This study was conducted to evaluate how sterubin affects rotenone-induced Parkinson's disease (PD) in rats. A total of 24 rats were distributed into 4 equal groups: normal saline control and rotenone control were administered saline or rotenone (ROT), respectively, orally; sterubin 10 received ROT + sterubin 10 mg/kg po; and sterubin alone was administered to the test group (10 mg/kg). Rats of the normal saline and sterubin alone groups received sunflower oil injection (sc) daily, 1 h after receiving the treatments cited above, while rats of the other groups received rotenone injection (0.5 mg/kg, sc). The treatment was continued over the course of 28 days daily. On the 29th day, catalepsy and akinesia were assessed. The rats were then euthanized, and the brain was extracted for estimation of endogenous antioxidants (MDA: malondialdehyde, GSH: reduced glutathione, CAT: catalase, SOD: superoxide dismutase), nitrative (nitrite) stress markers, neuroinflammatory cytokines, and neurotransmitter levels and their metabolites (3,4-dihydroxyphenylacetic acid (DOPAC), dopamine (DA), norepinephrine (NE), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA)). Akinesia and catatonia caused by ROT reduced the levels of endogenous antioxidants (GSH, CAT, and SOD), elevated the MDA level, and altered the levels of nitrites, neurotransmitters, and their metabolites. Sterubin restored the neurobehavioral deficits, oxidative stress, and metabolites of altered neurotransmitters caused by ROT. Results demonstrated the anti-Parkinson's activities of sterubin in ROT-treated rats. rotenoneinduced induced Parkinsons Parkinson s PD (PD 2 ROT, , (ROT) respectively orally mgkg mg kg po (1 mg/kg. . mg/kg) sc (sc daily above 0.5 05 0 5 (0. sc. sc) th day assessed euthanized (MDA malondialdehyde GSH glutathione CAT catalase SOD dismutase, dismutase dismutase) nitrite (nitrite markers cytokines 3,4dihydroxyphenylacetic 34dihydroxyphenylacetic dihydroxyphenylacetic 3,4 3 DOPAC, DOPAC (DOPAC) DA, DA (DA) NE, NE (NE) 5HT, 5HT HT (5-HT) 5hydroxyindoleacetic hydroxyindoleacetic 5HIAA, 5HIAA HIAA (5-HIAA) HVA. HVA (HVA)) GSH, (GSH SOD, SOD) level nitrites deficits antiParkinsons anti ROTtreated treated (ROT ( 0. (0 4dihydroxyphenylacetic 34 3, (DOPAC (DA (NE (5-HT (5-HIAA (HVA) (HVA

The treatment of arterial hypertension (AH) contributes to the reduction of morbidity and mortality. Gender differences are likely to play a role, as non-treatment is associated with clinical and sociodemographic aspects. The aim of this study was to investigate the factors associated with non-treatment of AH and gender differences in hypertensive individuals from the ELSA-Brasil cohort. The study was conducted with 5,743 baseline hypertensive cohort participants. AH was considered if there was a previous diagnosis or if systolic blood pressure (SBP) was ≥140 and/or diastolic BP (DBP) was ≥90 mmHg. Sociodemographic and anthropometric data, lifestyle, comorbidities, and use of antihypertensive medications were evaluated through interviews and in-person measurements. Treatment with renin-angiotensin-aldosterone system inhibitors (RAASi) or other antihypertensive medications and non-treatment were evaluated with multivariate logistic regression. Non-treatment was observed in 32.8% of hypertensive individuals. Of the 67.7% treated individuals, 41.1% received RAASi. Non-treatment was associated with alcohol consumption in women (OR=1.41; 95%CI: 1.15-1.73; P=0.001), lowest schooling level in men (OR=1.70; 95%CI: 1.32-2.19; P<0.001), and younger age groups in men and women (strongest association in males aged 35-44 years: OR=4.58, 95%CI: 3.17-6.6, P<0.001). Among those using RAASi, a higher proportion of white, older individuals, and with more comorbidities was observed. The high percentage of non-treatment, even in this civil servant population, indicated the need to improve the treatment cascade for AH. Public health policies should consider giving special attention to gender roles in groups at higher risk of non-treatment to reduce inequities related to AH in Brazil. (AH mortality role nontreatment non aspects ELSABrasil ELSA Brasil 5743 5 743 5,74 participants SBP (SBP 140 ≥14 andor DBP (DBP 90 ≥9 mmHg data lifestyle inperson person measurements reninangiotensinaldosterone renin angiotensin aldosterone RAASi (RAASi regression Nontreatment Non 328 32 8 32.8 677 67 7 67.7 411 41 1 41.1 OR=1.41 OR141 OR (OR=1.41 95%CI 95CI CI 95 1.151.73 115173 1.15 1.73 15 73 1.15-1.73 P=0.001, P0001 P P=0.001 , 0 001 P=0.001) OR=1.70 OR170 70 (OR=1.70 1.322.19 132219 1.32 2.19 2 19 1.32-2.19 P<0.001, P<0.001 P<0.001) strongest 3544 35 44 35-4 years OR458 4 58 OR=4.58 3.176.6, 31766 3.17 6.6, 3 17 6 3.17-6.6 P<0.001. . white nontreatment, treatment, population Brazil 574 74 5,7 14 ≥1 9 ≥ 32. 67. 41. OR=1.4 OR14 (OR=1.4 151 1.151.7 11517 115 1.1 173 1.7 1.15-1.7 P000 P=0.00 00 OR=1.7 OR17 (OR=1.7 322 1.322.1 13221 132 1.3 219 2.1 1.32-2.1 P<0.00 354 35- OR45 OR=4.5 176 3.176.6 3176 317 3.1 66 6.6 3.17-6. 57 5, OR=1. OR1 (OR=1. 1.151. 1151 11 1. 1.15-1. P00 P=0.0 1.322. 1322 13 21 2. 1.32-2. P<0.0 OR4 OR=4. 3.176. 31 3. 6. 3.17-6 OR=1 (OR=1 1.151 1.15-1 P0 P=0. 1.322 1.32-2 P<0. OR=4 3.176 3.17- OR= (OR= 1.15- P=0 1.32- P<0 (OR P= P<

“Penumbra sign” is a characteristic finding in magnetic resonance imaging (MRI) of Brodie's abscess, a rare variant of subacute osteomyelitis. We aimed to discuss the imaging finding penumbra sign that will help in the diagnosis of osteomyelitis and may be useful to clinicians in differential diagnosis. A 26-year-old male patient presented to the emergency department with complaints of pain and limping in the right knee that did not go away. He had a history of arthroscopic debridement and percutaneous fixation surgery due to osteochondral fragment 3 years ago. There were no additional findings in the patient's vital parameters, physical examination, and medical history. X-ray imaging revealed two screws in the distal femur and a well-defined sclerotic rim surrounding a radiolucent lesion anterior to the screws. MRI revealed a lesion in the distal femoral metaphysis with low-density fluid and hyperintense granulation tissue surrounding it. After surgical abscess drainage and local debridement, bone cement was placed in the resulting cavity. Teicoplanin treatment was started. The patient was discharged and complete recovery was achieved in the second month. The diagnosis of osteomyelitis is often missed or confused with bone tumors in non-traumatic cases presenting with persistent bone pain. MRI imaging is frequently used in differential diagnosis, and detection of characteristic imaging signs such as the penumbra sign accelerates the diagnosis. In this context, emergency department clinicians, in particular, should be cautious and not forget that early treatment can be started by recognizing these signs. Penumbra (MRI Brodies Brodie s 26yearold yearold 26 year old away ago patients parameters examination Xray X ray welldefined well defined lowdensity low density it cavity month nontraumatic non traumatic context particular 2

This study aimed to analyze the safety and applicability of a 90-min duration of infusion (SDI) of obinutuzumab in patients with B-cell non-Hodgkin's lymphoma (NHL) in a tertiary hospital in China. This exploratory clinical trial was performed at Jiangsu Province Hospital. All patients were treated with the standard infusion regimen for the first infusion. If no grade ≥3 infusion-related reactions (IRRs) occurred, the subsequent infusions were given as SDI. The primary endpoint was the incidence of IRR during the standard infusion (3-4 h) and 90-min SDI regimens. This study enrolled 208 patients and all completed cycle 1. Forty-one patients (19.71%) had IRRs: five (2.40%) with grade 1, twenty-eight (13.46%) with grade 2, and eight (3.85%) with grade 3. The 41 patients had 71 IRRs, mainly fever (40.85%), chest pain/tightness (12.68%), and dyspnea (9.86%). The occurrence of IRRs in the first infusion was significantly lower in patients who received oral acetaminophen prophylaxis than those who did not (10.72% vs 30.21%, P<0.001). For the subsequent cycles with 90-min SDI, only two (0.25%) IRRs occurred among 814 infusions (one grade 1 hand numbness and one grade 2 chill/fever). The 90-min obinutuzumab SDI might be safe and feasible in patients with B-cell NHL in China. 90min min 90 (SDI Bcell B cell nonHodgkins non Hodgkin s (NHL China Hospital 3 ≥ infusionrelated related (IRRs 34 4 (3- h regimens 20 Fortyone Forty 19.71% 1971 19 (19.71% 2.40% 240 40 (2.40% twentyeight twenty 13.46% 1346 13 46 (13.46% 3.85% 385 85 (3.85% 7 40.85%, 4085 40.85% , (40.85%) paintightness pain tightness 12.68%, 1268 12.68% 12 68 (12.68%) 9.86%. 986 9.86% . 9 86 (9.86%) 10.72% 1072 10 72 (10.72 3021 30 21 30.21% P<0.001. P0001 P P<0.001 0 001 P<0.001) 0.25% 025 25 (0.25% 81 chill/fever. chillfever chill/fever chill chill/fever) (3 19.71 197 (19.71 2.40 24 (2.40 13.46 134 (13.46 3.85 38 8 (3.85 408 40.85 (40.85% 126 12.68 6 (12.68% 98 9.86 (9.86% 10.72 107 (10.7 302 30.21 P000 P<0.00 00 0.25 02 (0.25 ( 19.7 (19.7 2.4 (2.4 13.4 (13.4 3.8 (3.8 40.8 (40.85 12.6 (12.68 9.8 (9.86 10.7 (10. 30.2 P00 P<0.0 0.2 (0.2 19. (19. 2. (2. 13. (13. (3. 40. (40.8 12. (12.6 9. (9.8 10. (10 30. P0 P<0. 0. (0. (19 (2 (13 (40. (12. (9. (1 P<0 (0 (40 (12 (9 P< (4

Abstract The aim of this study was to explore the association between differential percentages of dendritic cell (DC) subsets in peripheral blood and malignancy (grade and lymph node metastasis) of peritoneal adenocarcinoma patients and the frequencies of dendritic cell subsets in the normal controls. The peripheral blood of 30 patients with peritoneal adenocarcinoma and 12 healthy controls were collected for multicolor flow cytometry analysis. Peritoneal adenocarcinoma patients were grouped according to the malignant degree (grade and lymph node metastasis). Percentages of myeloid DCs (mDCs) and its subsets MDC1 and MDC2 in DCs were lower in peripheral blood of patients with peritoneal adenocarcinoma than in normal controls. The percentages of plasmacytoid dendritic cells (pDCs) and CD16+mDCs in DCs were higher than in normal controls. Compared with poor differentiation grade, patients with well/moderate differentiation grade had an increased percentage of CD16+mDCs. Contrary to CD16+mDCs, the percentage of MDC1 was lower in the well/moderate differentiation grade group. In patients with no lymph node metastasis, pDCs and CD16+mDCs levels were higher compared with patients with lymph node metastasis. mDCs and MDC1 levels had opposite results. pDCs were positively correlated with CD16+mDCs in peripheral blood of peritoneal patients, as was mDCs and MDC1. CD16+mDCs were negatively correlated with MDC1. The percentages of pDCs and CD16+mDCs in DCs were positively correlated with CD3+CD8+T cells, and pDCs also positively correlated with CD8+PD-1+T cells. Our results revealed that DCs subsets correlated with peritoneal adenocarcinoma malignancy. Dendritic cells play an independent role in the immune function of peritoneal adenocarcinoma. DC (DC metastasis 3 1 analysis . (mDCs MDC (pDCs CD16mDCs CDmDCs CD16 CD wellmoderate well moderate group CD3CD8T CDCDT CD3 CD8 T CD8+PD1+T CD8PD1T CDPDT CD8+PD 1+T PD CD1 PD1 CD8PD CDPD 1T

Abstract The cure rates for osteosarcoma have remained unchanged in the past three decades, especially for patients with pulmonary metastasis. Thus, a new and effective treatment for metastatic osteosarcoma is urgently needed. Anlotinib has been reported to have antitumor effects on advanced osteosarcoma. However, both the effect of anlotinib on autophagy in osteosarcoma and the mechanism of anlotinib-mediated autophagy in pulmonary metastasis are unclear. The effect of anlotinib treatment on the metastasis of osteosarcoma was investigated by transwell assays, wound healing assays, and animal experiments. Related proteins were detected by western blotting after anlotinib treatment, ATG5 silencing, or ATG5 overexpression. Immunofluorescence staining and transmission electron microscopy were used to detect alterations in autophagy and the cytoskeleton. Anlotinib inhibited the migration and invasion of osteosarcoma cells but promoted autophagy and increased ATG5 expression. Furthermore, the decreases in invasion and migration induced by anlotinib treatment were enhanced by ATG5 silencing. In addition, Y-27632 inhibited cytoskeletal rearrangement, which was rescued by ATG5 overexpression. ATG5 overexpression enhanced epithelial-mesenchymal transition (EMT). Mechanistically, anlotinib-induced autophagy promoted migration and invasion by activating EMT and cytoskeletal rearrangement through ATG5 both in vitro and in vivo. Our results demonstrated that anlotinib can induce protective autophagy in osteosarcoma cells and that inhibition of anlotinib-induced autophagy enhanced the inhibitory effects of anlotinib on osteosarcoma metastasis. Thus, the therapeutic effect of anlotinib treatment can be improved by combination treatment with autophagy inhibitors, which provides a new direction for the treatment of metastatic osteosarcoma. decades Thus needed However anlotinibmediated mediated unclear assays experiments ATG silencing cytoskeleton expression Furthermore addition Y27632 Y 27632 Y-2763 epithelialmesenchymal epithelial mesenchymal EMT. . (EMT) Mechanistically anlotinibinduced vivo inhibitors Y2763 2763 Y-276 (EMT Y276 276 Y-27 Y27 27 Y-2 Y2 2 Y-

Abstract The aim of this study was to evaluate the association between diabetes and cognitive performance in a nationally representative study in Brazil. We also aimed to investigate the interaction between frailty and diabetes on cognitive performance. A cross-sectional analysis of the Brazilian Longitudinal Study of Aging (ELSI-Brazil) baseline data that included adults aged 50 years and older was conducted. Linear regression models were used to study the association between diabetes and cognitive performance. A total of 8,149 participants were included, and a subgroup analysis was performed in 1,768 with hemoglobin A1c data. Diabetes and hemoglobin A1c levels were not associated with cognitive performance. Interaction of hemoglobin A1c levels with frailty status was found on global cognitive z-score (P-value for interaction=0.038). These results suggested an association between higher hemoglobin A1c levels and lower cognitive performance only in non-frail participants. Additionally, undiagnosed diabetes with higher hemoglobin A1c levels was associated with both poor global cognitive (β=-0.36; 95%CI: -0.62; -0.10, P=0.008) and semantic verbal fluency performance (β=-0.47; 95%CI: -0.73; -0.21, P=0.001). In conclusion, higher hemoglobin A1c levels were associated with lower cognitive performance among non-frail participants. Higher hemoglobin A1c levels without a previous diagnosis of diabetes were also related to poor cognitive performance. Future longitudinal analyses of the ELSI-Brazil study will provide further information on the role of frailty in the association of diabetes and glycemic control with cognitive decline. Brazil crosssectional cross sectional ELSIBrazil ELSI (ELSI-Brazil 5 conducted 8149 8 149 8,14 1768 1 768 1,76 Ac c zscore z score Pvalue P value interaction=0.038. interaction0038 interaction=0.038 . 0 038 interaction=0.038) nonfrail non frail Additionally β=0.36 β036 β β= 0.36 36 (β=-0.36 95%CI 95CI CI 95 0.62 062 62 -0.62 0.10, 010 10 -0.10 P=0.008 P0008 008 β=0.47 β047 0.47 47 (β=-0.47 0.73 073 73 -0.73 0.21, 021 21 -0.21 P=0.001. P0001 P=0.001 001 P=0.001) conclusion decline 814 14 8,1 176 76 1,7 interaction003 interaction=0.03 03 β=0.3 β03 036 0.3 3 (β=-0.3 9 0.6 06 6 -0.6 0.10 01 -0.1 P=0.00 P000 00 β=0.4 β04 047 0.4 4 (β=-0.4 0.7 07 7 -0.7 0.21 02 2 -0.2 81 8, 17 1, interaction00 interaction=0.0 β=0. β0 0. (β=-0. -0. 0.1 P=0.0 P00 04 0.2 interaction0 interaction=0. β=0 (β=-0 -0 P=0. P0 interaction=0 (β=- - P=0 interaction= (β= P= (β

Abstract The incidence of non-alcoholic fatty liver (NAFLD) remains high, and many NAFLD patients suffer from severe ischemia-reperfusion injury (IRI). Currently, no practical approach can be used to treat IRI. Puerarin plays a vital role in treating multiple diseases, such as NAFLD, stroke, diabetes, and high blood pressure. However, its role in the IRI of the fatty liver is still unclear. We aimed to explore whether puerarin could protect the fatty liver from IRI. C57BL/6J mice were fed with a high‐fat diet (HFD) followed by ischemia reperfusion injury. We showed that hepatic IRI was more severe in the fatty liver compared with the normal liver, and puerarin could significantly protect the fatty liver against IRI and alleviate oxidative stress. The PI3K-AKT signaling pathway was activated during IRI, while liver steatosis decreased the level of activation. Puerarin significantly protected the fatty liver from IRI by reactivating the PI3K-AKT signaling pathway. However, LY294002, a PI3K-AKT inhibitor, attenuated the protective effect of puerarin. In conclusion, puerarin could significantly protect the fatty liver against IRI by activating the PI3K-AKT signaling pathway. nonalcoholic non alcoholic (NAFLD ischemiareperfusion . (IRI) Currently diseases stroke diabetes pressure However unclear C57BL6J CBLJ C57BL 6J C BL J highfat fat HFD (HFD stress PI3KAKT PIKAKT PI3K AKT PI K activation LY294002 LY inhibitor conclusion (IRI CBL KAKT PIK LY29400 LY2940 LY294 LY29 LY2

Abstract MCH1 is a synthetic macamide that has shown in vitro inhibitory activity on fatty acid amide hydrolase (FAAH), an enzyme responsible for endocannabinoid metabolism. This inhibition can modulate endocannabinoid and dopamine signaling in the nucleus accumbens (NAc), potentially having an antidepressant-like effect. The present study aimed to evaluate the effect of the in vivo administration of MCH1 (3, 10, and 30 mg/kg, ip) in 2-month-old BALB/c male mice (n=97) on forced swimming test (FST), light-dark box (LDB), and open field test (OFT) and on early gene expression changes 2 h after drug injection related to the endocannabinoid system (Cnr1 and Faah) and dopaminergic signaling (Drd1 and Drd2) in the NAc core. We found that the 10 mg/kg MCH1 dose reduced the immobility time compared to the vehicle group in the FST with no effect on anxiety-like behaviors measured in the LDB or OFT. However, a 10 mg/kg MCH1 dose increased locomotor activity in the OFT compared to the vehicle. Moreover, RT-qPCR results showed that the 30 mg/kg MCH1 dose increased Faah gene expression by 2.8-fold, and 10 mg/kg MCH1 increased the Cnr1 gene expression by 4.3-fold compared to the vehicle. No changes were observed in the expression of the Drd1 and Drd2 genes in the NAc at either MCH1 dose. These results indicated that MCH1 might have an antidepressant-like effect without an anxiogenic effect and induces significant changes in endocannabinoid-related genes but not in genes of the dopaminergic signaling system in the NAc of mice. MCH FAAH, FAAH , (FAAH) metabolism NAc, (NAc) antidepressantlike antidepressant like 3, 3 (3 mgkg mg kg ip 2monthold monthold month old BALBc BALB c n=97 n97 n 97 (n=97 FST, (FST) lightdark light dark LDB, (LDB) (OFT Cnr (Cnr Drd (Drd core 1 anxietylike anxiety However Moreover RTqPCR RT qPCR 2.8fold, 28fold fold 2.8 fold, 8 2.8-fold 4.3fold 43fold 4.3 4 endocannabinoidrelated (FAAH (NAc ( n=9 n9 9 (n=9 (FST (LDB 8fold 2.8fold 28 2. 3fold 43 4. n= (n= (n

Abstract Bone regeneration is crucial for repairing bone tissue following various injuries. Research techniques that enable the study of metabolic changes in bone tissue under different conditions are important for understanding bone repair and remodeling. This study used bone scintigraphy to evaluate osteogenesis secondary to osteotomy in a preclinical model of New Zealand rabbits. For this purpose, we conducted a longitudinal, prospective, case-control study in which scintigraphic variables were measured in both the right forearm (case-operated) and the left forearm (control - non-operated). The study sample consisted of 10 rabbits subjected to osteotomy, followed by a 12-week postoperative evaluation period, divided into six imaging stages at 1, 2, 3, 4, 8, and 12 weeks. We observed that the operated forearm showed significantly higher external radiation than the control side, using the pinhole collimator, denoting an increase in the biodistribution and tropism of the radiopharmaceutical to the operated forearm. Among the three evaluated time points, osteoblastic activity was highest in the second week and presented a significant decline in the 8th and 12th weeks, denoting regeneration and resolution of the surgical injury; the control forearm was also influenced by the inactivity imposed by the operated forearm. This fact was notably evidenced by the reduction in the metabolic activity of osteoblasts in the left forearm. Our study suggested that bone scintigraphy was sensitive enough to semi-quantitatively differentiate the metabolic activity of osteoblasts in the operated forearm in the three temporal landmarks evaluated in the study. injuries remodeling purpose longitudinal prospective casecontrol case caseoperated (case-operated nonoperated. nonoperated non . non-operated) 1 12week period 2 3 4 8 weeks side collimator points th injury semiquantitatively semi quantitatively non-operated

Abstract The imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophages plays a critical role in the pathogenesis of sepsis-induced acute lung injury (ALI). Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may modulate macrophage polarization toward the M2 phenotype by altering mitochondrial activity. This study aimed to investigate the role of the PGC-1α agonist pioglitazone (PGZ) in modulating sepsis-induced ALI. A mouse model of sepsis-induced ALI was established using cecal ligation and puncture (CLP). An in vitro model was created by stimulating MH-S cells with lipopolysaccharide (LPS). qRT-PCR was used to measure mRNA levels of M1 markers iNOS and MHC-II and M2 markers Arg1 and CD206 to evaluate macrophage polarization. Western blotting detected expression of peroxisome proliferator-activated receptor gamma (PPARγ) PGC-1α, and mitochondrial biogenesis proteins NRF1, NRF2, and mtTFA. To assess mitochondrial content and function, reactive oxygen species levels were detected by dihydroethidium staining, and mitochondrial DNA copy number was measured by qRT-PCR. In the CLP-induced ALI mouse model, lung tissues exhibited reduced PGC-1α expression. PGZ treatment rescued PGC-1α expression and alleviated lung injury, as evidenced by decreased lung wet-to-dry weight ratio, pro-inflammatory cytokine secretion (tumor necrosis factor-α, interleukin-1β, interleukin-6), and enhanced M2 macrophage polarization. Mechanistic investigations revealed that PGZ activated the PPARγ/PGC-1α/mitochondrial protection pathway to prevent sepsis-induced ALI by inhibiting M1 macrophage polarization. These results may provide new insights and evidence for developing PGZ as a potential ALI therapy. proinflammatory pro inflammatory M antiinflammatory anti sepsisinduced sepsis induced . (ALI) proliferatoractivated proliferator 1alpha alpha 1 PGC1α PGCα PGC 1α α (PGC-1α activity (PGZ CLP. CLP (CLP) MHS MH S LPS. LPS (LPS) qRTPCR qRT PCR MHCII MHC II Arg CD CD20 PPARγ (PPARγ PGC1α, 1α, NRF1 NRF NRF2 mtTFA function staining qRTPCR. PCR. CLPinduced wettodry wet dry ratio tumor factorα, factorα factor α, factor-α interleukin1β, interleukin1β interleukinβ interleukin 1β, 1β β interleukin-1β interleukin6, interleukin6 6 , interleukin-6) PPARγ/PGC1α/mitochondrial PPARγPGC1αmitochondrial PPARγPGCαmitochondrial PPARγ/PGC 1α/mitochondrial therapy (ALI (CLP (LPS CD2 interleukin-6 PPARγPGC αmitochondrial 1αmitochondrial interleukin-

Abstract The incidences of periodontitis and osteoporosis are rising worldwide. Observational studies have shown that periodontitis is associated with increased risk of osteoporosis. We performed a Mendelian randomization (MR) study to genetically investigate the causality of periodontitis on osteoporosis. We explored the causal effect of periodontitis on osteoporosis by MR analysis. A total of 9 single nucleotide polymorphisms (SNP) were related to periodontitis. The primary approach in this MR analysis was the inverse variance-weighted (IVW) method. Simple median, weighted median, and penalized weighted median were used to analyze sensitivity. The fixed-effect IVW model and random-effect IVW model showed no significant causal effect of genetically predicted periodontitis on the risk of osteoporosis (OR=1.032; 95%CI: 0.923-1.153; P=0.574; OR=1.032; 95%CI: 0.920-1.158; P=0.588, respectively). Similar results were observed in simple mode (OR=1.031; 95%CI: 0.780-1.361, P=0.835), weighted mode (OR=1.120; 95%CI: 0.944-1.328, P=0.229), simple median (OR=1.003; 95%CI: 0.839-1.197, P=0.977), weighted median (OR=1.078; 95%CI: 0.921-1.262, P=0.346), penalized weight median (OR 1.078; 95%CI: 0.919-1.264, P=0.351), and MR-Egger method (OR=1.360; 95%CI: 0.998-1.853, P=0.092). There was no heterogeneity in the IVW and MR-Egger analyses (Q=7.454, P=0.489 and Q=3.901, P=0.791, respectively). MR-Egger regression revealed no evidence of a pleiotropic influence through genetic variants (intercept: -0.004; P=0.101). The leave-one-out sensitivity analysis indicated no driven influence of any individual SNP on the association between periodontitis and osteoporosis. The Mendelian randomization analysis did not show a significant detrimental effect of periodontitis on the risk of osteoporosis. worldwide (MR (SNP varianceweighted variance (IVW fixedeffect fixed randomeffect random OR=1.032 OR1032 OR 1 032 (OR=1.032 95%CI 95CI CI 95 0.9231.153 09231153 0.923 1.153 0 923 153 0.923-1.153 P=0.574 P0574 P 574 0.9201.158 09201158 0.920 1.158 920 158 0.920-1.158 P0588 588 P=0.588 respectively. respectively . respectively) OR=1.031 OR1031 031 (OR=1.031 0.7801.361, 07801361 0.780 1.361, 780 361 0.780-1.361 P=0.835, P0835 P=0.835 , 835 P=0.835) OR=1.120 OR1120 120 (OR=1.120 0.9441.328, 09441328 0.944 1.328, 944 328 0.944-1.328 P=0.229, P0229 P=0.229 229 P=0.229) OR=1.003 OR1003 003 (OR=1.003 0.8391.197, 08391197 0.839 1.197, 839 197 0.839-1.197 P=0.977, P0977 P=0.977 977 P=0.977) OR=1.078 OR1078 078 (OR=1.078 0.9211.262, 09211262 0.921 1.262, 921 262 0.921-1.262 P=0.346, P0346 P=0.346 346 P=0.346) 1.078 1078 0.9191.264, 09191264 0.919 1.264, 919 264 0.919-1.264 P=0.351, P0351 P=0.351 351 P=0.351) MREgger Egger OR=1.360 OR1360 360 (OR=1.360 0.9981.853, 09981853 0.998 1.853, 998 853 0.998-1.853 P=0.092. P0092 P=0.092 092 P=0.092) Q=7.454, Q7454 Q 7 454 (Q=7.454 P0489 489 P=0.48 Q3901 3 901 Q=3.901 P0791 791 P=0.791 intercept (intercept 0.004 0004 004 -0.004 P=0.101. P0101 P=0.101 101 P=0.101) leaveoneout leave one out OR=1.03 OR103 03 (OR=1.03 9231 0.9231.15 0923115 0923 0.92 1153 1.15 92 15 0.923-1.15 P=0.57 P057 57 9201 0.9201.15 0920115 0920 1158 0.920-1.15 P058 58 P=0.58 7801 0.7801.361 0780136 0780 0.78 1361 1.361 78 36 0.780-1.36 P083 P=0.83 83 OR=1.12 OR112 12 (OR=1.12 9441 0.9441.328 0944132 0944 0.94 1328 1.328 94 32 0.944-1.32 P022 P=0.22 22 OR=1.00 OR100 00 (OR=1.00 8391 0.8391.197 0839119 0839 0.83 1197 1.197 19 0.839-1.19 P097 P=0.97 97 OR=1.07 OR107 07 (OR=1.07 9211 0.9211.262 0921126 0921 1262 1.262 26 0.921-1.26 P034 P=0.34 34 1.07 107 9191 0.9191.264 0919126 0919 0.91 1264 1.264 91 0.919-1.26 P035 P=0.35 35 OR=1.36 OR136 (OR=1.36 9981 0.9981.853 0998185 0998 0.99 1853 1.853 99 85 0.998-1.85 P009 P=0.09 09 Q=7.454 Q745 45 (Q=7.45 P048 48 P=0.4 Q390 90 Q=3.90 P079 79 P=0.79 0.00 000 -0.00 P010 P=0.10 10 OR=1.0 OR10 (OR=1.0 0.9231.1 092311 0.9 115 1.1 0.923-1.1 P=0.5 P05 5 0.9201.1 092011 0.920-1.1 0.7801.36 078013 0.7 136 1.36 0.780-1.3 P08 P=0.8 8 OR=1.1 OR11 (OR=1.1 0.9441.32 094413 094 132 1.32 0.944-1.3 P02 P=0.2 2 0.8391.19 083911 083 0.8 119 1.19 0.839-1.1 P09 P=0.9 0.9211.26 092112 126 1.26 0.921-1.2 P03 P=0.3 1.0 0.9191.26 091912 091 0.919-1.2 OR=1.3 OR13 (OR=1.3 0.9981.85 099818 099 185 1.85 0.998-1.8 P00 P=0.0 Q=7.45 Q74 4 (Q=7.4 P04 P=0. Q39 Q=3.9 P07 P=0.7 0.0 -0.0 P01 P=0.1 OR=1. OR1 (OR=1. 0.9231. 09231 0. 11 1. 0.923-1. P0 0.9201. 09201 0.920-1. 0.7801.3 07801 13 1.3 0.780-1. 0.9441.3 09441 0.944-1. 0.8391.1 08391 08 0.839-1. 0.9211.2 09211 1.2 0.921-1. 0.9191.2 09191 0.919-1. 0.9981.8 09981 18 1.8 0.998-1. Q=7.4 Q7 (Q=7. P=0 Q3 Q=3. -0. OR=1 (OR=1 0.9231 0.923-1 0.9201 0.920-1 0.7801. 0.780-1 0.9441. 0.944-1 0.8391. 0.839-1 0.9211. 0.921-1 0.9191. 0.919-1 0.9981. 0.998-1 Q=7. (Q=7 P= Q=3 -0 OR= (OR= 0.923- 0.920- 0.7801 0.780- 0.9441 0.944- 0.8391 0.839- 0.9211 0.921- 0.9191 0.919- 0.9981 0.998- Q=7 (Q= Q= - (Q

Abstract Autophagy-related gene (ATG) 5 regulates blood lipids, chronic inflammation, CD4+ T-cell differentiation, and neuronal death and is involved in post-stroke cognitive impairment. This study aimed to explore the correlation of serum ATG5 with CD4+ T cells and cognition impairment in stroke patients. Peripheral blood was collected from 180 stroke patients for serum ATG5 and T helper (Th) 1, Th2, Th17, and regulatory T (Treg) cell detection via enzyme-linked immunosorbent assays and flow cytometry. The Mini-Mental State Examination (MMSE) scale was completed at enrollment, year (Y)1, Y2, and Y3 in stroke patients. Serum ATG5 was also measured in 50 healthy controls (HCs). Serum ATG5 was elevated in stroke patients compared to HCs (P<0.001) and was positively correlated to Th2 cells (P=0.022), Th17 cells (P<0.001), and Th17/Treg ratio (P<0.001) in stroke patients but not correlated with Th1 cells, Th1/Th2 ratio, or Treg cells (all P>0.050). Serum ATG5 (P=0.037), Th1 cells (P=0.022), Th17 cells (P=0.002), and Th17/Treg ratio (P=0.018) were elevated in stroke patients with MMSE score-identified cognition impairment vs those without cognition impairment, whereas Th2 cells, Th1/Th2 ratio, and Treg cells were not different between them (all P>0.050). Importantly, serum ATG5 was negatively linked with MMSE score at enrollment (P=0.004), Y1 (P=0.002), Y2 (P=0.014), and Y3 (P=0.001); moreover, it was positively related to 2-year (P=0.024) and 3-year (P=0.012) MMSE score decline in stroke patients. Serum ATG5 was positively correlated with Th2 and Th17 cells and estimated cognitive function decline in stroke patients. Autophagyrelated Autophagy ATG (ATG lipids inflammation CD4 CD Tcell differentiation poststroke post 18 Th (Th 1 (Treg enzymelinked enzyme cytometry MiniMental Mini Mental (MMSE Y1, Y (Y)1 HCs. . (HCs) P<0.001 P0001 P 0 001 (P<0.001 P=0.022, P0022 P=0.022 , 022 (P=0.022) P<0.001, Th17Treg ThTreg Th1Th2 ThTh Th1/Th all P>0.050. P0050 P>0.050 050 P>0.050) P=0.037, P0037 P=0.037 037 (P=0.037) P=0.002, P0002 P=0.002 002 (P=0.002) P=0.018 P0018 018 (P=0.018 scoreidentified identified Importantly P=0.004, P0004 P=0.004 004 (P=0.004) P=0.014, P0014 P=0.014 014 (P=0.014) P=0.001 (P=0.001) moreover 2year 2 P=0.024 P0024 024 (P=0.024 3year 3 P=0.012 P0012 012 (P=0.012 (Y) (HCs P<0.00 P000 00 (P<0.00 P002 P=0.02 02 (P=0.022 Th1Th P005 P>0.05 05 P003 P=0.03 03 (P=0.037 P=0.00 (P=0.002 P=0.01 P001 01 (P=0.01 (P=0.004 (P=0.014 (P=0.001 (P=0.02 (Y P<0.0 P00 (P<0.0 P=0.0 P>0.0 (P=0.03 (P=0.00 (P=0.0 P<0. P0 (P<0. P=0. P>0. (P=0. P<0 (P<0 P=0 P>0 (P=0 P< (P< P= P> (P= (P

Abstract The complex pathogenesis of castration-resistant prostate cancer (CRPC) makes it challenging to identify effective treatment methods. Matrix metalloproteinase (MMP)-12 can degrade elastin as well as various extracellular matrix (ECM) components, which is associated with cancer progression. However, the relationship between MMP-12 and CRPC progression is poorly understood. In this study, we observed the effect of MMP-12 on the progression of CRPC and further explored its potential mechanism of action. High levels of MMP-12 were observed in patients with CRPC. We therefore developed cell co-culture and mouse models to study the function of MMP-12. Silencing MMP-12 in CRPC cells disrupted lipid utilization and autophagy marker expression via the CD36/CPT1 and P62/LC3 pathways, respectively, leading to reduced CRPC cell migration and invasion. Moreover, animal experiments confirmed that MMP-12-knockdown CRPC xenograft tumors exhibited reduced tumor growth, and the mechanisms involved the promotion of cancer cell autophagy and the inhibition of lipid catabolism. According to our results, MMP-12 played important roles in the progression of CRPC by disrupting adipocyte maturation and regulating cancer migration and invasion via the modulation of autophagy and lipid catabolism pathways. castrationresistant castration resistant (CRPC methods MMP12 MMP 12 (MMP)-1 ECM (ECM components However MMP-1 understood action coculture co culture MMP12. 12. CD36CPT1 CDCPT CD36 CPT1 CD CPT CD36/CPT P62LC3 PLC P62 LC3 P LC P62/LC pathways respectively Moreover MMP12knockdown MMPknockdown knockdown growth results MMP1 1 (MMP)- MMP- CD36CPT CD3 P62LC P6 (MMP) (MMP

There's limited evidence of the potential benefits of cardiopulmonary and metabolic rehabilitation (CPMR) in patients with heart failure with preserved ejection fraction (HFpEF) or mildly reduced ejection fraction (HFmrEF) and coronary artery disease (CAD). The aim of this study was to investigate the impact of CPMR on the myocardial ischemia response (MIR), exercise-induced arrhythmias (EIA), New York Heart Association (NYHA) functional class, heart rate recovery (HRR), Borg CR10 perceived symptoms, and the SF-36 physical and mental health summary scores. A prospective cohort study was conducted with 106 patients undergoing 12 weeks of CPMR who completed two exercise tests pre- and post-CPMR: 1) maximum incremental test (CPX) and 2) submaximal constant load test (SUB). After CPMR, the effects on MIR, EIA, NYHA functional class, and HRR during both tests were analyzed. There was a significant change in NYHA functional classes after CPMR, with 96% of the patients in class I (vs 62% pre-CPMR, P<0.0001), 4% in class II (vs 32%), and none in class III (vs 6%). There was a significant reduction in the frequency of EIA (P<0.05) and MIR (P<0.001) and a significantly improved performance on both CPX and SUB tests (P<0.0001). Lastly, there was significant progress in the recovery metrics like HRR (P<0.0001), the Borg CR10 (P<0.0001), and the SF-36 summary scores (P<0.0001). The CPMR resulted in a significant decrease in EIA, delayed ischemia threshold in CPX and SUB tests, increased functional capacity, and improved quality of life. Theres s (CPMR HFpEF (HFpEF HFmrEF (HFmrEF CAD. CAD . (CAD) , (MIR) exerciseinduced induced (EIA) (NYHA HRR, (HRR) CR CR1 symptoms SF36 SF 36 SF-3 10 1 pre postCPMR post post-CPMR (CPX 2 SUB. (SUB) analyzed 96 vs 62 preCPMR, preCPMR pre-CPMR P<0.0001, P00001 P P<0.0001 0 0001 P<0.0001) 4 32%, 32 32% 32%) 6%. 6 6% 6%) P<0.05 P005 05 (P<0.05 P<0.001 P0001 001 (P<0.001 P<0.0001. (P<0.0001) Lastly capacity life (CAD (MIR (EIA (HRR SF3 3 SF- (SUB 9 P0000 P<0.000 000 P<0.0 P00 (P<0.0 P<0.00 P000 00 (P<0.00 (P<0.0001 P<0. P0 (P<0. (P<0.000 P<0 (P<0 P< (P< (P