Autophagy inhibition mediated by intrauterine miR-1912-3p/CTSD programming participated in the susceptibility to osteoarthritis induced by prenatal dexamethasone exposure in male adult offspring rats.

Autophagy inhibition is known to be involved in the development of adult osteoarthritis. Dexamethasone, as a synthetic glucocorticoid, is widely used for premature delivery and related pregnancy diseases in clinics. We have previously shown that prenatal dexamethasone exposure (PDE) was associated with increased susceptibility to postnatal osteoarthritis in offspring. However, whether the occurrence of fetal-originated adult osteoarthritis induced by PDE is related to autophagy remains unclear. In this study, we first found that PDE could increase the mRNA and protein expression of cartilage matrix-degrading enzymes (MMP3, MMP13, and ADAMTS5) and decrease the cartilage matrix contents in adult offspring, and the in vitro results suggested that this might be related to the autophagy inhibition of chondrocytes. Further, we demonstrated a persistent autophagy inhibition with autolysosome accumulation, low expression of cathepsin D (CTSD), increased H3K9ac level, and expression of miR-1912-3p in the cartilage of PDE offspring from fetus to adulthood. In vitro experiments showed that dexamethasone inhibited autophagy flux and CTSD expression in fetal chondrocytes, while overexpression of CTSD could alleviate the inhibition of autophagic flux induced by dexamethasone. Finally, we confirmed that dexamethasone increased the H3K9ac level and expression of miR-1912-3p through activation of the glucocorticoid receptor (GR), resulting in the decreased expression of CTSD and inhibition of autophagy flux in fetal chondrocytes. In conclusion, intrauterine miR-1912-3p/CTSD programming-mediated autophagy inhibition promoted the susceptibility to osteoarthritis in PDE adult offspring rats. This study provides new ideas for exploring early prevention and therapeutic targets in fetal-originated osteoarthritis.

Public acceptance of COVID-19 control measures and associated factors during Omicron-dominant period in China: a cross-sectional survey.

OBJECTIVES: This study aims to evaluate the public acceptance of coronavirus disease 2019 (COVID-19) control measures during the Omicron-dominant period and its associated factors. METHODS: A cross-sectional design was conducted and 1391 study participants were openly recruited to participate in the questionnaire survey. Logistic regression model was performed to assess the association between the public acceptance and potential factors more specifically. RESULTS: By August 26, 2022, 58.9% of the study participants were less acceptive of the control measures while 41.1% expressed higher acceptance. Factors associated with lower acceptance included young age, such as < 18 (OR = 8.251, 95% CI: 2.009 to 33.889) and 18-29 (OR = 2.349, 95% CI: 1.564 to 3.529), and household per capita monthly income lower than 5000 yuan (OR = 1.512, 95% CI: 1.085 to 2.105). Furthermore, individuals who perceived that the case fatality rate (CFR) of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was very low (OR = 6.010, 95% CI: 2.475 to 14.595) and that the restrictions could be eased once the CFR dropped to 2-3 times of the influenza (OR = 2.792, 95% CI: 1.939 to 4.023) showed greater oppositional attitudes. Likewise, respondents who were dissatisfied with control measures (OR = 9.639, 95% CI: 4.425 to 20.998) or preferred fully relaxation as soon as possible (OR = 13.571, 95% CI: 7.751 to 23.758) had even lower acceptability. By contrast, rural residents (OR = 0.683, 95% CI: 0.473 to 0.987), students (OR = 0.510, 95% CI: 0.276 to 0.941), public (OR = 0.417, 95% CI: 0.240 to 0.727) and private (OR = 0.562, 95% CI: 0.320 to 0.986) employees, and vaccinated participants (OR = 0.393, 95% CI: 0.204 to 0.756) were more compliant with control measures. CONCLUSION: More than half of the Chinese public were less supportive of COVID-19 control measures during Omicron-dominant period, which varied based on their different demographic characteristics, cognition and overall attitude towards SARS-CoV-2 infection. Control measures that struck a balance between public safety and individual freedom would be more acceptable during the pandemic.

Maternal antibody transfer rate of vaccination against SARS-CoV-2 before or during early pregnancy and its protective effectiveness on offspring.

This study focuses on maternal antibody transfer following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) before or during early pregnancy and its potential protective effects on infants, providing scientific evidence for vaccination strategies. This prospective study tested the samples for SARS-CoV-2 IgG antibody titers and neutralizing capacity and tracked the infections after birth. Perform multivariate analysis of factors influencing antibody transfer rate, newborn antibody titers, and infant infection. Total 87.1% (122/140) women received coronavirus disease 2019 (COVID-19) vaccine before or during early pregnancy, and 28 of them had breakthrough infection. The maternal and neonatal IgG positive rates at delivery were 60.7% (85/140) and 60.8% (87/143), respectively. A positive correlation was found between neonatal and maternal IgG antibody titers. Compared with the median IgG antibody transfer rate of infected pregnant women, that of vaccinated but not infected pregnant women was higher (1.21 versus: 1.53 [two doses], 1.71 [three doses]). However, neonatal IgG antibodies were relatively low (174.91 versus: 0.99 [two doses], 8.18 [three doses]), and their neutralizing capacity was weak. The overall effectiveness of maternal vaccination in preventing infant infection was 27.0%, and three doses had higher effectiveness than two doses (64.3% vs. 19.6%). Multivariate analysises showed that in vaccination group women receiving three doses or in infection group women with longer interval between infection and delivery had a higher antibody transfer rate and neonatal IgG antibody titer. More than half of women vaccinated before or during early pregnancy can achieve effective antibody transfer to newborns. However, the neonatal IgG antibody titer is low and has a weak neutralizing capacity, providing limited protection to infants.

Does potential antibody-dependent enhancement occur during SARS-CoV-2 infection after natural infection or vaccination? A meta-analysis.

Coronavirus disease 2019 (COVID-19) continues to constitute an international public health emergency. Vaccination is a prospective approach to control this pandemic. However, apprehension about the safety of vaccines is a major obstacle to vaccination. Amongst health professionals, one evident concern is the risk of antibody-dependent enhancement (ADE), which may increase the severity of COVID-19. To explore whether ADE occurs in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and increase confidence in the safety of vaccination, we conducted a meta-analysis to investigate the relationship between post-immune infection and disease severity from a population perspective. Databases, including PubMed, EMBASE, Chinese National Knowledge Infrastructure, SinoMed, Scopus, Science Direct, and Cochrane Library, were searched for articles on SARS-CoV-2 reinfection published until 25 October 2021. The papers were reviewed for methodological quality, and a random effects model was used to analyse the results. Heterogeneity was assessed using the I2 statistic. Publication bias was evaluated using a funnel plot and Egger's test. Eleven studies were included in the final meta-analysis. The pooled results indicated that initial infection and vaccination were protective factors against severe COVID-19 during post-immune infection (OR = 0.55, 95%CI = 0.31-0.98). A subgroup (post-immune infection after natural infection or vaccination) analysis showed similar results. Primary SARS-CoV-2 infection and vaccination provide adequate protection against severe clinical symptoms after post-immune infection. This finding demonstrates that SARS-CoV-2 may not trigger ADE at the population level.

miR-148a/LDLR mediates hypercholesterolemia induced by prenatal dexamethasone exposure in male offspring rats.

Epidemiology suggests that adverse environmental exposure during pregnancy may predispose children to hypercholesterolemia in adulthood. This study aimed to demonstrate hypercholesterolemia induced by prenatal dexamethasone exposure (PDE) in adult male offspring rats and explore the intrauterine programming mechanisms. Pregnant Wistar rats were injected subcutaneously with dexamethasone (0, 0.1, 0.2, and 0.4 mg/kg∙d) from gestational days (GD) 9 to 21, and the serum and liver of the male offsprings were collected at GD21, postnatal week (PW) 12 and 28. Furthermore, the effects of dexamethasone on the expression of low-density lipoprotein receptor (LDLR) and its epigenetic mechanism was confirmed in the bone marrow mesenchymal stem cells (BMSCs) hepatoid differentiated cells and continuous hepatocyte line. PDE could reduce the birth weight of male offsprings, increase the serum total cholesterol (TCH) level in adult rats, and decrease the liver low-density lipoprotein receptor (LDLR) expression. Serum TCH level and liver LDLR expression were decreased in PDE male fetuses in utero (GD21). Moreover, PDE increased the translocation of the glucocorticoid receptor (GR) in the fetal liver, the expression of DiGeorge syndrome critical region 8 gene (DGCR8), the pre- and post-natal expression of miR-148a. The results of PDE offspring in vivo and in vitro exhibited similar changes. These changes could be reversed by overexpressing LDLR, inhibiting miR-148a or GR. PDE caused hypercholesterolemia in male adult offspring rats, which was mediated via dexamethasone activated intrauterine hepatic GR, enhanced the expression of DGCR8 and miR-148a, thereby reducing the expression of LDLR, leading to impaired liver cholesterol reverse transport function, and finally causing hypercholesterolemia in adult rats.

TIGAR regulates mitochondrial functions through SIRT1-PGC1α pathway and translocation of TIGAR into mitochondria in skeletal muscle.

TP53-induced glycolysis and apoptosis regulator (TIGAR), a glycolytic inhibitor, plays vital roles in regulating cellular metabolism and oxidative stress. However, the role of highly expressed TIGAR in skeletal muscle remains unexplored. In the present study, TIGAR levels varied in different skeletal muscles and fibers. An exhaustive swimming test with a load corresponding to 5% of body weight was utilized in mice to assess the effects of TIGAR on exercise-induced fatigue and muscle damage. The running time and metabolic indicators were significantly greater in wild-type (WT) mice compared with TIGAR knockout (KO) mice. Poor exercise capacity was accompanied by decreased type IIA fibers in TIGAR KO mice. Decreased mitochondrial number and mitochondrial oxidative phosphorylation were observed more in TIGAR KO mice than in WT mice, which were involved in sirtuin 1 (SIRT1)-mediated deacetylation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), and resveratrol treatment in TIGAR KO mice can increase mitochondrial content and exercise time. Much more TIGAR was also detected in mitochondria during exhaustive exercise. In addition, TIGAR, rather than mitochondria-targeted TIGAR achieved by in vitro plasmid transfection, promoted SIRT1-PGC1α pathway. Glutathione S-transferase-TIGAR pull-down assay followed by liquid chromatography mass spectrometry found that TIGAR interacted with ATP synthase F1 subunit α (ATP5A1), and its binding to ATP5A1 increased during exhaustive exercise. Overexpression of mitochondrial-TIGAR enhanced ATP generation, maintained mitochondrial membrane potential and reduced mitochondrial oxidative stress under hypoxia condition. Taken together, our results uncovered a novel role for TIGAR in mitochondrial regulation in fast-twitch oxidative skeletal muscle through SIRT1-PGC1α and translocation into mitochondria, which contribute to the increase in exercise endurance of mice.-Geng, J., Wei, M., Yuan, X., Liu, Z., Wang, X., Zhang, D., Luo, L., Wu, J., Guo, W., Qin, Z.-H. TIGAR regulates mitochondrial functions through SIRT1-PGC1α pathway and translocation of TIGAR into mitochondria in skeletal muscle.

Attitudes of consumers and live-poultry workers to central slaughtering in controlling H7N9: a cross-sectional study.

BACKGROUND: Guangdong Province in the Pearl River Delta of Southeast China is among the areas in the country with the highest rates of avian flu cases. In order to control the outbreak of human-infected H7N9 cases, Guangdong launched a new policy on the central slaughtering of live poultry in 2015. This study aims to evaluate attitudes of consumers and live-poultry workers toward the policy. The live-poultry workers consisted of two sub-groups: live-poultry traders and poultry farm workers. METHODS: Consumers and live-poultry workers from Guangdong were enrolled by stratified multi-stage random sampling. Online and field surveys were conducted to investigate participants' attitudes on policy implementation. Questionnaires were developed to quantify participant demographics, to collect information about attitudes toward the policy, and to identify influential factors of policy acceptability. Proportional odds logistics regression was used in the univariate and multivariate analyses. A total of 1449 consumers, 181 live-poultry traders, and 114 poultry farm workers completed the study. RESULTS: Policy acceptability percentages among consumers, live-poultry traders, and poultry farm workers were 57.1, 37.9, and 62.6%, respectively. Logistics regression shows that consumers tended not to support the policy if they were males, if they were concerned with the food safety of chilled products, and if they preferred purchasing live poultry. Live-poultry traders tended not to support if they were subsidized by the government, if they were males, if they experienced a drop in trading volume, and if they were unclear whether avian flu was a preventable disease. Finally, poultry farm workers tended not to support if they experienced a drop in trading volume, if they operated a poultry farm on a small to medium scale, and if they experienced inconvenience in their work due to the policy. CONCLUSIONS: The study reveals a substantial refusal or slowness to accept the policy. Failure to accept the policy results from varying reasons. Among consumers, concern about food safety and dietary preference are two major causes of disapproval. Policy acceptability among live-poultry workers diverges within the two sub-groups. While a large percentage of poultry farm workers accept the policy, the drop in trading and an insufficient subsidy hamper acceptance by live-poultry traders. We recommend that policy-makers promote health education and alleviate the policy impact on trading with a reformed subsidy policy to increase acceptability. These findings are crucial for the prevention of human-infected H7N9 cases in Guangdong.

Correction: Development of bioactive and ultrasound-responsive microdroplets for preventing ovariectomy (OVX)-induced osteoporosis.

Correction for 'Development of bioactive and ultrasound-responsive microdroplets for preventing ovariectomy (OVX)-induced osteoporosis' by Yi Zhang et al., J. Mater. Chem. B, 2023, 11, 11344-11356, https://doi.org/10.1039/D3TB01726E.

Density functional theory-based study on the structural, electronic and spectral properties of gas-phase PbMg n - (n = 2-12) clusters.

Gas-phase PbMg n- (n = 2-12) cluster structures were globally searched on their potential energy surfaces by means of the CALYPSO prediction software. Structural optimization and calculations of properties such as relative energy and electronic structure were then carried out by density functional theory for each size of low energy isomer. The structural, relative stability, natural charge population, natural electronic configuration and distribution of the strongest peaks of the infrared and Raman spectra of the low energy isomers of PbMg n- (n = 2-12) clusters were systematically investigated in the present work. It was shown that the PbMg7- cluster ground state isomer exhibits the highest stability, for which special electronic excitation and chemical bonding analyses were performed. It is reasonable to believe that this work enriches the structural, spectroscopic and other data of magnesium-based clusters and provides some theoretical basis for possible future experimental syntheses.

Autophagy activated by GR/miR-421-3p/mTOR pathway as a compensatory mechanism participates in chondrodysplasia induced by prenatal caffeine exposure in male fetal rats.

Autophagy has been implicated in the developmental toxicity of multiple organs in offspring caused by adverse environmental conditions during pregnancy. We have previously found that prenatal caffeine exposure (PCE) can cause fetal overexposure to maternal glucocorticoids, leading to chondrodysplasia. However, whether autophagy is involved and what role it plays has not been reported. In this study, a PCE rat model was established by gavage of caffeine (120 mg/kg.d) on gestational day 9-20. The results showed that reduced cartilage matrix synthesis in male fetal rats in the PCE group was accompanied by increased autophagy compared to the control group. Furthermore, the expression of mTOR, miR-421-3p, and glucocorticoid receptor (GR) in male fetal rat cartilage of PCE group was increased. At the cellular level, we confirmed that corticosterone inhibited matrix synthesis in fetal chondrocytes while increasing autophagic flux. However, administration of autophagy enhancer (rapamycin) or inhibitor (bafilomycin A1 or 3-methyladenine) partially increased or further decreased aggrecan expression respectively. At the same time, we found that corticosterone could increase the expression of miR-421-3p through GR and target to inhibit the expression of mTOR, thereby enhancing autophagy. In conclusion, PCE can cause chondrodysplasia and autophagy enhancement in male fetal rats. Intrauterine high corticosterone activates GR/miR-421-3p signaling and down-regulates mTOR signaling in fetal chondrocytes, resulting in enhanced autophagy, which can partially compensate for corticosterone-induced fetal chondrodysplasia. This study confirmed the compensatory protective effect of autophagy on the developmental toxicity of fetal cartilage induced by PCE and its epigenetic mechanism, providing novel insights for exploring the early intervention and therapeutic target of fetal-originated osteoarthritis.

Have Previous COVID-19 Vaccinations Shaped the Potential Enhancing Infection of Variant Strains?

OBJECTIVE: This study aimed to investigate the infection status of Omicron in the population and the association between COVID-19 vaccination and infection with Omicron. METHODS: We conducted a cross-sectional study to openly recruit participants for a survey of SARS-CoV-2 infection by convenience sampling from 1 January to 15 January 2023 after a COVID-19 pandemic swept across China. Additionally, the binary logistic regression model was adopted to evaluate the association between COVID-19 vaccination and the infection outcomes or symptom severity, respectively. Meanwhile, the relations between the vaccination and duration of the symptoms were estimated via ordinal logistic analysis. RESULTS: Of the 2007 participants, the prevalence of infection with Omicron was 82.9%. Compared with unvaccinated individuals, inactivated COVID-19 vaccination could increase the risk of Omicron infection (OR = 1.942, 95% CI: 1.093-3.448), and the receipt of at least one dose of non-inactivated COVID-19 vaccines was a protective factor against infection (OR = 0.428, 95% CI: 0.226-0.812). By contrast, no relations were observed in COVID-19 vaccination with the symptoms of infection and duration of symptoms (p > 0.05). CONCLUSIONS: This cross-sectional study concluded that inactivated COVID-19 vaccination might increase the risk of Omicron infection, which should be a concern during COVID-19 vaccination and the treatment of variant infections in the future, and the receipt of at least one dose of non-inactivated COVID-19 vaccine was a protective factor against infection.

Effects of the timing of maternal SARS-CoV-2 infection and vaccination status on placental transfer of antibodies to neonates: A cross-sectional study.

OBJECTIVES: To assess the effects of timing of maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination status on placental transfer of antibodies to neonates. METHODS: In this cross-sectional study, chemiluminescence was employed to measure SARS-CoV-2 IgG antibody titers in paired maternal-infant samples from women infected during pregnancy who were vaccinated or unvaccinated. Generalized linear regression assessed factors affecting antibody transfer in infected pregnant women and neonatal titers. RESULTS: The group with ≥90 days between infection and delivery showed a higher antibody transfer rate than the <90 days group (ß= 0.33, 95%CI: 0.01-0.65). Neonatal IgG titers correlated significantly with maternal titers and with maternal infections more than 90 days before delivery. Among infected pregnant women, those who had received 2 or 3 doses of vaccine before pregnancy had higher neonatal antibody titers than those who were not vaccinated (ß = 57.70, 95%CI: 31.33-84.07). CONCLUSION: Neonates born to pregnant women who were vaccinated before infection showed higher antibody titers than neonates of pregnant women who were not vaccinated before infection. The transfer rate is higher in pregnant women with ≥90 days from infection to delivery than in those with <90 days. These findings highlight the importance of timely maternal vaccination to optimize maternal and infant immunity.

Development of bioactive and ultrasound-responsive microdroplets for preventing ovariectomy (OVX)-induced osteoporosis.

As a common bone disease in the elderly population, osteoporosis-related bone loss and bone structure deterioration represent a major public health problem. Therapeutic strategies targeting excessive osteoclast formation are frequently used for osteoporosis treatment; however, potential side effects have been recorded. Here, we have developed a novel therapeutic strategy using microdroplets (MDs) encapsulated with NFATc1-siRNA and investigated the role of bioactive MDs-NFATc1 biocompatibility in RAW 264.7 macrophages and human mesenchymal stem cells (hBMSCs), respectively. Its role in regulating osteoclast differentiation and formation was also investigated in vitro. We first fabricated MDs with spherical morphology along with a well-defined core-shell structure. The ultrasound-responsive study demonstrated time-dependent responsive structural changes following ultrasound stimulation. The internalization study into unstimulated macrophages, inflammatory macrophages, and hBMSCs indicated good delivery efficiency. Furthermore, the results from the MTT assay, the live/dead assay, and the cellular morphological analysis further indicated good biocompatibility of our bioactive MDs-NFATc1. Following MDs-NFATc1 treatment, the number of osteoclasts was greatly reduced, indicating their inhibitory effect on osteoclastogenesis and osteoclast formation. Subsequently, osteoporotic rats that underwent ovariectomy (OVX) were used for the in vivo studies. The rats treated with MDs-NFATc1 exhibited significant resistance to bone loss induced by OVX. In conclusion, our results demonstrate that MDs-NFATc1 could become an important regulator in osteoclast differentiation and functions, thus having potential applications in osteoclast-related bone diseases.

[Research updates of osteoimmunomodulation in osteogenesis].

The gold-standard for bone substitution of large bone defects continues to be autogenous bone graft. Artificial bone substitutes are difficult to replace the autogenous bone grafting due to excessive immune response, fast biodegradation characteristics and inappropriate biocompatibility. Given these drawbacks, osteoimmunology and its advanced functional biomaterials have gained growing attention in recent years. Immune system plays an essential role during bone healing via regulating the shift from inflammatory to anti-inflammation phenotype, and inflammatory cytokines response. The inflammatory reaction mainly include infiltration of immune cells (such as macrophages, neutrophils, T cells, B cells, etc) and release of inflammatory factors (such as IL-1ß, IL-6, TNF-α, etc.) at the bone defects, which subsequently affect the step-wised process of bone healing rejuvenation. Hence, advanced bone biomaterials with immunomodulatory properties is of great significance for the treatment of patients with recalcitrant bone defects, especially for delayed healing or non-union. The reciprocal mechanism of immuno-modulated bone healing, however, is not fully understood and more research is required in the future.

Effectiveness of Maternal Inactivated COVID-19 Vaccination against Omicron Infection in Infants during the First 12 Months of Life: A Test-Negative Case-Control Study.

This study aims to evaluate the effectiveness of maternal inactivated COVID-19 vaccination before delivery for infants against Omicron infection in Guangzhou, China. A test-negative case-control design was conducted. This study selected infants born from 1 November 2021 to 23 November 2022 and tested for SARS-CoV-2 between 13 April 2022 and 30 November 2022 during outbreaks in Guangzhou. Multivariable logistic regression was performed to compare the maternal vaccination status of inactivated COVID-19 vaccines before delivery in cases and controls to estimate vaccine effectiveness (VE) for infants within 12 months. According to eligibility criteria, we finally selected 205 test-positive and 114 test-negative infants, as well as their mothers. The effectiveness of inactivated COVID-19 vaccines among fully vaccinated mothers was 48.4% (7.3% to 71.7%) for infants within 12 months, with the effectiveness of partial and booster vaccination showing no significant difference. Effectiveness for full vaccination presented a slight increase according to infants' age at testing, with 49.6% (-12.3% to 78.4%) for 0-6 months and 59.9% (-0.6% to 84.4%) for over 6 months. A greater protective effect of two-dose vaccination was manifested in infants whose mother had received the second dose during the first trimester (65.9%, 95% CI: 7.7% to 87.9%) of pregnancy rather than preconception (43.5%, 95% CI: -8.7% to 71.1%). Moreover, VE could be improved to 77.1% (11.1% to 95.3%) when mothers received two doses both during pregnancy and 91.8% (41.1% to 99.6%) with receipt of a booster dose during pregnancy. Maternal vaccination with two doses of inactivated COVID-19 vaccines before delivery was moderately effective against Omicron infection in infants during the first 12 months of life. Full vaccination or a booster dose during pregnancy could confer better protection against Omicron for infants, although it might be overestimated due to the insufficient sample size in subgroups.

Advances of Blood Coagulation Factor XIII in Bone Healing.

The biologic process of bone healing is complicated, involving a variety of cells, cytokines, and growth factors. As a result of bone damage, the activation of a clotting cascade leads to hematoma with a high osteogenic potential in the initial stages of healing. A major factor involved in this course of events is clotting factor XIII (FXIII), which can regulate bone defect repair in different ways during various stages of healing. Autografts and allografts often have defects in clinical practice, making the development of advanced materials that support bone regeneration a critical requirement. Few studies, however, have examined the promotion of bone healing by FXIII in combination with biomaterials, in particular, its effect on blood coagulation and osteogenesis. Therefore, we mainly summarized the role of FXIII in promoting bone regeneration by regulating the extracellular matrix and type I collagen, bone-related cells, angiogenesis, and platelets, and described the research progress of FXIII = related biomaterials on osteogenesis. This review provides a reference for investigators to explore the mechanism by which FXIII promotes bone healing and the combination of FXIII with biomaterials to achieve targeted bone tissue repair.

Cathepsin D mediates prenatal caffeine exposure-caused NAFLD susceptibility in male rat offspring by regulating autophagy.

Epidemiological evidence has revealed that non-alcoholic fatty liver disease (NAFLD) harbors an intrauterine origin. Autophagy is known to be involved in the protective mechanism in the development of adult NAFLD, but whether it engages in the occurrence of fetal-originated NAFLD remains unclear. In this study, a rat model of fetal-originated NAFLD was established by giving a high-fat diet or chronic stress after birth on prenatal caffeine exposure (PCE) male offspring. The alterations of liver morphologic analysis, lipid metabolism, and autophagy before and after birth were determined to confirm autophagy mechanism, NAFLD susceptibility, and intrauterine origin in PCE male adult offspring. Our results revealed that PCE-induced intrauterine high concentration of corticosterone exposure blocked autophagic flux by inhibiting cathepsin D expression in hepatocytes, leading to ß-oxidation inhibition and lipid accumulation in the liver. Moreover, high concentration of corticosterone upregulated miR-665 by activating the glucocorticoid receptor to suppress cathepsin D, thus causing lysosomal degradation dysfunction and autophagy flux blockade. Notably, hepatic overexpression of cathepsin D could reverse PCE-induced postnatal NAFLD susceptibility in male rat offspring. This study elucidates the epigenetic programming mechanism of intrauterine autophagy-related fetal-originated NAFLD susceptibility, and identifies cathepsin D as its early intervention target, providing an experimental basis for exploring early prevention and treatment strategies for fetal-originated NAFLD.

Fabrication of Interleukin-4 Encapsulated Bioactive Microdroplets for Regulating Inflammation and Promoting Osteogenesis.

Background: Despite the inherent regenerative ability of bone, large bone defect regeneration remains a major clinical challenge for orthopedic surgery. Therapeutic strategies medicated by M2 phenotypic macrophages or M2 macrophage inducer have been widely used to promote tissue remodeling. In this study, ultrasound-responsive bioactive microdroplets (MDs) encapsulated with bioactive molecule interleukin-4 (IL4, hereafter designated MDs-IL4) were fabricated to regulate macrophage polarization and potentiate the osteogenic differentiation of human mesenchymal stem cells (hBMSCs). Materials and Methods: The MTT assay, live and dead staining, and phalloidin/DAPI dual staining were used to evaluate biocompatibility in vitro. H&E staining was used to evaluate biocompatibility in vivo. Inflammatory macrophages were further induced via lipopolysaccharide (LPS) stimulation to mimic the pro-inflammatory condition. The immunoregulatory role of the MDs-IL4 was tested via macrophage phenotypic marker gene expression, pro-inflammatory cytokine level, cell morphological analysis, and immunofluorescence staining, etc. The immune-osteogenic response of hBMSCs via macrophages and hBMSCs interactions was further investigated in vitro. Results: The bioactive MDs-IL4 scaffold showed good cytocompatibility in RAW 264.7 macrophages and hBMSCs. The results confirmed that the bioactive MDs-IL4 scaffold could reduce inflammatory phenotypic macrophages, as evidenced by changing in morphological features, reduction in pro-inflammatory marker gene expression, increase of M2 phenotypic marker genes, and inhibition of pro-inflammatory cytokine secretion. Additionally, our results indicate that the bioactive MDs-IL4 could significantly enhance the osteogenic differentiation of hBMSCs via its potential immunomodulatory properties. Conclusion: Our results demonstrate that the bioactive MDs-IL4 scaffold could be used as novel carrier system for other pro-osteogenic molecules, thus having potential applications in bone tissue regeneration.

Protective Effect of Inactivated COVID-19 Vaccines against Omicron BA.2 Infection in Guangzhou: A Test-Negative Case-Control Real-World Study.

This study aims to explore the relationship between the doses of inactivated COVID-19 vaccines received and SARS-CoV-2 Omicron infection in the real-world setting, so as to preliminarily evaluate the protective effect induced by COVID-19 vaccination. We conducted a test-negative case-control study and recruited the test-positive cases and test-negative controls in the outbreak caused by Omicron BA.2 in April 2022 in Guangzhou, China. All the participants were 3 years and older. The vaccination status between the case group and the control group was compared in the vaccinated and all participants, respectively, to estimate the immune protection of inactivated COVID-19 vaccines. After adjusting for sex and age, compared with a mere single dose, full vaccination of inactivated COVID-19 vaccines (OR = 0.191, 95% CI: 0.050 to 0.727) and booster vaccination (OR = 0.091, 95% CI: 0.011 to 0.727) had a more superior protective effect. Compared with one dose, the second dose was more effective in males (OR = 0.090), as well as two doses (OR = 0.089) and three doses (OR = 0.090) among individuals aged 18-59. Whereas, when compared with the unvaccinated, one dose (OR = 7.715, 95% CI: 1.904 to 31.254) and three doses (OR = 2.055, 95% CI: 1.162 to 3.635) could contribute to the increased risk of Omicron infection after adjusting for sex and age. Meanwhile, by contrast with unvaccinated individuals, the result of increased risk was also manifested in the first dose in males (OR = 12.400) and one dose (OR = 21.500), two doses (OR = 1.890), and a booster dose (OR = 1.945) in people aged 18-59. In conclusion, the protective effect of full and booster vaccination with inactivated COVID-19 vaccines exceeded the incomplete vaccination, of which three doses were more effective. Nevertheless, vaccination may increase the risk of Omicron infection compared with unvaccinated people. This may result from the transmission traits of BA.2, the particularity and stronger protection awareness of the unvaccinated population, as well as the ADE effect induced by the decrease of antibody titers after a long time of vaccination. It is crucial to explore this issue in depth for the formulation of future COVID-19 vaccination strategies.

The role of autophagy in bone metabolism and clinical significance.

The skeletal system is the basis of the vertebral body composition, which affords stabilization sites for muscle attachment, protects vital organs, stores mineral ions, supplies places to the hematopoietic system, and participates in complex endocrine and immune system. Not surprisingly, bones are constantly reabsorbed, formed, and remodeled under physiological conditions. Once bone metabolic homeostasis is interrupted (including inflammation, tumors, fractures, and bone metabolic diseases), the body rapidly initiates bone regeneration to maintain bone tissue structure and quality. Macroautophagy/autophagy is an essential metabolic process in eukaryotic cells, which maintains metabolic energy homeostasis and plays a vital role in bone regeneration by controlling molecular degradation and organelle renewal. One relatively new observation is that mesenchymal cells, osteoblasts, osteoclasts, osteocytes, chondrocytes, and vascularization process exhibit autophagy, and the molecular mechanisms and targets involved are being explored and updated. The role of autophagy is also emerging in degenerative diseases (intervertebral disc degeneration [IVDD], osteoarthritis [OA], etc.) and bone metabolic diseases (osteoporosis [OP], osteitis deformans, osteosclerosis). The use of autophagy regulators to modulate autophagy has benefited bone regeneration, including MTOR (mechanistic target of rapamycin kinase) inhibitors, AMPK activators, and emerging phytochemicals. The application of biomaterials (especially nanomaterials) to trigger autophagy is also an attractive research direction, which can exert superior therapeutic properties from the material-loaded molecules/drugs or the material's properties such as shape, roughness, surface chemistry, etc. All of these have essential clinical significance with the discovery of autophagy associated signals, pathways, mechanisms, and treatments in bone diseases in the future.Abbreviations: Δψm: mitochondrial transmembrane potential AMPK: AMP-activated protein kinase ARO: autosomal recessive osteosclerosis ATF4: activating transcription factor 4 ATG: autophagy-related ß-ECD: ß-ecdysone BMSC: bone marrow mesenchymal stem cell ER: endoplasmic reticulum FOXO: forkhead box O GC: glucocorticoid HIF1A/HIF-1α: hypoxia inducible factor 1 subunit alpha HSC: hematopoietic stem cell HSP: heat shock protein IGF1: insulin like growth factor 1 IL1B/IL-1ß: interleukin 1 beta IVDD: intervertebral disc degradation LPS: lipopolysaccharide MAPK: mitogen-activated protein kinase MSC: mesenchymal stem cell MTOR: mechanistic target of rapamycin kinase NP: nucleus pulposus NPWT: negative pressure wound therapy OA: osteoarthritis OP: osteoporosis PTH: parathyroid hormone ROS: reactive oxygen species SIRT1: sirtuin 1 SIRT3: sirtuin 3 SQSTM1/p62: sequestosome 1 TNFRSF11B/OPG: TNF receptor superfamily member 11b TNFRSF11A/RANK: tumor necrosis factor receptor superfamily, member 11a TNFSF11/RANKL: tumor necrosis factor (ligand) superfamily, member 11 TSC1: tuberous sclerosis complex 1 ULK1: unc-51 like autophagy activating kinase 1.