Protective effect of clusterin against interleukin-1ß-induced apoptosis and inflammation in human knee osteoarthritis chondrocytes.

Chondrocyte apoptosis is recognized as one of the pathological features involved in cartilage degeneration driving the onset and progression of knee osteoarthritis (OA). This study aimed to determine the molecular mechanism underlying the effect of clusterin (CLU), anti-apoptotic molecule, in human knee OA chondrocytes. Primary knee OA chondrocytes were isolated from the cartilage of knee OA patients and divided into five groups: (1) the cells treated with interleukin (IL)-1ß, (2) CLU alone, (3) a combination of IL-1ß and CLU, (4) LY294002 (PI3K inhibitor) along with IL-1ß and CLU, and (5) the untreated cells. Production of apoptotic, inflammatory, anabolic, and catabolic mediators in knee OA chondrocytes was determined after treatment for 24 h. Our in vitro study uncovered that CLU significantly suppressed the production of inflammatory mediators [nitric oxide (NO), IL6, and tumor necrosis factor (TNF)-α] and apoptotic molecule (caspase-3, CASP3). CLU significantly upregulated messenger ribonucleic acid (mRNA) expressions of anabolic factors [SRY-box transcription factor-9 (SOX9) and aggrecan (ACAN)], but significantly downregulated mRNA expressions of IL6, nuclear factor kappa-B (NF-κB), CASP3, and matrix metalloproteinase-13 (MMP13). Anti-apoptotic and anti-inflammatory effects of CLU were mediated through activating PI3K/Akt signaling pathway. The findings suggest that CLU might have beneficial effects on knee OA chondrocytes by exerting anti-apoptotic and anti-inflammatory functions via PI3K/Akt pathway, making CLU a promising target for potential therapeutic interventions in knee OA.

Cartilage oligomeric matrix protein as a potential biomarker for knee osteoarthritis.

Aims: This study aimed to determine the expression and clinical significance of a cartilage protein, cartilage oligomeric matrix protein (COMP), in knee osteoarthritis (OA) patients. Methods: A total of 270 knee OA patients and 93 healthy controls were recruited. COMP messenger RNA (mRNA) and protein levels in serum, synovial fluid, synovial tissue, and fibroblast-like synoviocytes (FLSs) of knee OA patients were determined using enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and immunohistochemistry. Results: COMP protein levels were significantly elevated in serum and synovial fluid of knee OA patients, especially those in the advanced stages of the disease. Serum COMP was significantly correlated with radiological severity as well as measures of body composition, physical performance, knee pain, and disability. Receiver operating characteristic curve analysis unveiled a diagnostic value of serum COMP as a biomarker of knee OA (41.64 ng/ml, area under the curve (AUC) = 1.00), with a sensitivity of 99.6% and a specificity of 100.0%. Further analysis uncovered that COMP mRNA expression was markedly upregulated in the inflamed synovium of knee OA, consistent with immunohistochemical staining revealing localization of COMP protein in the lining and sub-lining layers of knee OA inflamed synovium. Most notably, relative COMP mRNA expression in knee OA synovium was positively associated with its protein levels in serum and synovial fluid of knee OA patients. In human knee OA FLSs activated with tumour necrosis factor-alpha, COMP mRNA expression was considerably up-regulated in a time-dependent manner. Conclusion: All results indicate that COMP might serve as a supportive diagnostic marker for knee OA in conjunction with the standard diagnostic methods.

Immunogenicity and durability against Omicron BA.1, BA.2 and BA.4/5 variants at 3-4 months after a heterologous COVID-19 booster vaccine in healthy adults with a two-doses CoronaVac vaccination.

Background: Several countries have authorized a booster vaccine campaign to combat the spread of COVID-19. Data on persistence of booster vaccine-induced immunity against new Omicron subvariants are still limited. Therefore, our study aimed to determine the serological immune response of COVID-19 booster after CoronaVac-priming. Methods: A total of 187 CoronaVac-primed participants were enrolled and received an inactivated (BBIBP), viral vector (AZD1222) or mRNA vaccine (full-/half-dose BNT162B2, full-/half-dose mRNA-1273) as a booster dose. The persistence of humoral immunity both binding and neutralizing antibodies against wild-type and Omicron was determined on day 90-120 after booster. Results: A waning of total RBD immunoglobulin (Ig) levels, anti-RBD IgG, and neutralizing antibodies against Omicron BA.1, BA.2, and BA.4/5 variants was observed 90-120 days after booster vaccination. Participants who received mRNA-1273 had the highest persistence of the immunogenicity response, followed by BNT162b2, AZD1222, and BBIBP-CorV. The responses between full and half doses of mRNA-1273 were comparable. The percentage reduction of binding antibody ranged from 50 % to 75 % among all booster vaccine. Conclusions: The antibody response substantially waned after 90-120 days post-booster dose. The heterologous mRNA and the viral vector booster demonstrated higher detectable rate of humoral immune responses against the Omicron variant compared to the inactivated BBIBP booster. Nevertheless, an additional fourth dose is recommended to maintain immune response against infection.

Elevated serum IL-34 is correlated with disease severity in patients with biliary atresia following Kasai portoenterostomy.

BACKGROUND: Biliary atresia (BA) is a severe congenital disorder with progressive obstructive cholangiopathy in young children. The inflammatory process has been recognized as one of the pathological mechanisms driving bile duct injury. Since interleukin-34 (IL-34) has been reportedly linked to several pathological liver disorders, including inflammation, the current study aimed to analyze circulating IL-34 and the association of circulating IL-34 with hepatic deterioration and clinical outcomes in post-Kasai BA children. METHODS: Circulating IL-34 levels were analyzed in 89 post-Kasai BA subjects and 45 healthy individuals using an ELISA. Liver stiffness (hardness) was measured by ultrasound elastography. RESULTS: Circulating IL-34 was substantially higher in BA children than in control individuals, particularly those with unfavorable outcomes including hepatic dysfunction, jaundice, and portal hypertension. In BA group, circulating IL-34 was positively correlated with liver stiffness (r = 0.515, p < 0.001), AST (r = 0.403, p < 0.001), ALT (r = 0.279, p = 0.008), total bilirubin (r = 0.224, p = 0.03), ALP (r = 0.255, p = 0.016), and serum IL-6 (r = 0.590, p < 0.001) but inversely correlated with albumin (r = -0.417, p < 0.001). Kaplan-Meier survival analysis showed that higher circulating IL-34 levels were significantly associated with reduced survival rates in BA subjects (p = 0.002). CONCLUSION: Higher circulating IL-34 values were directly associated with hepatic impairment and the BA severity, implicating thatserum IL-34 could be applied as a noninvasive marker for the monitoring of the severity in BA subjects following Kasai portoenterostomy and therapeutic efficacy.

Real-World Study: Hybrid Immunity against SARS-CoV-2 Influences the Antibody Levels and Persistency Lasting More than One Year.

This study investigated the impact of hybrid immunity on antibody responses in the participants who received two to seven doses of the COVID-19 vaccine. The study was conducted between April and June 2023. Out of 771 serum samples analyzed, 71.7% exhibited hybrid immunity (positive for total anti-N Ig), while 28.3% showed vaccine-induced immunity (negative for total anti-N Ig). Participants were categorized based on the number of vaccine doses: 2, 3, 4, and ≥5. The findings highlight a trend where a higher number of vaccine doses received was associated with a lower infection rate. There was no significant difference in total RBD Ig levels between those who received 3, 4, or ≥5 doses in both the hybrid immunity and vaccination alone groups across all observed durations as follows: <6 months, 6 to <9 months, 9 to <12 months, and ≥12 months. Hybrid immunity consistently maintained higher total RBD Ig levels and durability compared to vaccination alone, with estimated half-lives (T1/2) of 189.5 days versus 106.8 days for vaccine alone. This investigation underscored the potential benefit of hybrid immunity and raised questions about the optimal strategies for further vaccine dosing.

Effect of vitamin D supplementation on circulating level of autophagosome protein LC3A, inflammation, and physical performance in knee osteoarthritis.

Aberrant autophagic activity is observed in osteoarthritic joints. Vitamin D was shown to alleviate not only osteoarthritis severity, but also autophagy process. However, the influence of vitamin D on autophagy in knee osteoarthritis (KOA) remains ambiguous. This study aimed to determine the effect of vitamin D2 on serum levels of autophagosome protein LC3A in patients with KOA and whether LC3A levels were correlated with serum 25-hydroxyvitamin D (25(OH)D) and clinical outcomes of patients with KOA. A total of 165 patients with KOA and 25 healthy controls were recruited. Vitamin D2 (ergocalciferol) was administered to patients with KOA at a weekly dosage of 40,000 IU. Serum LC3A, knee pain and functional scores, muscle strength, physical performance, and biochemical parameters were examined before and after 6 months of vitamin D2 supplementation. Serum LC3A levels were significantly higher in patients with KOA than healthy controls. In patients with KOA, vitamin D2 supplementation significantly decreased serum LC3A levels. Furthermore, baseline levels of serum LC3A were significantly associated with radiographic severity, pain and functional scores, total cholesterol, hs-CRP, IL-6, protein carbonyl, and serum 25(OH)D. After adjusting for established confounders, independent relationships among serum LC3A and radiographic severity, pain and functional scores, total cholesterol, hs-CRP, IL-6, protein carbonyl, and serum 25(OH)D were also observed. Vitamin D2 supplementation was shown to not only decrease serum levels of LC3A, inflammatory markers, as well as oxidative stress, but also improve muscle strength and physical performance in patients with KOA.

Effect of galectin-3 on synovial inflammation in knee osteoarthritis via stimulating phosphatidylinositol-3-kinase/Akt pathway.

Galectin-3 (Gal-3), a glycan-binding protein responsible for inflammation, has been reportedly implicated in inflammatory arthritis. This study aimed to determine clinical and pathological effects of Gal-3 on inflammation in knee osteoarthritis (OA). Gal-3 mRNA and protein levels in synoviocytes, synovium, synovial fluid, and plasma of knee OA patients were determined using real-time polymerase chain reaction, immunohistochemistry, and enzyme-linked immunosorbent assay. Signaling mechanism underlying inflammatory effect of Gal-3 was further elucidated in human knee OA synoviocytes. Clinical study uncovered significant increases in plasma and synovial fluid Gal-3 levels in knee OA patients, particularly those with advanced-stage. In knee OA patients, plasma Gal-3 was significantly associated with radiographic severity and indicators of body composition, physical performance, and knee pain and disability. In the inflamed synovium of knee OA patients, further analysis depicted a marked up-regulation of Gal-3 mRNA expression, consistent with immunohistochemical analysis showing localization of Gal-3 protein in the lining and sublining layers of the inflamed synovium. An in vitro study unveiled that aberrant Gal-3 mRNA expression was regulated by tumor necrosis factor (TNF)-α in knee OA synoviocytes. Gal-3 significantly enhanced production of NO and IL-6, up-regulated mRNA expressions of IL-6, NF-κB, and MMP-13, and down-regulated mRNA expressions of ACAN and SOX-9 via stimulating Akt phosphorylation in knee OA synoviocytes. Gal-3 exerted an inflammatory action, which might emerge as a possible mediator of synovitis and cartilage degeneration in knee OA.

The Fourth Dose of mRNA COVID-19 Vaccine Following 12 Different Three-Dose Regimens: Safety and Immunogenicity to Omicron BA.4/BA.5.

The aim of this study is to investigate the reactogenicity and immunogenicity of the fourth dose using monovalent mRNA vaccines after different three-dose regimens and to compare the 30 µg BNT162b2 and 50 µg mRNA-1273 vaccines. This prospective cohort study was conducted between June and October 2022. The self-recorded reactogenicity was evaluated on the subsequent 7 days after a fourth dose. The binding and neutralizing activity of antibodies against the Omicron BA.4/5 variants were determined. Overall, 292 healthy adults were enrolled and received BNT162b2 or mRNA-1273. Reactogenicity was mild to moderate and well tolerated after a few days. Sixty-five individuals were excluded. Thus, 227 eligible individuals received a fourth booster dose of BNT162b2 (n = 109) and mRNA-1273 (n = 118). Most participants, regardless of the type of previous three-dose regimens, elicited a significantly high level of binding antibodies and neutralizing activity against Omicron BA.4/5 28 days after a fourth dose. The neutralizing activity against Omicron BA.4/5 between the BNT162b2 (82.8%) and mRNA-1273 (84.2%) groups was comparable with a median ratio of 1.02. This study found that the BNT162b2 and mRNA-1273 vaccines can be used as a fourth booster dose for individuals who were previously immunized with any prior three-dose mix-and-match COVID-19 vaccine regimens.

Vitamin D Inadequacy Affects Skeletal Muscle Index and Physical Performance in Lumbar Disc Degeneration.

Lumbar disc degeneration (LDD) is one of the fundamental causes of low back pain. The aims of this study were to determine serum 25-hydroxyvitamin D (25(OH)D) levels and physical performance and to investigate the relationship between serum vitamin D levels, muscle strength and physical activity in elderly patients with LDD. The participants were 200 LDD patients, including 155 females and 45 males aged 60 years and over. Data on body mass index and body composition were collected. Serum 25(OH)D and parathyroid hormone levels were measured. Serum 25(OH)D was classified into the insufficiency group: <30 ng/mL and the sufficiency group: ≥30 ng/mL. Muscle strength was assessed by grip strength, and physical performance (short physical performance battery) was evaluated by the balance test, chair stand test, gait speed, and Timed Up and Go (TUG) test. Serum 25(OH)D levels in LDD patients with vitamin D insufficiency were significantly lower than in those with vitamin D sufficiency (p < 0.0001). LDD patients with vitamin D insufficiency had a prolonged time in physical performance on gait speed (p = 0.008), chair stand test (p = 0.013), and TUG test (p = 0.014) compared to those with vitamin D sufficiency. Additionally, we found that serum 25(OH)D levels were significantly correlated with gait speed (r = -0.153, p = 0.03) and TUG test (r = -0.168, p = 0.017) in LDD patients. No significant associations with serum 25(OH)D status were observed for grip strength and balance tests among patients. These findings demonstrate that higher serum 25(OH)D levels are associated with better physical performance in LDD patients.

Safety and immunogenicity of a third dose of COVID-19 protein subunit vaccine (CovovaxTM) after homologous and heterologous two-dose regimens.

OBJECTIVES: To report the safety and immunogenicity profile of a protein subunit vaccine (CovovaxTM) given as a third (booster) dose to individuals primed with different primary vaccine regimens. METHODS: A third dose was administered to individuals with an interval range of 3-10 months after the second dose. The four groups were classified according to their primary vaccine regimens, including two-dose BBIBP-CorV, AZD1222, BNT162b2, and CoronaVac/AZD1222. Immunogenicity analysis was performed to determine binding antibodies, neutralizing activity, and the T-cell responses. RESULTS: Overall, 210 individuals were enrolled and boosted with the CovovaxTM vaccine. The reactogenicity was mild to moderate. Most participants elicited a high level of binding and neutralizing antibody against Wild-type and Omicron variants after the booster dose. In participants who were antinucleocapsid immunoglobulin G-negative from all groups, a booster dose could elicit neutralizing activity to Wild-type and Omicron variants by more than 95% and 70% inhibition at 28 days, respectively. The CovovaxTM vaccine could elicit a cell-mediated immune response. CONCLUSION: The protein subunit vaccine (CovovaxTM) can be proposed as a booster dose after two different priming dose regimens. It has strong immunogenicity and good safety profiles.

PEG Reinforced Scaffold Promotes Uniform Distribution of Human MSC-Created Cartilage Matrix.

Previously, we used a gelatin/hyaluronic acid (GH)-based scaffold to induce chondrogenic differentiation of human bone marrow-derived mesenchymal stromal cells (hBMSC). The results showed that hBMSCs underwent robust chondrogenesis and facilitated in vivo cartilage regeneration. However, it was noticed that the GH scaffolds display a compressive modulus that is markedly lower than native cartilage. In this study, we aimed to enhance the mechanical strength of GH scaffolds without significantly impairing their chondrosupportive property. Specifically, polyethylene glycol diacrylate (PEGDA) and photoinitiators were infiltrated into pre-formed hBMSC-laden GH scaffolds and then photo-crosslinked. Results showed that infiltration of PEG at the beginning of chondrogenesis significantly increased the deposition of glycosaminoglycans (GAGs) in the central area of the scaffold. To explore the mechanism, we compared the cell migration and proliferation in the margin and central areas of GH and PEG-infiltrated GH scaffolds (GH+PEG). Limited cell migration was noticed in both groups, but more proliferating cells were observed in GH than in GH+PEG. Lastly, the in vitro repairing study with bovine cartilage explants showed that PEG- impregnated scaffolds integrated well with host tissues. These results indicate that PEG-GH hybrid scaffolds, created through infiltrating PEG into pre-formed GH scaffolds, display good integration capacity and represent a new tool for the repair of chondral injury.

Telomere Length Is Correlated with Resting Metabolic Rate and Aerobic Capacity in Women: A Cross-Sectional Study.

This study investigated the associations between relative telomere length (RTL) and resting metabolic rate (RMR), resting fat oxidation (RFO), and aerobic capacity and whether oxidative stress and inflammation are the underlying mechanisms in sedentary women. We also aimed to determine whether the correlations depend on age and obesity. Sixty-eight normal weight and 66 obese women participated in this study. After adjustment for age, energy expenditure, energy intake, and education level, the RTL of all participants was negatively correlated with absolute RMR (RMRAB) and serum high-sensitivity C-reactive protein (hsCRP) concentration, and positively correlated with maximum oxygen consumption (V˙O2max) (all p < 0.05). After additional adjustment for adiposity indices and fat-free mass (FFM), RTL was positively correlated with plasma vitamin C concentration (p < 0.05). Furthermore, after adjustment for fasting blood glucose concentration, RTL was negatively correlated with age and positively correlated with V˙O2max (mL/kg FFM/min). We found that normal weight women had longer RTL than obese women (p < 0.001). We suggest that RTL is negatively correlated with RMRAB and positively correlated with aerobic capacity, possibly via antioxidant and anti-inflammatory mechanisms. Furthermore, age and obesity influenced the associations. We provide useful information for the management of promotion strategies for health-related physical fitness in women.

Effects of Irvingia gabonensis Extract on Metabolism, Antioxidants, Adipocytokines, Telomere Length, and Aerobic Capacity in Overweight/Obese Individuals.

We investigated the effects of Irvingia gabonensis (IG) kernel extract on the metabolism, adiposity indices, redox status, inflammation, adipocytokines, blood leukocyte relative telomere length (RTL), and aerobic capacity of overweight/obese individuals. All participants used the first 12-week phase to monitor body weight. They were then randomly divided into two groups: (1) 300 mg IG or (2) placebo (PLA). Both groups took one tablet per day for 12 weeks. The variables were measured before supplementation and after 3, 6, and 12 weeks of supplementation. RTL and aerobic capacity were measured before and after 12 weeks. Compared with the PLA, the IG increased plasma vitamin C after supplementation at 6 (p < 0.01) and 12 weeks (p < 0.05) and serum adiponectin after 3 weeks (p < 0.05). Compared with before supplementation, plasma malondialdehyde in the IG and serum leptin in the PLA were decreased after 12-week supplementation, without any differences between the groups. There were no differences between groups with respect to metabolism, inflammation, RTL, and aerobic capacity after the supplementation. We suggest that 12-week daily IG supplementation improved plasma vitamin C and adiponectin. The findings show the possible mechanism contributing to the effect of IG supplementation on a reduction in obesity-related complications.

Association between Common Variants in VEGFA Gene and the Susceptibility of Primary Knee Osteoarthritis.

OBJECTIVES: This study aimed to analyze the relationship between vascular endothelial growth factor A (VEGFA) gene polymorphisms, plasma VEGFA, and the susceptibility of knee osteoarthritis (OA). DESIGN: A total of 404 subjects, 202 knee OA subjects and 202 healthy volunteers, were enrolled into the study. Four distinct polymorphisms of the VEGFA gene were evaluated using polymerase chain reaction-restriction fragment length polymorphism: -2578C/A (rs699947), -1154G/A (rs1570360), -634C/G (rs2010963), and +936C/T (rs3025039). Plasma VEGFA levels were analyzed using enzyme-linked immunosorbent assay. RESULTS: The most common nucleotides in both knee OA subjects and healthy controls were CC for -2578C/A, GG for -1154G/A, CG for -634C/G, and CC for +936C/T in the VEGFA gene. Genotype distribution and allele frequencies of VEGFA -2578C/A, -1154G/A, -634C/G, and +936C/T single nucleotide polymorphisms did not differ between OA patients and the controls. Plasma VEGFA levels showed no difference between OA patients and the controls. In contrast, plasma VEGFA levels of -634C/C genotype were significantly higher in OA patients than in the controls (P = 0.035). According to the -2578A/A genotype, patients with early stage OA had a higher odds ratio than those with advanced stage OA (P = 0.023). CONCLUSIONS: VEGFA -2578C/A (rs699947), -1154G/A (rs1570360), -634C/G (rs2010963), and +936C/T (rs3025039) polymorphisms may not be responsible for OA susceptibility in the Thai population. However, the OA patients with A/A genotype at the -2578C/A seemed to have a lower potential risk of developing severe OA than those with the C/A and C/C genotypes. These findings would help elucidate and facilitate a better understanding of the genetic fundamentals of OA.

Telomere Shortening and Increased Oxidative Stress in Lumbar Disc Degeneration.

Lumbar disc degeneration (LDD) contributes to low back pain. This study aimed to determine relative telomere length (RTL), oxidative stress status, and antioxidant levels and examine the relationships between RTL, oxidative stress, and the severity in LDD patients. A total of 100 subjects, 50 LDD patients and 50 healthy controls, were enrolled in the case−control study. Blood leukocyte RTL was analyzed using quantitative real-time polymerase chain reaction. Lipid peroxidation was determined by malondialdehyde (MDA) assay. Plasma 8-hydroxy 2'-deoxyguanosine (8-OHdG) values were determined using enzyme-linked immunosorbent assay. Total antioxidant capacity (TAC) and ferric reducing antioxidant power (FRAP) in plasma were also measured. The LDD patients had significantly shorter telomeres than the healthy controls (p = 0.04). Blood leukocyte RTL was inversely correlated with the LDD severity (r = −0.41, p = 0.005). Additionally, plasma MDA and 8-OHdG levels were markedly greater in LDD patients than in the controls (p = 0.01 and p = 0.002, respectively). Furthermore, the plasma MDA level showed a positive correlation with the radiographic severity (r = 0.49, p = 0.001). There was a positive correlation between plasma 8-OHdG and the severity (r = 0.60, p < 0.001). Moreover, plasma TAC and FRAP levels were significantly lower in LDD patients than in the controls (p = 0.04). No significant differences in plasma TAC and FRAP were observed among the three groups of LDD severity. We found that RTL was negatively correlated with the severity while plasma MDA and 8-OHdG levels were positively correlated with the severity. These findings suggest that blood leukocyte RTL, plasma MDA, and 8-OHdG may have potential as noninvasive biomarkers for the assessment of severity in LDD.

Comparison of the reactogenicity and immunogenicity of a reduced and standard booster dose of the mRNA COVID-19 vaccine in healthy adults after two doses of inactivated vaccine.

The coronavirus disease 2019 (COVID-19) pandemic has been a serious healthcare problem worldwide since December 2019. The third dose of heterologous vaccine was recently approved by World Health Organization. The present study compared the reactogenicity and immunogenicity of the reduced and standard third booster dose of the BNT162b2 and mRNA-1273 vaccine in adults who previously received the two-dose CoronaVac vaccine. Results showed that headache, joint pain, and diarrhea were more frequent in the 15 µg- than the 30 µg-BNT162b2 groups, whereas joint pain and chilling were more frequent in the 100 µg- than the 50 µg-mRNA-1273 groups. No significant differences in immunogenicity were detected. These findings demonstrate that the reduced dose of the mRNA vaccines elicited antibody responses against the SARS-CoV-2 delta and omicron variants that were comparable to the standard dose. The reduced dose could be used to increase vaccine coverage in situations of limited global vaccine supply.

Persistence of immunity against Omicron BA.1 and BA.2 variants following homologous and heterologous COVID-19 booster vaccines in healthy adults after a two-dose AZD1222 vaccination.

OBJECTIVES: The SARS-CoV-2 Omicron variant presents numerous mutations potentially able to evade neutralizing antibodies (NAbs) elicited by COVID-19 vaccines. Therefore, this study aimed to provide evidence on a heterologous booster strategy to overcome the waning immunity against Omicron variants. METHODS: Participants who completed the Oxford/AstraZeneca (hereafter AZD1222) vaccine dose for 5-7 months were enrolled. The reactogenicity and persistence of immunogenicity in both humoral and cellular response after a homologous or heterologous booster with the AZD1222 and messenger RNA (mRNA) vaccines (BNT162b2, full, or half-dose mRNA-1273) administered 6 months after primary vaccination were determined. RESULTS: A total of 229 individuals enrolled, and waning of immunity was observed 5-7 months after the AZD1222-primed vaccinations. Total receptor-binding domain (RBD) immunoglobulin (Ig) levels, anti-RBD IgG, and focus reduction neutralization test against Omicron BA.1 and BA.2 variants and T cell response peaked at 14-28 days after booster vaccination. Both the full and half dose of mRNA-1273 induced the highest response, followed by BNT162b2 and AZD1222. At 90 days, the persistence of immunogenicity was observed among all mRNA-boosted individuals. Adverse events were acceptable for all vaccines. CONCLUSION: A heterologous mRNA booster provided a significantly superior boost of binding and NAbs levels against the Omicron variant compared with a homologous booster in individuals with AZD1222-primed vaccinations.

Clusterin exacerbates interleukin-1ß-induced inflammation via suppressing PI3K/Akt pathway in human fibroblast-like synoviocytes of knee osteoarthritis.

This study aimed to examine, a multifaceted chaperon-like protein exerting anti-inflammatory action, clusterin (CLU), mRNA and protein levels in the systemic and local joint environment of knee osteoarthritis (OA) patients and to determine whether CLU inhibited interleukin (IL)-1ß-induced inflammation in knee OA fibroblast-like synoviocytes (FLSs) through modulating phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway. CLU protein and mRNA expressions in the synovium and its protein levels in plasma and synovial fluid of knee OA patients were measured using immunohistochemistry, real-time PCR, and ELISA, respectively. Anti-inflammatory effect of CLU was further elucidated in knee OA FLSs treated with IL-1ß in the absence or presence of CLU, CLU alone, or PI3K inhibitor (LY294002) along with IL-1ß and CLU. In a clinical study, compared with knee OA patients without synovitis, CLU protein and mRNA were expressed in the synovium of knee OA patients with synovitis, especially those with high-grade, consistent with analyses of its plasma and synovial fluid levels. CLU mRNA and protein levels were both associated with synovitis severity. An in vitro study uncovered that CLU significantly alleviated IL-1ß-induced overproduction of nitric oxide and IL-6 in knee OA FLSs. Furthermore, CLU significantly attenuated inflammation and extracellular matrix degradation induced by IL-1ß via down-regulating expressions of IL-6, nuclear factor kappa B, and matrix metalloproteinase-13. Mechanistically, CLU significantly impeded IL-1ß-induced Akt phosphorylation in knee OA FLSs, in line with addition of LY294002 along with IL-1ß and CLU. These findings suggest that CLU may have potential as a novel therapeutic target for synovitis and cartilage destruction in knee OA.