Construction of lymph nodes-targeting tumor vaccines by using the principle of DNA base complementary pairing to enhance anti-tumor cellular immune response.

Tumor vaccines, a crucial immunotherapy, have gained growing interest because of their unique capability to initiate precise anti-tumor immune responses and establish enduring immune memory. Injected tumor vaccines passively diffuse to the adjacent draining lymph nodes, where the residing antigen-presenting cells capture and present tumor antigens to T cells. This process represents the initial phase of the immune response to the tumor vaccines and constitutes a pivotal determinant of their effectiveness. Nevertheless, the granularity paradox, arising from the different requirements between the passive targeting delivery of tumor vaccines to lymph nodes and the uptake by antigen-presenting cells, diminishes the efficacy of lymph node-targeting tumor vaccines. This study addressed this challenge by employing a vaccine formulation with a tunable, controlled particle size. Manganese dioxide (MnO2) nanoparticles were synthesized, loaded with ovalbumin (OVA), and modified with A50 or T20 DNA single strands to obtain MnO2/OVA/A50 and MnO2/OVA/T20, respectively. Administering the vaccines sequentially, upon reaching the lymph nodes, the two vaccines converge and simultaneously aggregate into MnO2/OVA/A50-T20 particles through base pairing. This process enhances both vaccine uptake and antigen delivery. In vitro and in vivo studies demonstrated that, the combined vaccine, comprising MnO2/OVA/A50 and MnO2/OVA/T20, exhibited robust immunization effects and remarkable anti-tumor efficacy in the melanoma animal models. The strategy of controlling tumor vaccine size and consequently improving tumor antigen presentation efficiency and vaccine efficacy via the DNA base-pairing principle, provides novel concepts for the development of efficient tumor vaccines.

The effect of TG2-inhibitory monoclonal antibody zampilimab on tissue fibrosis in human in vitro and primate in vivo models of chronic kidney disease.

Fibrotic remodeling is the primary driver of functional loss in chronic kidney disease, with no specific anti-fibrotic agent available for clinical use. Transglutaminase 2 (TG2), a wound response enzyme that irreversibly crosslinks extracellular matrix proteins causing dysregulation of extracellular matrix turnover, is a well-characterized anti-fibrotic target in the kidney. We describe the humanization and characterization of two anti-TG2 monoclonal antibodies (zampilimab [hDC1/UCB7858] and BB7) that inhibit crosslinking by TG2 in human in vitro and rabbit/cynomolgus monkey in vivo models of chronic kidney disease. Determination of zampilimab half-maximal inhibitory concentration (IC50) against recombinant human TG2 was undertaken using the KxD assay and determination of dissociation constant (Kd) by surface plasmon resonance. Efficacy in vitro was established using a primary human renal epithelial cell model of tubulointerstitial fibrosis, to assess mature deposited extracellular matrix proteins. Proof of concept in vivo used a cynomolgus monkey unilateral ureteral obstruction model of chronic kidney disease. Zampilimab inhibited TG2 crosslinking transamidation activity with an IC50 of 0.25 nM and Kd of <50 pM. In cell culture, zampilimab inhibited extracellular TG2 activity (IC50 119 nM) and dramatically reduced transforming growth factor-ß1-driven accumulation of multiple extracellular matrix proteins including collagens I, III, IV, V, and fibronectin. Intravenous administration of BB7 in rabbits resulted in a 68% reduction in fibrotic index at Day 25 post-unilateral ureteral obstruction. Weekly intravenous administration of zampilimab in cynomolgus monkeys with unilateral ureteral obstruction reduced fibrosis at 4 weeks by >50%, with no safety signals. Our data support the clinical investigation of zampilimab for the treatment of kidney fibrosis.

Light-Triggered Nanozymes Remodel the Tumor Hypoxic and Immunosuppressive Microenvironment for Ferroptosis-Enhanced Antitumor Immunity.

Cancer immunotherapy holds significant promise for addressing diverse malignancies. Nevertheless, its efficacy remains constrained by the intricate tumor immunosuppressive microenvironment. Herein, a light-triggered nanozyme Fe-TCPP-R848-PEG (Fe-MOF-RP) was designed for remodeling the immunosuppressive microenvironment. The Fe-TCPP-MOFs were utilized not only as a core catalysis component against tumor destruction but also as a biocompatible delivery vector of an immunologic agonist, improving its long circulation and tumor enrichment. Concurrently, it catalyzes the decomposition of H2O2 within the tumor, yielding oxygen to augment photodynamic therapy. The induced ferroptosis, in synergy with photodynamic therapy, prompts the liberation of tumor-associated antigens from tumor cells inducing immunogenic cell death. Phototriggered on-demand release of R848 agonists stimulated the maturation of dendritic cells and reverted the tumor-promoting M2 phenotypes into adoptive M1 macrophages, which further reshaped the tumor immunosuppressive microenvironment. Notably, the nanozyme effectively restrains well-established tumors, such as B16F10 melanoma. Moreover, it demonstrates a distal tumor-inhibiting effect upon in situ light treatment. What is more, in a lung metastasis model, it elicits robust immune memory, conferring enduring protection against tumor rechallenge. Our study presents a straightforward and broadly applicable strategy for crafting nanozymes with the potential to effectively thwart cancer recurrence and metastasis.

Mechanism of Porphyra Yezoensis Polysaccharides in Inhibiting Hyperoxalate-Induced Renal Injury and Crystal Deposition.

Oxidative damage to the kidneys is a primary factor in the occurrence of kidney stones. This study explores the inhibitory effect of Porphyra yezoensis polysaccharides (PYP) on oxalate-induced renal injury by detecting levels of oxidative damage, expression of adhesion molecules, and damage to intracellular organelles and revealed the molecular mechanism by molecular biology methods. Additionally, we validated the role of PYP in vivo using a crystallization model of hyperoxalate-induced rats. PYP effectively scavenged the overproduction of reactive oxygen species (ROS) in HK-2 cells, inhibited the adhesion of calcium oxalate (CaOx) crystals on the cell surface, unblocked the cell cycle, restored the depolarization of the mitochondrial membrane potential, and inhibited cell death. PYP upregulated the expression of antioxidant proteins, including Nrf2, HO-1, SOD, and CAT, while decreasing the expression of Keap-1, thereby activating the Keap1/Nrf2 signaling pathway. PYP inhibited CaOx deposition in renal tubules in the rat crystallization model, significantly reduced high oxalate-induced renal injury, decreased the levels of the cell surface adhesion proteins, improved renal function in rats, and ultimately inhibited the formation of kidney stones. Therefore, PYP, which has crystallization inhibition and antioxidant properties, may be a therapeutic option for the treatment of kidney stones.

Modulation of adipose tissue metabolism by exosomes in obesity.

Obesity and its related metabolic complications represent a significant global health challenge. Central to this is the dysregulation of glucolipid metabolism, with a predominant focus on glucose metabolic dysfunction in the current research, whereas adipose metabolism impairment garners less attention. Exosomes (EXs), small extracellular vesicles (EVs) secreted by various cells, have emerged as important mediators of intercellular communication and have the potential to be biomarkers, targets, and therapeutic tools for diverse diseases. In particular, EXs have been found to play a role in adipose metabolism by transporting cargoes such as noncoding RNAs (ncRNA), proteins, and other factors. This review article summarizes the current understanding of the role of EXs in mediating adipose metabolism disorders in obesity. It highlights their roles in adipogenesis (encompassing adipogenic differentiation and lipid synthesis), lipid catabolism, lipid transport, and white adipose browning. The insights provided by this review offer new avenues for developing exosome-based therapies to treat obesity and its associated comorbidities.

Global knowledge mapping and emerging research trends in the microbiome and asthma: A bibliometric and visualized analysis using VOSviewer and CiteSpace.

Background: Numerous prior studies have extensively highlighted the significance of the microbiome in association with asthma. While several studies have concentrated on the asthma microbiome in previous research, there is currently a lack of publications that employ bibliometric methods to assess this area. Methods: In this study, the Web of Science Core Collection database was utilized as the data source, and the SCI-EXPANDED index was employed to ensure that the retrieved data were comprehensive and accurate. All original research articles and review articles related to the correlation between asthma and the microbiome were systematically searched from the inception of the database until June 20, 2023. These articles were subsequently visualized and analyzed using VOSviewer and CiteSpace software. Results: A total of 1366 relevant publications were acquired, indicating a consistent annual increase in global publications in the field. The United States and China emerged as the top two contributors to international publications. Among prolific authors, Susan V. Lynch achieved the highest publication record, with Hans Bisgaard and Jakob Stokholm sharing the second position. The majority of publications concentrated on allergy-related and microbiome areas, with a few comprehensive journals standing out. Journals with 40 or more publications included the Journal of Allergy and Clinical Immunology, Allergy, Frontiers in Immunology, and PLOS One. The top 5 cited journals were the Journal of Allergy and Clinical Immunology, PLOS One, American Journal of Respiratory and Critical Care Medicine, Clinical and Experimental Allergy, and Nature. Upon analyzing keywords, high-frequency terms, such as asthma, gut microbiota, microbiome, children, childhood asthma, allergy, risk, exposure, inflammation, diversity, and chain fatty acids emerged as representative terms in the field. Conclusion: This study systematically presented a comprehensive overview of the literature regarding the association between asthma and the microbiome over the last two decades. Through a bibliometric perspective, the findings may assist researchers with a better understanding of the essential information in the field.

Corn Silk Polysaccharides with Different Carboxyl Contents Reduce the Oxidative Damage of Renal Epithelial Cells by Inhibiting Endocytosis of Nano-calcium Oxalate Crystals.

OBJECTIVE: Renal epithelial cell injury and cell-crystal interaction are closely related to kidney stone formation. METHODS: This study aims to explore the inhibition of endocytosis of nano-sized calcium oxalate monohydrate (nano-COM) crystals and the cell protection of corn silk polysaccharides (CCSPs) with different carboxyl contents (3.92, 7.75, 12.90, and 16.38%). The nano-COM crystals protected or unprotected by CCSPs were co-cultured with human renal proximal tubular epithelial cells (HK-2), and then the changes in the endocytosis of nano-COM and cell biochemical indicators were detected. RESULTS: CCSPs could inhibit the endocytosis of nano-COM by HK-2 cells and reduce the accumulation of nano-COM in the cells. Under the protection of CCSPs, cell morphology is restored, intracellular superoxide dismutase levels are increased, lipid peroxidation product malondialdehyde release is decreased, and mitochondrial membrane potential and lysosomal integrity are increased. The release of Ca2+ ions in the cell, the level of cell autophagy, and the rate of cell apoptosis and necrosis are also reduced. CCSPs with higher carboxyl content have better cell protection abilities. CONCLUSION: CCSPs could inhibit the endocytosis of nano-COM crystals and reduce cell oxidative damage. CCSP3, with the highest carboxyl content, shows the best biological activity.

Macro-microporous ZIF-8 MOF complexed with lysosomal pH-adjusting hexadecylsulfonylfluoride as tumor vaccine delivery systems for improving anti-tumor cellular immunity.

Tumor vaccine therapy, which can induce tumor antigen-specific cellular immune responses to directly kill tumor cells, is considered to be one of the most promising tumor immunotherapies. How to elicit effective tumor antigen-specific cellular immunity is the key for the development of tumor vaccines. However, current tumor vaccines with conventional antigen delivery systems mainly induce humoral immunity but not effective cellular immunity. In this study, based on pH-sensitive, ordered macro-microporous zeolitic imidazolate framework-8 (SOM-ZIF-8) and hexadecylsulfonylfluoride (HDSF), an intelligent tumor vaccine delivery system SOM-ZIF-8/HDSF was developed to elicit potent cellular immunity. Results demonstrated that the SOM-ZIF-8 particles could efficiently encapsulate antigen into the macropores, promote antigen uptake by antigen-presenting cells, facilitate lysosomal escape, and enhance antigen cross-presentation and cellular immunity. In addition, the introduction of HDSF could up-regulate the lysosomal pH to protect antigens from acid degradation, which further promoted antigen cross-presentation and cellular immunity. The immunization tests showed that the tumor vaccines based on the delivery system improved antigen-specific cellular immune response. Moreover, the tumor vaccines significantly inhibited tumor growth in B16 melanoma-bearing C57BL/6 mice. These results indicate that SOM-ZIF-8/HDSF as an intelligent vaccine delivery system could be used for the development of novel tumor vaccines.

Oral Oxytocin Facilitates Responses to Emotional Faces in Reward and Emotional-Processing Networks in Females.

INTRODUCTION: Oxytocin (OXT) is proposed as a potential therapeutic peptide for social dysfunction due to its modulatory actions on socioemotional regulation in humans. While the majority of studies have used intranasal OXT administration, we have recently shown that oral (lingual spray), but not intranasal, administration can significantly enhance activity of the brain reward system in response to emotional faces in males; however, its effects on females are unknown. METHODS: Seventy healthy females participated in the current randomized, placebo-controlled, pharmaco-imaging clinical trial, and the results were compared with our previous data from 75 males who underwent the same protocol. Participants were randomly assigned to OXT (24 IU) or placebo (PLC) groups and completed an implicit emotional face paradigm (angry/fear/happy/neutral) where they were only required to identify face gender. RESULTS: In line with previous results in males, oral OXT significantly increased plasma OXT concentration changes and enhanced putamen responses to all emotional faces compared to PLC in females. Additionally, OXT increased left amygdala activity to happy and angry faces and enhanced putamen-superior temporal gyrus functional coupling during processing of happy faces in females which was significantly different from males. CONCLUSION: Our findings suggest that oral OXT enhances responses in both reward and emotional-processing networks in females as well as males, and additionally, in females, it strengthens coupling between reward and social cognition regions.

Cell Protection and Crystal Endocytosis Inhibition by Sulfated Laminaria Polysaccharides Against Nano-COM-Induced Oxidative Damage in Renal Epithelial Cells.

Background: The damage to renal tubular epithelial cells is closely related to the formation of kidney stones. At present, research on drugs that can protect cells from damage remains limited. Methods: This study aims to explore the protective effects of four different sulfate groups (-OSO3 -) of Laminaria polysaccharides (SLPs) on human kidney proximal tubular epithelial (HK-2) cells and determine the difference in the endocytosis of nano-sized calcium oxalate monohydrate (COM) crystals before and after protection. COM with a size of 230 ± 80 nm was used to damage HK-2 cells to establish a damage model. The protection capability of SLPs (LP0, SLP1, SLP2, and SLP3) with -OSO3 - contents of 0.73, 15, 23, and 31%, respectively, against COM crystal damage and the effect of SLPs on the endocytosis of COM crystals were studied. Results: Compared with that of the SLP-unprotected COM-injured group, the cell viability of the SLP-protected group was improved, healing capability was enhanced, cell morphology was restored, production of reactive oxygen species was reduced, mitochondrial membrane potential and lysosome integrity were increased, intracellular Ca2+ level and autophagy were decreased, cell mortality was reduced, and internalized COM crystals were lessened. The capability of SLPs to protect cells from damage and inhibit the endocytosis of crystals in cells enhanced with an increase in the -OSO3 - content of SLPs. Conclusions: SLPs with a high -OSO3 - content may become a potential green drug for preventing the formation of kidney stones.

Magnetic nanoparticles enhance the cellular immune response of dendritic cell tumor vaccines by realizing the cytoplasmic delivery of tumor antigens.

Dendritic cells (DCs)-based tumor vaccines have the advantages of high safety and rapid activation of T cells, and have been approved for clinical tumor treatment. However, the conventional DC vaccines have some severe problems, such as poor activation of DCs in vitro, low level of antigen presentation, reduced cell viability, and difficulty in targeting lymph nodes in vivo, resulting in poor clinical therapeutic effects. In this research, magnetic nanoparticles Fe3O4@Ca/MnCO3 were prepared and used to actively and efficiently deliver antigens to the cytoplasm of DCs, promote antigen cross-presentation and DC activation, and finally enhance the cellular immune response of DC vaccines. The results show that the magnetic nanoparticles can actively and quickly deliver antigens to the cytoplasm of DCs by regulating the magnetic field, and achieve cross-presentation of antigens. At the same time, the nanoparticles degradation product Mn2+ enhanced immune stimulation through the interferon gene stimulating protein (STING) pathway, and another degradation product Ca2+ ultimately promoted cellular immune response by increasing autophagy. The DC vaccine constructed with the magnetic nanoparticles can more effectively migrate to the lymph nodes, promote the proliferation of CD8+ T cells, prolong the time of immune memory, and produce higher antibody levels. Compared with traditional DC vaccines, cytoplasmic antigen delivery with the magnetic nanoparticles provides a new idea for the construction of novel DC vaccines.

Regional superficial amygdala resting-state functional connectivity in adults infers childhood maltreatment severity.

Background: Childhood maltreatment (CM) is a potential risk factor for some neuropsychiatric disorders in adulthood (e.g. depression and anxiety) and alters trajectories of brain development. Accumulating evidence suggests that functional connectivity of the limbic system, especially the amygdala, is highly associated with childhood maltreatment, although not all studies have found this. These inconsistent results may be due to differential alterations of amygdala resting-state functional connectivity (rsFC) following childhood maltreatment. Objective: Our aim was to investigate the relationship between the rsFC of amygdala subregions and CM severity, as well as to develop a stable rsFC-based model for inferring the severity of CM. Methods: In this study, we employed the Childhood Trauma Questionnaire (CTQ) to assess CM severity in each individual. We explored the relationship between the rsFC of amygdala subregions (i.e. centromedial -CMA, basolateral -BLA, superficial-SFA amygdala) and CM experience in a discovery dataset of n = 110 healthy Chinese participants by linear multiple regression analysis. Subsequent dimensional and categorical approach were performed to elucidate the relationship between rsFCs and CM severity and CM subtypes, respectively. A support vector regression model was then conducted to validate the associations between rsFCs and total CTQ scores. Moreover, we also verified the model into another independent replication dataset (n = 38). Results: Our findings suggested that childhood maltreatment was negatively associated with rsFC between the right superficial amygdala and perigenual anterior cingulate cortex (pgACC)/postcentral gyrus (PCG) but not the other two amygdala subregions. Moreover, SFA-pgACC coupling was more associated with physical neglect whereas the SFA-PCG was more related to emotional neglect. In addition, supervised machine learning confirmed that using these two rsFCs as predictors could stably estimate continuous maltreatment severity in both discovery and replication datasets. Conclusion: The current study supports that the rsFCs of superficial amygdala are related to childhood maltreatment and which may be a potential biomarker for the effects of childhood maltreatment-related psychiatric disorders (i.e. depression and anxiety).

Natural blood plasma-based hydrogels as tumor vaccines delivery systems to enhance biomimetic recruitment of antigen presenting cells for tumor immunotherapy.

Tumor vaccines can inhibit or eliminate tumors by vaccinating hosts with tumor antigens to activate antigen-specific immune responses and have gained wild attention. However, their clinical application efficacy is often comprised due to the low safety and poor efficiency of vaccine adjuvants/carriers. Specifically, the adjuvants/carriers usually could not efficiently recruit antigen presenting cells (APCs) to capture the vaccines or directly damage these cells. Therefore, ideal tumor vaccine adjuvants/carriers should effectively recruit APCs and be friendly to the cells for well keeping their bio-functions. In this work, injectable natural blood plasma hydrogel was used for the first time to encapsulate tumor antigens and adjuvant (Mn2+) for the construction of a personalized tumor vaccine. This kind of natural hydrogel with extremely high bio-safety has great potential to friendly recruit APCs in a biomimetic manner by simulating the natural degradation process of subcutaneous blood stasis. The obtained results show that the natural blood plasma hydrogel-based tumor vaccines could significantly promote the recruitment of APCs, well maintain the immuno-functions of the cells, and finally induce efficient anti-tumor immune responses. Compared with traditional tumor vaccines, this natural blood plasma-based hydrogel provides a new strategy for the development of safe and effective tumor vaccines.

Circular RNA profile in Graves' disease and potential function of hsa_circ_0090364.

Background: Graves' disease is a common autoimmune disease. Cytokines and their signalling pathways play a major part in the pathogenesis of Graves' disease; however, the underlying mechanism needs to be clarified. Aims: The aim of this study was to explore whether circular RNAs participate in the immunological pathology of Graves' disease via cytokine-related signalling pathways. Methods: Bioinformatics analysis was performed to identify differentially expressed circular RNAs and their targets and associated pathways. A total of three patients with Graves' disease and three sex- and age-matched healthy controls were enrolled for validation with microarray analysis and real-time quantitative PCR (qPCR). An additional 24 patients with Graves' disease and 24 gender- and age-matched controls were included for validation by real-time fluorescent qPCR. Flow cytometry and CCK8 assays were used to detect the apoptotic and proliferative levels of Jurkat cells (T lymphocytes) with the silenced expression of circRNA. ELISA was performed to detect the growth and apoptosis-related proteins. The competition mechanism of endogenous RNA was explored by real-time fluorescence qPCR. Results: A total of 366 significantly differentially expressed circular RNAs were identified in the Graves' disease group compared to healthy controls. The level of hsa_circ_0090364 was elevated in Graves' disease patients and positively correlated with thyroid-stimulating hormone receptor antibodies. Further analyses suggested that hsa_circ_0090364 may regulate the JAK-STAT pathway via the hsa-miR-378a-3p/IL-6ST/IL21R axis to promote cell growth. Conclusions: These results provide novel clues into the pathophysiological mechanisms of Graves' disease and potential targets for drug treatment.

Multifunctional manganese-containing vaccine delivery system Ca@MnCO3/LLO for tumor immunotherapy.

The ideal vaccine delivery systems can not only deliver antigens in intelligent manners but also act as adjuvants. Recently found that Mn2+ can effectively stimulate anti-tumor immune responses, and Ca2+ can regulate autophagy to promote the cross-presentation of antigens. Thus, we constructed such a manganese-containing multimode vaccine delivery system by using calcium-doped manganese carbonate microspheres (Ca@MnCO3) and perforin-listeria hemolysin (LLO), as termed as Ca@MnCO3/LLO. The two components Ca@MnCO3 and LLO, not only act as vaccine adjuvants by themselves, but also contribute to achieve cellular immunity. Among them, Ca@MnCO3 microspheres as an excellent Mn2+ and Ca2+ reservoir, can continuously release adjuvants Mn2+ and Ca2+ to enhance immune response in dendritic cells, while LLO can contribute to induce lysosomal escape. Particularly, Ca2+ was added firstly to MnCO3 microspheres to improve the stability and load capacity of the microspheres. Along with the degradation of intracellular Ca@MnCO3 microspheres, and the lysosomal membrane-lytic effects of perforin LLO, the Mn2+, Ca2+ and OVA were released to the cytoplasm. These outcomes cooperatively promote antigen cross-presentation, elicit CD8+ T cell proliferation, and finally achieve prominent anti-tumor effects. The results indicate that the manganese-containing vaccine delivery system Ca@MnCO3/LLO provides a promising platform for the construction of tumor vaccines.

The Effect of Inactivated SARS-CoV-2 Vaccines on TRAB in Graves' Disease.

Background: The ongoing coronavirus disease 2019 (COVID-19) pandemic has forced the development of vaccines. Reports have suggested that vaccines play a role in inducing autoimmune diseases (AIDs). Scattered cases have reported that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines may promote thyroid disease, including Graves' disease (GD). However, the effect of inactivated SARS-CoV-2 vaccine on GD remains unclear. The aim of the present study was to investigate the response of thyrotropin receptor antibody (TRAB) to inactivated SARS-COV-2 vaccines. Methods: We conducted a retrospective study to observe the differences in thyroid function and TRAB trends between pre-vaccination (n=412) and post-vaccination (n=231) groups at an interval of 2 months. We then retrospectively observed the differences in serum thyroid function and TRAB levels at 3 months before (n=280), 1 month before (n=294), 1 month after (n=306), and 3 months after (n=250) vaccination. Subsequently, 173 GD patients who were not vaccinated with inactivated SARS-COV-2 vaccines were selected for a prospective study. Thyroid function and TRAB assessment were performed before 3 and 1 months and 1 and 3 months after the first dose of vaccination and were then compared by repeated measures ANOVA to explore their dynamic changes. Results: A retrospective study preliminarily observed that the trend of TRAB post-vaccination was opposite of that pre-vaccination (p=0.000), serum TRAB levels decreased before vaccination and increased after vaccination. In this prospective study, repeated measures ANOVA indicated significant differences in serum FT3 (p=0.000), FT4 (p=0.000), TSH (p=0.000), and TRAB (p=0.000) levels at different time points before and after vaccination. Serum TRAB levels showed dynamic changes that decreased significantly at 1 month before vaccination (p=0.000), no significant differences at 1 month after vaccination (p=0.583), and reflected an upward trend at 3 months after vaccination (p=0.034). Serum FT3 and FT4 levels showed similar trends to serum TRAB levels before and after vaccination. Instead, the serum TSH levels showed a continuous upward trend over time. Conclusion: Based on the results obtained in both retrospective and prospective studies, we concluded that serum TRAB levels decreased less after inactivated SARS-CoV-2 vaccination and showed an upward trend, which may be related to humoral immunity induced by vaccination.

Blood compatibility evaluations of CaCO3particles.

CaCO3particles, due to their unique properties such as biodegradation, pH-sensitivity, and porous surface, have been widely used as carrier materials for delivering drugs, genes, vaccines, and other bioactive molecules. In these applications, CaCO3particles are often administered intravenously. In this sense, the interaction between CaCO3particles and blood components plays a key role in their delivery efficacy and biosafety, though the hemocompatibility of CaCO3particles has not been evaluated until now. Deficiency in the biosafety information has delayed the clinical use of CaCO3particles in delivery systems. In this work, we investigated the biosafety of CaCO3particles, focusing on theirin vitroandin vivoeffects on key blood components (red blood cells, platelets, etc) and coagulation functions. We foundin vitrothat high concentrations of CaCO3particles can cause the aggregation and hemolysis of red blood cells, with platelet activation and coagulation prolongation.In vivo, we found that intravenously injected CaCO3particles at 50 mg kg-1significantly disturbed the red blood cells, and platelet-related blood routine indexes, but did not induce visible abnormalities in the tissue structures of the key organs. Overall, these effects may be due to the enormous adsorption capability of the porous surface of CaCO3particles. 0.1 mg ml-1of the CaCO3particles exhibit excellent compatibility for their practical applications. These results would be expected to greatly promote thein vivoapplications and clinical use of CaCO3particles in biomedicine.

Effects of ZIF-8 MOFs on structure and function of blood components.

ZIF-8 MOFs, with their large specific surface area and void volume, unique biodegradability and pH sensitivity, and significant loading capacity, have been widely used as carrier materials for bioactive molecules such as drugs, vaccines and genes. In these applications, ZIF-8 MOFs are usually delivered intravenously. Therefore, it is necessary to know the interaction between ZIF-8 MOFs and blood components, which from this sense is a key factor affecting their delivery effectiveness and biosafety. However, until now there has been no report on the evaluation of hemocompatibility of ZIF-8 MOFs. The lack of biosafety information of ZIF-8 MOFs seriously impedes their clinical applications. In this work, we studied the biosafety of two different sizes of ZIF-8 MOFs, mainly focusing on their in vivo and in vitro effects on the key components of blood (red blood cells (RBCs), platelets, etc.) and the coagulation function. It was found that, in vitro, a high concentration of ZIF-8 MOFs could induce RBC aggregation and hemolysis, and prolong the coagulation time. In vivo, intravenous administration of 45 mg kg-1 ZIF-8 MOFs significantly disturbed the RBC and platelet-related blood routine indexes, as well as coagulation function indexes, but it did not cause significant abnormalities in blood coagulation and tissue structures (heart, liver, spleen, lung, and kidney).

Development of a unilateral ureteral obstruction model in cynomolgus monkeys.

Background: Chronic kidney disease (CKD) has a high global prevalence and large unmet need. Central to developing new CKD therapies are in vivo models in CKD. However, next-generation antibody, protein, and gene therapies are highly specific, meaning some do not cross-react with rodent targets. This complicates preclinical development, as established in vivo rodent models cannot be utilized unless tool therapeutics are also developed. Tool compounds can be difficult to develop and, if available, typically have different epitopes, sequences, and/or altered affinity, making it unclear how efficacious the lead therapeutic may be, or what dosing regimen to investigate. To address this, we aimed to develop a nonhuman primate model of CKD. Methods: In vivo rodent unilateral ureteral obstruction (UUO) models kidney fibrosis and is commonly used due to its rapidity, consistency, and ease. We describe translation of this model to the cynomolgus monkey, specifically optimizing the model duration to allow adequate time for assessment of novel therapeutics prior to the fibrotic plateau. Results: We demonstrated that disease developed more slowly in cynomolgus monkeys than in rodents post-UUO, with advanced fibrosis developing by 6 weeks. The tubulointerstitial fibrosis in cynomolgus monkeys was more consistent with human obstructive disease than in rodents, having a more aggressive tubular basement expansion and a higher fibroblast infiltration. The fibrosis was also associated with increased transglutaminase activity, consistent with that seen in patients with CKD. Conclusion: This cynomolgus monkey UUO model can be used to test potential human-specific therapeutics in kidney fibrosis.

Seaweed Porphyra yezoensis polysaccharides with different molecular weights inhibit hydroxyapatite damage and osteoblast differentiation of A7R5 cells.

Vascular calcification (VC) is a common pathological manifestation in patients with cardiovascular diseases, leading to high mortality in patients with chronic kidney diseases. The deposition of hydroxyapatite (HAP) crystals on vascular smooth muscle cells leads to cell damage, which promotes osteogenic transformation. In this study, four different molecular weights (MWs ) of Porphyra yezoensis polysaccharides (PYP1, PYP2, PYP3, and PYP4 with MWs of 576, 49.5, 12.6, and 4.02 kDa, respectively) were used to coat HAP, and the differences in toxicity and calcification of HAP on A7R5 cells before and after coating were studied. The results showed that PYPs could effectively reduce HAP damage to the A7R5 cells. Under the protection of PYPs, cell viability increased and lactate dehydrogenase release, active oxygen level, and cell necrosis rate decreased; also, the amount of the HAP crystals adhering to cell surfaces and entering cells decreased. PYPs with low molecular weights presented better protective effects than high-molecular-weight PYPs. PYPs also inhibited the osteogenic transformation of the A7R5 cells induced by HAP and decreased alkaline phosphatase (ALP) activity and expressions of bone/chondrocyte phenotype genes (runt-related factor 2, ALP, osteopontin, and osteocalcin). In the adenine-induced chronic renal failure (CRF) mouse VC model, PYP4 was found to obviously inhibit the aortic calcium level, and it also inhibited the serum creatinine, serum phosphorus and serum BUN levels. PYP4 (least molecular weight) showed the best inhibitory effect on calcification and may be considered as a candidate drug with therapeutic potential for inhibiting cellular damage and osteoblast differentiation induced by the HAP crystals.