopeful implement for cancer therapy. In this review, we discuss the latest knowledge of the roles of exosomal noncoding RNAs in tumor angiogenesis Understanding the biology of exosomal noncoding RNAs can help scientists plan exosomes-based innovations for the treatment of cancer angiogenesis and cancer biomarkers.

High-fat diet-induced biogenesis of pulmonary exosomes in an experimental rat model.

BACKGROUND: High-fat diets (HFD) have recently become a public health concern. We hypothesize that HFD induces exosomes biogenesis in the lung tissue of rat model. METHODS AND RESULTS: Sixteen adult male Wistar rats were fed with HFD or a regular chow diet for 3 months. The histopathological changes in lung tissues were measured by hematoxylin and eosin (H&E) staining. Bronchoalveolar lavage (BAL) was performed to assay exosomes by acetylcholinesterase enzyme (AhCE) activity. Real-time PCR (qPCR) was used to evaluate Rab27-b, Alix, and IL-1ß expression, while the immunohistochemical examination was performed for CD81 expression in lung tissues. In addition, expression of IL-1ß was detected by ELISA. We found pathological alterations in the lung tissue of HFD animals. AhCE activity along with the expression level of Rab27-b, Alix, and IL-1ß was increased in HFD animals (p < 0.05). Immunohistochemical staining showed that expression of CD81 was increased in lung tissues of HFD animals compared with the control group (p < 0.05). CONCLUSION: Hence, HFD induced exosomes biogenesis and histopathological changes with IL-1ß expression in rats' lung tissues.

Swimming training reduced inflammation and apoptotic changes in pulmonary tissue in type 1 diabetic mice.

Background: Despite the vulnerability of pulmonary tissue to diabetic conditions, there are few reports related to the detrimental effects of hyperglycemia and therapeutic modalities on lung parenchyma. Here, the apoptotic changes were monitored in the diabetic pulmonary tissue of mice (DM1) subjected to a four‒week swimming plan. Methods: The mice were randomly allocated into Control; Control + Swimming (S); Diabetic group (D); and Diabetic + Swimming (D + S) groups (each in 8 mice). In the D and D + S groups, mice received intraperitoneally 50 mg/kg of streptozotocin (STZ). After 14 days, swimming exercise was done for four weeks. The expression of il-1ß, bcl-2, bax, and caspase-3 was investigated using real-time PCR analysis. A histological examination was performed using H&E staining. Results: DM1 significantly upregulated il-1ß, bax, and caspase-3, and down-regulated bcl-2 compared to the non-diabetic mice (p < 0.05). We noted that swimming exercises reversed the expression pattern of all genes in the diabetic mice and closed to basal levels (p < 0.05). Data indicated that swimming exercise could diminish emphysematous changes, and interstitial pneumonitis induced by STZ. Along with these changes, swimming exercise had protective effects to reduce the thickness of the inter-alveolar septum and mean alveolar area in diabetic mice. Conclusion: These data demonstrated that swimming exercises could decrease DM1-related pathologies in mouse lungs by regulating apoptosis and inflammatory response.

Therapeutic application of mesenchymal stem cells derived exosomes in neurodegenerative diseases: A focus on non-coding RNAs cargo, drug delivery potential, perspective.

Despite the massive efforts advanced over recent years in emerging therapies for neurodegenerative diseases, effective treatment for these diseases is still an urgent need. The application of mesenchymal stem cells (MSCs) derived exosomes (MSCs-Exo) as a novel therapy for neurodegenerative diseases holds great promise. A growing body of data now suggests that an innovative cell-free therapy, MSCs-Exo, may establish a fascinating alternative therapy due to their unique advantages over MSCs. Notable, MSCs-Exo can infiltrate the blood-brain barrier and then well distribute non-coding RNAs into injured tissues. Research shows that non-coding RNAs of MSCs-Exo are vital effectors that participate in the treatment of neurodegenerative diseases through neurogeneration and neurite outgrowth, modulation of the immune system, reducing neuroinflammation, repairmen of damaged tissue, and promotion of neuroangiogenesis. In addition, MSCs-Exo can serve as a drug delivery system for delivering non-coding RNAs to neurons in neurodegenerative conditions. In this review, we summarize the recent progress in the therapeutic role of non-coding RNAs of MSCs-Exo for various neurodegenerative diseases. This study also discusses the potential drug delivery role of MSCs-Exo and challenges and opportunities in the clinical translation of MSCs-Exo-based therapies for neurodegenerative diseases in the future.

Type 2 diabetes mellitus induced autophagic response within pulmonary tissue in the rat model.

Introduction: The current experiment aimed to address the impact of type 2 diabetes mellitus on autophagy status in the rat pulmonary tissue. Methods: In this study, 20 male Wistar rats were randomly allocated into two groups as follows: control and diabetic groups. To induce type 2 diabetes mellitus, rats received a combination of streptozotocin (STZ) and a high-fat diet. After confirmation of diabetic condition, rats were maintained for 8 weeks and euthanized for further analyses. The pathological changes were assessed using H&E staining. We also measured transforming growth factor-ß (TGF-ß), bronchoalveolar lavage fluid (BALF), and tumor necrosis factor-α (TNF-α) in the lungs using ELISA and real-time PCR analyses, respectively. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were monitored in diabetic lungs to assess oxidative status. We also measured the expression of becline-1, LC3, and P62 to show autophagic response under diabetic conditions. Using immunofluorescence staining, protein levels of LC3 was also monitored. Results: H&E staining showed pathological changes in diabetic rats coincided with the increase of TNF-α (~1.4-fold) and TGF-ß (~1.3-fold) compared to those in the normal rats (P<0.05). The levels of MDA (5.6 ± 0.4 versus 6.4 ± 0.27 nM/mg protein) were increased while SOD (4.2 ± 0.28 versus 3.8 ± 0.13 U/mL) activity decreased in the diabetic rats (P<0.05). Real-time polymerase chain reaction (PCR) analysis showed the up-regulation of Becline-1 (~1.35-fold) and LC3 (~2-fold) and down-regulation of P62 (~0.8-fold) (P<0.05), showing incomplete autophagic flux. We noted the increase of LC3+ cells in diabetic condition compared to that in the control samples. Conclusion: The prolonged diabetic condition could inhibit the normal activity of autophagy flux, thereby increasing pathological outcomes.

Type 2 diabetes mellitus stimulated pulmonary vascular inflammation and exosome biogenesis in rats.

It has been shown that type 2 Diabetes Mellitus (T2DM) changes the paracrine activity of several cell types. Whether the biogenesis of exosomes is changed during diabetic conditions is the subject of debate. Here, we investigated the effect of T2M on exosome biogenesis in rat pulmonary tissue. Rats received a high-fat diet regime and a single low dose of Streptozocin to mimic the T2DM-like condition. A total of 8 weeks after induction of T2DM, rats were subjected to several analyses. Besides histological examination, vascular cell adhesion molecule 1 (VCAM-1) levels were detected using immunohistochemistry (IHC) staining. Transcription of several genes such as IL-1ß, Alix, and Rab27b was calculated by real-time polymerase chain reaction assay. Using western blot analysis, intracellular CD63 levels were measured. The morphology and exosome secretion activity were assessed using acetylcholinesterase (AChE) assay and scanning electron microscopy, respectively. Histological results exhibited a moderate-to-high rate of interstitial pneumonia with emphysematous changes. IHC staining showed an increased VCAM-1 expression in the diabetic lungs compared with the normal conditions (p < .05). Likewise, we found the induction of IL-1ß, and exosome-related genes Alix and Rab27b under diabetic conditions compared with the control group (p < .05). Along with these changes, protein levels of CD63 and AChE activity were induced upon the initiation of T2DM, indicating accelerated exosome biogenesis. Taken together, current data indicated the induction of exosome biogenesis in rat pulmonary tissue affected by T2DM. It seems that the induction of inflammatory niche is touted as a stimulatory factor to accelerate exosome secretion.

Electrochemical biosensors in exosome analysis; a short journey to the present and future trends in early-stage evaluation of cancers.

The tumor microenvironment consists of a multiplicity of cells such as cancer cells, fibroblasts, endothelial cells, and immune cells within the specific parenchyma. It has been indicated that cancer cells can educate other cells within the tumor niche in a paracrine manner by the release of nano-sized extracellular vesicles namely exosomes (Exo), resulting in accelerated tumor mass growth. It is suggested that exosomal cargo with remarkable information can reflect any changes in metabolic and proteomic profiles in parent tumor cells. Therefore, exosomes can be touted as prognostic, diagnostic, and therapeutic elements with specific biomarkers in patients with different tumor types. Despite the advantages, conventional exosome separation and purification protocols are time-consuming and laborious with low abnormal morphology and purity rate. During the last decades, biosensor-based modalities, as emerging instruments, have been used to detect and analyze Exo in biofluids. Due to suitable specificity, sensitivity, and real-time readout, biosensors became promising approaches for the analysis of Exo in in vitro and in vivo settings. The inherent advantages and superiority of electrochemical biosensors in the determination of tumor grade based on exosomal cargo and profile were also debated. Present and future challenges were also discussed related to the application of electrochemical biosensors in the clinical setting. In this review, the early detection of several cancer types associated with ovaries, breast, brain, colon, lungs, T and B lymphocytes, liver and rare types of cancers were debated in association with released exosomes.

Harnessing Normal and Engineered Mesenchymal Stem Cells Derived Exosomes for Cancer Therapy: Opportunity and Challenges.

There remains a vital necessity for new therapeutic approaches to combat metastatic cancers, which cause globally over 8 million deaths per year. Mesenchymal stem cells (MSCs) display aptitude as new therapeutic choices for cancer treatment. Exosomes, the most important mediator of MSCs, regulate tumor progression. The potential of harnessing exosomes from MSCs (MSCs-Exo) in cancer therapy is now being documented. MSCs-Exo can promote tumor progression by affecting tumor growth, metastasis, immunity, angiogenesis, and drug resistance. However, contradictory evidence has suggested that MSCs-Exo suppress tumors through several mechanisms. Therefore, the exact association between MSCs-Exo and tumors remains controversial. Accordingly, the applications of MSCs-Exo as novel drug delivery systems and standalone therapeutics are being extensively explored. In addition, engineering MSCs-Exo for targeting tumor cells has opened a new avenue for improving the efficiency of antitumor therapy. However, effective implementation in the clinical trials will need the establishment of standards for MSCs-Exo isolation and characterization as well as loading and engineering methods. The studies outlined in this review highlight the pivotal roles of MSCs-Exo in tumor progression and the promising potential of MSCs-Exo as therapeutic drug delivery vehicles for cancer treatment.

Effects of crocin on T-bet/GATA-3 ratio, and miR-146a and miR-106a expression levels in lung tissue of ovalbumin-sensitized mice.

Objectives: Although various studies have revealed the beneficial effects of crocin (derived from saffron), such as anti-inflammatory, anti-cancer, antioxidant, and immune modulator, however, its exact mechanism is unknown. The present study aimed to investigate the effect of crocin on the expression ratio of T-bet/GATA-3 as an indicator of altered immune responses in the lung tissue of ovalbumin (OVA)-sensitized mice. In addition, the effect of crocin on the expression level of miR-146a and miR-106a in the lung tissue OVA-sensitized mice was investigated. Materials and Methods: Mice were randomly divided into five groups (n=6): Control; OVA, OVA + Crocin 25, OVA + Cro 50, and OVA + Cro100 groups. Crocin was administrated intraperitoneally at doses of 25, 50, and 100 mg/kg for five consecutive days. One day after asthma induction, animals were euthanized, and lungs were sampled for pathological and gene expression analysis. Results: OVA-sensitization led to increased inflammation and histopathological changes in the lung tissue of mice. In addition, GATA-3 expression increased (P<0.001) and T-bet expression decreased (P<0.001) in OVA-sensitized groups. The T-bet/GATA3 ratio was also reduced markedly in asthma groups (P<0.001). Furthermore, increased expression of miR-146a and miR-106a levels was evident in the lung tissue of OVA-sensitized mice (P<0.001 for both). Intervention with high concentrations of crocin (50 and 100 mg/kg) significantly reduced airway inflammation, GATA-3 expression, miR-146a expression, and miR-106a expression and corrected the T-bet/GATA-3 ratio (P<0.05 to P<0.001). Conclusion: Treatment with crocin led to a decrease in the severity of lung inflammation in OVA-sensitized mice, which is probably through the reduction of the T-bet/GATA-3 ratio, and mir-146a and mir-106a expression level.

Engineered extracellular vesicles: A novel platform for cancer combination therapy and cancer immunotherapy.

Extracellular vesicles (EVs), phospholipid membrane-bound vesicles, produced by most cells, contribute to cell-cell communication. They transfer several proteins, lipids, and nucleic acids between cells both locally and systemically. Owing to the biocompatibility and immune activity of EVs, therapeutic approaches using these vesicles as drug delivery systems are being developed. Different methods are used to design more effective engineered EVs, which can serve as smart tools in cancer therapy and immunotherapy. Recent progress in the field of targeted-cancer therapy has led to the gradual use of engineered EVs in combinational therapy to combat heterogeneous tumor cells and multifaceted tumor microenvironments. The high plasticity, loading ability, and genetic manipulation capability of engineered EVs have made them the ideal platforms to realize numerous combinations of cancer therapy approaches. From the combination therapy view, engineered EVs can co-deliver chemotherapy with various therapeutic agents to target tumor cells effectively, further taking part in immunotherapy-related cancer combination therapy. However, a greater number of studies were done in pre-clinical platforms and the clinical translation of these studies needs further scrutiny because some challenges are associated with the application of engineered EVs. Given the many therapeutic potentials of engineered EVs, this review discusses their function in various cancer combination therapy and immunotherapy-related cancer combination therapy. In addition, this review describes the opportunities and challenges associated with the clinical application of engineered EVs.

Mesenchymal stem cells derived extracellular vesicles: A promising nanomedicine for drug delivery system.

An ideal drug delivery system should selectively deliver incorporated therapeutics to the target site, escape from immune cells recognition and degradation, and act controlled release of incorporated therapeutics in the site targeted. Extracellular vesicles (EVs) have gained great attention for their potential application as a drug delivery system in nanomedicine. EVs such as exosomes are membrane-bound vesicles that contribute to intracellular communication by transferring various biomolecules including RNAs, proteins, and lipids. EVs derived from mesenchymal stem cells (MSCs-EVs) have several advantages such as low immunogenicity, high biocompatibility, and stability against conventional synthetic carriers, opening new avenues for delivering theaputic agents to target cells. To obtain modified MSCs-EVs, several loading methods are used to incorporate different therapeutic agents including proteins, RNAs, and chemotherapeutic drugs into MSCs-EVs. In addition, modification of MSCs-EVs surface may improve their potential in targeted therapies. Modified MSCs-EVs have been shown to improve many diseases including, cancer, cardiovascular diseases, and diabetes mellitus. While land greatly potential, the application of MSCs-EVs as a drug-delivery system has been hampered by several challenges. Clinical translation of modified-EVs needs further scrutiny. In this review, we discuss the biogenesis and production of EVs along with the loading and modification methods of MSCs-EVs. We also describe numerous MSCs-EVs based delivery studies with a focus on advantages and challenges when using them as a drug delivery system.

Impacts of wood species and moisture content on emissions from residential wood heaters.

Homeowners burn wood of a wide range of species and moisture content (MC) in residential cordwood and pellet stoves. An effective emission certification test protocol must account for and accurately measure the impact of those variables in order to ensure a reasonable correlation between laboratory results and in-use emissions and to promote the design and manufacture of cleaner burning appliances. This study explored the effect of wood species and MC on emissions and efficiency in four cordwood and four pellet stoves. PM emissions were consistently lower with pellets manufactured from softwood than for hardwood species and were highly correlated with ash content. Higher MC oak fuel substantially increased PM emissions in a non-catalytic cordwood stove; however, a hybrid cordwood stove was able to meet federal emissions limits even with the higher MC fuel. The results of this study, in combination with previous research, suggest that certification tests that use softwood fuel likely report lower emissions than tests that use hardwood. Requiring hardwood and higher MC cordwood fuel in certification tests would enable the assessment of an appliance's ability to operate well even when fuel conditions are not optimized.Implications: The emission testing results reported in this paper call into question the adequacy of the fuel moisture content and fuel species specifications in testing protocols approved for certifying compliance with EPA's New Source Performance Standards for cordwood and pellet stoves. We recommend changes in those specifications, including the prohibition of testing with Douglas fir and other low ash softwood species, requiring the use of cordwood test fuel with a higher moisture content, and requiring pellet stoves to be tested using hardwood pellets. Adoption of these measures would increase the replicability of tests. allow for the identification of stoves that are unlikely to perform well in the field when fuel conditions are not ideal, and, ultimately, result in the design of cleaner burning stoves.

Development of an integrated duty cycle test method to assess cordwood stove performance.

The US Environmental Protection Agency's (EPA's) New Source Performance Standards (NSPS) for Residential Wood Heaters (RWH) require certification emission testing of prototype appliances. In 2015, EPA revised those standards to further reduce particulate matter emissions from this critical source. However, to achieve that goal, lower emissions measured in certification tests must reflect lower emissions when the appliance is operated in homes. Woodstove certification tests have used either the Federal Reference Method (FRM), a crib wood method, or a cordwood testing method developed by ASTM International that was designated as a broadly applicable Alternative Test Method (ATM) by the EPA until December 2021, when that status was revoked. There is broad agreement that the FRM and ASTM procedures do not simulate typical fueling and operating of wood stoves in the field, raising questions about the efficacy of the current program. Effective emission reduction efforts require robust, accurate, and reproducible test methods. With input from a range of stakeholders, the Northeast States for Coordinated Air Use Management (NESCAUM) developed the Integrated Duty Cycle Test Method for Certification of Wood-Fired Stoves Using Cordwood (IDC), a cordwood testing protocol designed to improve the efficacy of residential wood heater certification testing. That method was approved by EPA as a broadly applicable ATM in 2021. IDC test runs assess appliance performance under a range of operating and fueling conditions representative of typical consumer use patterns. Unlike previous test methods, the IDC protocol requires three replicate runs to assess appliance performance variability. Including variable fueling and operating conditions, along with the requirement for replicates runs, will increase the effectiveness of certification testing and promote the development of improved wood stove technology. This paper reports on experiments conducted to develop and test the IDC method.Implications: Residential wood heating is one of the largest sources of primary particulate matter pollution nationwide. EPA's New Source Performance Standards (NSPS) establish emission limits for this source category and require certification testing of prototype wood appliances to demonstrate compliance with those limits. However, the operating and fueling requirements in NSPS compliance testing protocols do not represent typical conditions in the field. We developed a new testing approach, the Integrated-Duty Cycle (IDC) Test Method, to address the shortcomings of current certification test approaches. The IDC procedure for cordwood stoves, which was approved by EPA as a broadly applicable alternative test method in 2021, assesses appliance operations over various operating and fueling conditions representing typical consumer use patterns in an integrated run and requires three replicate runs to enable the assessment of variability in stove performance. Stoves certified with this method will be equipped to meet the NSPS limits consistently in field operation.