Synthesis and Evaluation of Chloride-Substituted Ramalin Derivatives for Alzheimer's Disease Treatment.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid-beta plaques and hyperphosphorylated tau proteins, leading to cognitive decline and neuronal death. However, despite extensive research, there are still no effective treatments for this condition. In this study, a series of chloride-substituted Ramalin derivatives is synthesized to optimize their antioxidant, anti-inflammatory, and their potential to target key pathological features of Alzheimer's disease. The effect of the chloride position on these properties is investigated, specifically examining the potential of these derivatives to inhibit tau aggregation and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) activity. Our findings demonstrate that several derivatives, particularly RA-3Cl, RA-4Cl, RA-26Cl, RA-34Cl, and RA-35Cl, significantly inhibit tau aggregation with inhibition rates of approximately 50%. For BACE-1 inhibition, Ramalin and RA-4Cl also significantly decrease BACE-1 expression in N2a cells by 40% and 38%, respectively, while RA-23Cl and RA-24Cl showed inhibition rates of 30% and 35% in SH-SY5Y cells. These results suggest that chloride-substituted Ramalin derivatives possess promising multifunctional properties for AD treatment, warranting further investigation and optimization for clinical applications.

Relationship Between Revision Rate, Osteoarthritis, and Obesity for ACL Reconstruction: A Nationwide Retrospective Cohort Study.

Background: The long-term goal of anterior cruciate ligament (ACL) reconstruction is to prevent secondary osteoarthritis due to instability. Obesity itself is also a risk factor for osteoarthritis and shows an increase in its incidence, but little is known about the relationship between obesity and the outcome of ACL reconstruction. Purpose/Hypothesis: This study aimed to determine the relationship between the outcome of ACL reconstruction and obesity. It was hypothesized that obesity would be associated with the revision rate of ACL reconstruction and additional surgical treatment for osteoarthritis in patients who undergo ACL reconstruction. Study design: Cohort study; Level of evidence, 3. Methods: Claims and health screening data of the National Health Insurance Service were used to analyze patients who underwent ACL reconstruction between January 1, 2003, and December 31, 2021. The association between obesity and risk of revision ACL reconstruction and additional surgical treatment for osteoarthritis or meniscal lesion was analyzed. Body mass index (BMI) was used to classify patients as underweight (BMI, <18.5), normal weight (BMI, 18.5-24.9), overweight (BMI, 25.0-29.9), obese (BMI, 30.0-39.9), or morbidly obese (BMI, ≥40.0). Multivariable Cox proportional hazards model analysis was conducted. Results: A total of 56,734 patients were included. Of them, 311 (0.5%) patients were underweight, 26,613 (46.9%) were normal weight, 24,372 (43.0%) were overweight, 5324 (9.4%) were obese, and 114 (0.2%) patients were morbidly obese. The underweight group showed a significantly lower risk of revision ACL reconstruction than the normal weight group (hazard ratio [HR], 0.54; 95% CI, 0.31-0.93; P = .0273). However, the overweight, obese, and morbidly obese groups had no significant difference from the normal weight group. The risk of high tibial osteotomy (HTO) or total knee arthroplasty (TKA) was significantly high for the overweight (HR, 1.93; 95% CI, 1.70-2.19; P < .0001) and obese (HR, 2.71; 95% CI, 2.23-3.30; P < .0001) groups. Subgroup analysis performed in patients ≥40 years of age for the risk of HTO showed a significant increased risk in the overweight group (HR, 1.889; 95% CI, 1.56-2.29; P < .0001) and obese group (HR, 2.78; 95% CI, 2.10-3.69; P < .0001). Subgroup analysis performed in patients ≥50 years of age for the risk of TKA also showed a significant increased risk in the overweight group (HR, 2.03; 95% CI, 1.67-2.47; P < .0001) and obese group (HR, 2.53; 95% CI, 1.83-3.50; P < .0001). After adjusting for meniscal injury at index surgery by multivariate regression analysis, 1.87- and 2.75-fold increased risks of HTO were identified for the overweight and obese groups, respectively, for patients aged >40 years. For patients aged >50 years, 2.02-fold and 2.52-fold increased risks of TKA were observed for the overweight and obese groups, respectively. The risk of additional surgery due to the meniscal lesion was high for the overweight (HR, 1.09; 95% CI, 1.03-1.15; P = .002) and obese (HR, 1.10; 95% CI, 1.01-1.21; P = .0351) groups, while no significant difference was found for the underweight and morbidly obese groups. Conclusion: This study highlights that obesity does not increase the revision rate of ACL reconstruction. However, the risk of additional surgical treatment for osteoarthritis and meniscal lesions increased as BMI increased. Further investigation is needed to determine the efficacy of ACL reconstruction for preventing osteoarthritis in obese patients.

Cycloolivil Isolated from Nardostachys jatamansi Inhibits TNF-α/IFN-γ-Induced Chemokine Production by Blocking NF-κB and JAK/STAT Activation in HaCaT Keratinocytes.

Nardostachys jatamansi is widely used as a traditional medicine in Asian countries. Numerous recent studies have reported the biological activities of its secondary metabolites and extracts. In this study, a total of 14 components were isolated, including cycloolivil and 2-(3'-hydroxy-5'-ethoxyphenyl)-3-hydroxylmethyl-7-methoxy-2,3-dihydrobenzofuran-5-carboxylic acid, which were first discovered in N. jatamansi. The isolated compounds were investigated for their anti-inflammatory effects on HaCaT keratinocytes and their potential to alleviate skin inflammation. The results of the screening revealed that cycloolivil and 4ß-hydroxy-8ß-methoxy-10-methylene-2,9-dioxatricyclo[4.3.1.03,7]decane reduced the production of inflammatory cytokines induced by TNF-α/IFN-γ, such as IL-6, IL-8, and RANTES, in keratinocytes. This study focused on exploring the biological effects of cycloolivil, and the results suggested that cycloolivil inhibits the expression of COX-2 proteins. Further mechanistic evaluations confirmed that the anti-inflammatory effects of cycloolivil were mediated by blockage of the NF-κB and JAK/STAT signaling pathways. These results suggest that cycloolivil isolated from N. jatamansi could be used to treat skin inflammatory diseases.

Efficacy of pulse oximetry for early diagnosis of pulmonary embolism after total knee arthroplasty.

INTRODUCTION: Early diagnosis and aggressive treatment of pulmonary embolism (PE) are crucial for preventing severe complications after total knee arthroplasty (TKA). This study aimed to examine the efficacy of measuring oxygen saturation (SpO2) using a pulse oximeter for early diagnosis of PE after total knee arthroplasty (TKA). MATERIALS AND METHODS: We consecutively examined 1645 patients who underwent TKA between January 2015 and November 2019. Postoperative SpO2 was measured with a pulse oximeter, which was stopped if SpO2 was maintained at ≥ 95% until postoperative day 2 (POD2). To diagnose PE, computed tomographic pulmonary angiography (CTPA) was performed for specific indications, including persistently low SpO2 < 95% (group 1), sudden decrease in SpO2 (group 2), and decrease in SpO2 after POD3 with presenting symptoms (group 3). Also, we divided the patients into unilateral, simultaneous and sequential TKA groups and compared the results with specific statistical techniques. RESULTS: Of the 1645 patients who underwent TKA, there were 20 patients with PE (1.2%), and symptomatic PE was observed in only 4 patients (0.24%). CTPA was performed in 58 (3.5%) patients, of whom 20 were diagnosed with PE. In groups 1 (n = 34), 2 (n = 21), and 3 (n = 3), CTPA was performed 2.4, 2.6, and 8.3 days after TKA, respectively, and 12, 8, and 0 patients were diagnosed with PE, respectively. Of the 782, 416, and 447 unilateral, simultaneous, and sequential (done in same admission with interval 1 or 2 weeks) patients with TKA, 38, 18, and 2 received CTPA, and 13, 6, and 1 were diagnosed with PE, respectively. All patients diagnosed with PE have persistently low SpO2 < 95% (group 1), or sudden decrease in SpO2 (group 2) until POD2. Of the patients diagnosed with PE, SpO2 decreased without the presentation of symptoms in 16 patients (11 and 5 from groups 1 and 2, respectively) and with the presentation of symptoms, such as mild dyspnea and chest discomfort, in 4 patients (1 and 3 from groups 1 and 2, respectively). CONCLUSIONS: Measuring SpO2 using a pulse oximeter until POD2 was an effective method for early diagnosis of PE after TKA. No case of morbidity or mortality was observed after early diagnosis with early stage CTPA and management of PE. We recommend measuring SpO2 with a pulse oximeter for early diagnosing of PE in TKA.

The Incidence Rate, Microbiological Etiology, and Results of Treatments of Prosthetic Joint Infection following Total Knee Arthroplasty.

Periprosthetic joint infection (PJI) remains among the most challenging and costly complications. PJI rates vary from 0.39% to 3.9% after total knee arthroplasty (TKA). This study aimed to identify the causative microorganisms involved and to report our experience of subsequent treatment of PJI following over 7000 TKAs performed over 19 years. A retrospective study was conducted on 4547 patients (7019 cases) from March 2000 to September 2019. The incidence rate of PJI was 0.5%. Gram-positive bacteria accounted for 88.8% (n = 16) of the 18 cases, and S. aureus was the most commonly isolated pathogen (n = 7, 38.8%). There were six cases of MSSA and one case of MRSA. Streptococcus species (n = 7, 38.8%) also showed the same pattern. The CoNS species (n = 2, 11.1%) and Gram-negative bacteria (n = 1, 5.5%) were also reported. Candida species were isolated from 1 patient (5.5%). Successful I&D and implant retention (DAIR procedures) was achieved at the final follow-up in 19 patients (82.6%). The incidence of causative microorganisms was different for each PJI onset type. The overall infection rate of PJI was less than 1%. Although the success rate of DAIR procedures is lower than the two-stage exchange arthroplasty in this study, it is possible to achieve acceptable success rates if DAIR procedures are carefully selected considering the virulence of the microorganism, duration since symptom onset, and early-onset infection.

Plasmon Energy Transfer Driven by Electrochemical Tuning of Methylene Blue on Single Gold Nanorods.

Plasmonic photocatalysis has attracted interest for its potential to generate energy-efficient reactions, but ultrafast internal conversion limits efficient plasmon-based chemistry. Resonance energy transfer (RET) to surface adsorbates offers a way to outcompete internal conversion pathways and also eliminate the need for sacrificial counter-reactions. Herein, we demonstrate RET between methylene blue (MB) and gold nanorods (AuNRs) using in situ single-particle spectroelectrochemistry. During electrochemically driven reversible redox reactions between MB and leucomethylene blue (LMB), we show that the homogeneous line width is broadened when spectral overlap between AuNR scattering and absorption of MB is maximized, indicating RET. Additionally, electrochemical oxidative oligomerization of MB allowed additional dipole coupling to generate RET at lower energies. Time-dependent density functional theory-based simulated absorption provided theoretical insight into the optical properties, as MB molecules were electrochemically oligomerized. Our findings show a mechanism for driving efficient plasmon-assisted processes by RET through the change in the chemical states of surface adsorbates.

Active Control of Energy Transfer in Plasmonic Nanorod-Polyaniline Hybrids.

The hybridization of plasmonic energy and charge donors with polymeric acceptors is a possible means to overcome fast internal relaxation that limits potential photocatalytic applications for plasmonic nanomaterials. Polyaniline (PANI) readily hybridizes onto gold nanorods (AuNRs) and has been used for the sensitive monitoring of local refractive index changes. Here, we use single-particle spectroscopy to quantify a previously unreported plasmon damping mechanism in AuNR-PANI hybrids while actively tuning the PANI chemical structure. By eliminating contributions from heterogeneous line width broadening and refractive index changes, we identify efficient resonance energy transfer (RET) between AuNRs and PANI. We find that RET dominates the optical response in our AuNR-PANI hybrids during the dynamic tuning of the spectral overlap of the AuNR donor and PANI acceptor. Harnessing RET between plasmonic nanomaterials and an affordable and processable polymer such as PANI offers an alternate mechanism toward efficient photocatalysis with plasmonic nanoparticle antennas.

Macrosphelides from Antarctic fungus Pseudogymnoascus sp. (strain SF-7351) and their neuroprotective effects on BV2 and HT22 cells.

Strategies for reducing inflammation in neurodegenerative diseases have attracted increasing attention. Herein, we discovered and evaluated the neuroprotective potential of fungal metabolites isolated from the Antarctic fungus Pseudogymnoascus sp. (strain SF-7351). The chemical investigation of the EtOAc extract of the fungal strain isolate revealed a novel naturally occurring epi-macrosphelide J (1), a novel secondary metabolite macrosphelide N (2), and three known compounds, namely macrosphelide A (3), macrosphelide B (4), and macrosphelide J (5). Their structures were established unambiguously using spectroscopic methods, such as one-dimensional and two-dimensional nuclear magnetic resonance (1D and 2D-NMR) spectroscopy, high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), and gauge-including atomic orbital (GIAO) NMR chemical shift calculations, with the support of the advanced statistical method DP4+. Among the isolated metabolites, the absolute configuration of epi-macrosphelide J (1) was further confirmed using single-crystal X-ray diffraction analysis. The neuroprotective effects of the isolated metabolites were evaluated in lipopolysaccharide (LPS)-induced BV2 and glutamate-stimulated HT22 cells. Only macrosphelide B (4) displayed substantial protective effects in both BV2 and HT22 cells. Molecular mechanisms underlying this activity were investigated using western blotting and molecular docking studies. Macrosphelide B (4) inhibited the inflammatory response by reducing the nuclear translocation of NF-κB (p65) in LPS-induced BV2 cells and induced the Nrf2/HO-1 signaling pathway in both BV2 and HT22 cells. The neuroprotective effect of macrosphelide B (4) is related to the interaction between Keap1 and p65. These results suggest that macrosphelide B (4), present in the fungus Pseudogymnoascus sp. (strain SF-7351), may serve as a candidate for the treatment of neurodegenerative diseases.

Joint Replacement Surgery in Patients with Rheumatoid Arthritis in South Korea: Analysis of a Large National Database.

Background: We aimed to investigate the current trend of joint replacement surgery incidence in patients with rheumatoid arthritis (RA) in South Korea and to compare the incidence of joint replacement surgery in each affected joint. Methods: We performed this big data analysis to investigate the current trend of joint replacement surgery incidence in patients with RA in South Korea and to compare the incidence of joint replacement surgery in each affected joint. This retrospective study was based on data from the Korea National Health Insurance claims database. Results: The prevalence of RA increased every year (0.13% in 2008, 0.25% in 2016). The number of newly diagnosed patients increased from 29,184 in 2010 to 38,347 in 2016. The incidence rate of joint replacement surgery in patients with RA increased from 0.72% in 2010 to 4.03% in 2016. The knee (68.3%) was the most commonly replaced joint. The relative risk (RR) of additional joint replacement surgery was highest for the shoulder joint (RR,1.454; 95% confidence interval, 0.763-2.771). The median time from diagnosis to surgery was the shortest in the elbow joint (379 days) and the longest in the shoulder joint (955 days). The median time for each joint was short in order of the elbows, ankles, hips, knees, and shoulders (p < 0.01). Conclusions: The most frequently and initially replaced joints were different, but the prevalence and incidence of RA, as well as those of joint replacement surgery, have recently increased in South Korea. Joint replacement surgery in RA was the highest for the knee joint. The median time from diagnosis to surgery was shortest for the elbow, followed by the ankle, hip, knee, and shoulder. Regardless of whether patients are symptomatic, evaluation of large joints such as the knee, elbow, ankle, and hip should be considered from an early stage.

Anti-Neuroinflammatory and Neuroprotective Effect of Intermedin B Isolated from the Curcuma longa L. via NF-κB and ROS Inhibition in BV2 Microglia and HT22 Hippocampal Cells.

Compounds derived from Curcuma longa L. (C. longa) have been extensively studied and reported to be effective and safe for the prevention and treatment of various diseases, but most research has been focused on curcuminoids derived from C. longa. As neurodegenerative diseases are associated with oxidation and inflammation, the present study aimed to isolate and identify active compounds other than curcuminoids from C. longa to develop substances to treat these diseases. Seventeen known compounds, including curcuminoids, were chromatographically isolated from the methanol extracts of C. longa, and their chemical structures were identified using 1D and 2D NMR spectroscopy. Among the isolated compounds, intermedin B exhibited the best antioxidant effect in the hippocampus and anti-inflammatory effect in microglia. Furthermore, intermedin B was confirmed to inhibit the nuclear translocation of NF-κB p-65 and IκBα, exerting anti-inflammatory effects and inhibiting the generation of reactive oxygen species, exerting neuroprotective effects. These results highlight the research value of active components other than curcuminoids in C. longa-derived compounds and suggest that intermedin B may be a promising candidate for the prevention of neurodegenerative diseases.

Shaping Copper Oxide Layers on Gold Nanoparticle Ensembles by Controlled Electrodeposition with Single Particle Scatterometry.

Electrodeposition of copper on gold nanoelectrode ensembles result in the formation of uniform copper oxide layers on individual nanoparticles. A linear sweep of voltammetric change induces three distinct morphologies dependent upon particle density. Ex situ imaging and in situ scatterometry at a single-particle level identifies multi-step electrochemical growth sequences that deviated from classical nucleation and growth pathways. In addition, the study demonstrated the possibility of synthesizing sophisticated structures based on the symmetry of nanoelectrodes. This result guides the nanoscale morphology control of electrode ensembles with potential application in electrocatalysis and sensing.

Combined PCL and PLC Reconstruction Improves Residual Laxity in PCL Injury Patients with Posterolateral Knee Laxity Less Than Grade III.

PURPOSE: To compare the short-term clinical and radiologic outcomes of combined posterior cruciate ligament (PCL) and posterolateral complex (PLC) reconstruction to those of isolated PCL reconstruction (PCLR) for patients with posterolateral knee laxity less than grade III. MATERIALS AND METHODS: We retrospectively reviewed 49 patients (51 knees) who underwent PCLR between January 2008 and December 2015. Patients with a minimum follow-up of 24 months were included and divided into two groups (group A, isolated PCLR; group B, combined PCL and PLC reconstruction). Clinical outcomes were evaluated as the International Knee Documentation Committee (IKDC) subjective, Lysholm, and Tegner activity scale scores. Radiologic outcomes were also assessed using the side-to-side differences in posterior tibial translation via stress radiographs. RESULTS: A total of 30 cases were analyzed. There were no significant differences in the Lysholm and Tegner activity scale scores between the two groups preoperatively and at the final follow-up. However, group B showed a higher IKDC subjective score compared to group A at the final follow-up (group A, 72.8±8.9; group B, 77.7±10.1; p<0.05). Regarding the radiologic outcomes, group B also showed a significantly less side-to-side difference in posterior tibial translation compared to group A at the final follow-up (group A, 4.8±2.3 mm; group B, 3.8±2.1 mm; p<0.05). CONCLUSION: Combined PCL and PLC reconstruction resulted in improved clinical and radiologic outcomes than isolated PCLR in patients who have less than grade III posterolateral laxity of the knee. In cases of PCL rupture with ambiguous PLC injury, combined PCL and PLC reconstruction may help to improve posterior residual laxity of the knee.

Synthetic Glabridin Derivatives Inhibit LPS-Induced Inflammation via MAPKs and NF-κB Pathways in RAW264.7 Macrophages.

Glabridin is a polyphenolic compound with reported anti-inflammatory and anti-oxidative effects. In the previous study, we synthesized glabridin derivatives-HSG4112, (S)-HSG4112, and HGR4113-based on the structure-activity relationship study of glabridin to improve its biological efficacy and chemical stability. In the present study, we investigated the anti-inflammatory effects of the glabridin derivatives in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. We found that the synthetic glabridin derivatives significantly and dose-dependently suppressed the production of nitric oxide (NO) and prostaglandin E2 (PGE2), and decreased the level of inducible nitric oxygen synthase (iNOS) and cyclooxygenase-2 (COX-2) and the expression of pro-inflammatory cytokines interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor alpha (TNF-α). The synthetic glabridin derivatives inhibited the nuclear translocation of the NF-κB by inhibiting phosphorylation of the inhibitor of κB alpha (IκB-α), and distinctively inhibited the phosphorylation of ERK, JNK, and p38 MAPKs. In addition, the compounds increased the expression of antioxidant protein heme oxygenase (HO-1) by inducing nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) through ERK and p38 MAPKs. Taken together, these results indicate that the synthetic glabridin derivatives exert strong anti-inflammatory effects in LPS-stimulated macrophages through MAPKs and NF-κB pathways, and support their development as potential therapeutics against inflammatory diseases.

Anti-Inflammatory Effects Exerted by 14-Methoxyalternate C from Antarctic Fungal Strain Pleosporales sp. SF-7343 via the Regulation of NF-κB and JAK2/STAT3 in HaCaT Human Keratinocytes.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with a profound negative impact on patients' quality of life. Four known secondary fungal metabolites were found in the chemical study of the Antarctic fungus Pleosporales sp. SF-7343, including 14-methoxyalternate C (1), 5'-methoxy-6-methyl-biphenyl-3,4,3'-triol (2), 3,8,10-trihydroxy-4-methoxy-6-methylbenzocoumarin (3), and alternariol monomethyl ether (4). Additionally, we identified the skin anti-inflammatory composition from the SF-7343 strain. Interleukin-8 and -6 Screening results showed that compound 1 inhibited IL-8 and IL-6 in tumor necrosis factor-α/interferon-γ stimulated HaCaT cells. Compound 1 showed inhibitory effects on MDC and RANTES. It also downregulated the expression of intercellular adhesion molecule-1 (ICAM-1) and upregulated the expression of involucrin. The results of the mechanistic study showed that compound 1 inhibited the nuclear translocation of nuclear factor-kappa B p65 and STAT3. In conclusion, this study demonstrates the potential of the Antarctic fungal strain SF-7343 as a bioactive resource to inhibit skin inflammation, such as AD.

Arecae pericarpium water extract alleviates chronic pancreatitis by deactivating pancreatic stellate cells.

Chronic pancreatitis (CP) is a chronic inflammatory disease of the pancreas with irreversible morphological changes. Arecae pericarpium (ARP), known to improve gastrointestinal disorders, has not yet been reported to inhibit fibrosis in CP. Therefore, we investigated the beneficial effects of ARP on cerulein-induced CP. Cerulein (50 µg/kg) was administered intraperitoneally to mice every hour, six times a day, four times a week for a total of 3 weeks to induce CP. To ascertain the prophylactic effects of ARP, ARP water extract (50, 100, or 200 mg/kg) or saline was administered intraperitoneally 1 h before the onset of CP. To determine the therapeutic effects of ARP, ARP water extract (200 mg/kg) or saline was administered for a total of 1 week or 2 weeks, starting 2 weeks or 1 week after the onset of CP. The pancreas was collected immediately for histological analysis. Additionally, to determine the effectiveness and mechanism of ARP in alleviating pancreatic fibrosis, pancreatic stellate cells (PSCs) were isolated. ARP treatment considerably improved glandular atrophy and inflammation and repressed collagen deposition in the pancreas. Furthermore, ARP water extract inhibited extracellular matrix (ECM) constituents such as alpha-smooth muscle actin (α-SMA), collagen I, and fibronectin 1 (FN1) in pancreatic tissue and PSCs. ARP also suppressed transforming growth factor-ß (TGF-ß) signaling by inhibiting Smad2 phosphorylation. Our study suggests that ARP exhibits anti-fibrotic effects in cerulein-induced CP by inhibiting TGF-ß/Smad signaling.

Mortality of septic knee arthritis in Korea: risk factors analysis of a large national database.

This study aimed to analyze the risk factors for mortality of septic knee arthritis in Korea through a large nationwide data research. The National Health Insurance Service-Health Screening database was used to analyze 89,120 hospitalizations for septic knee arthritis between 2005 and 2018. In-hospital, thirty-day, and ninety-day mortality, and their association with patient's demographic factors, various comorbidities (i.e., cerebrovascular disease, congestive heart failure, and myocardial infarction) and Charlson Comorbidity Index (CCI) were assessed. Secondary outcomes of complications (osteomyelitis, knee arthroplasty, recurrence) were analyzed. The number of hospitalization with septic knee arthritis increased from 1847 cases in 2005 to 8749 cases in 2018. There was no significant difference in mortality after diagnosis of septic knee arthritis between years. The risk of mortality in patients who hospitalized with septic knee arthritis increased in comorbidities like Congestive heart failure, dementia, myocardial infarction, chronic kidney disease. Hazard ratio (HR) decreased in patients who have comorbidities such as rheumatoid arthritis, liver disease, rheumatologic disease. HR for mortality in septic knee arthritis increased in patients with CCI more than 1. The risk factors for mortality in all periods were male sex, old age, high CCI, comorbidities such as congestive heart failure, dementia, myocardial infarction, chronic kidney disease. Efforts to reduce mortality should be concentrate more on patients with these risk factors.

Identification of Potential Anti-Neuroinflammatory Inhibitors from Antarctic Fungal Strain Aspergillus sp. SF-7402 via Regulating the NF-κB Signaling Pathway in Microglia.

Microglia play a significant role in immune defense and tissue repair in the central nervous system (CNS). Microglial activation and the resulting neuroinflammation play a key role in the pathogenesis of neurodegenerative disorders. Recently, inflammation reduction strategies in neurodegenerative diseases have attracted increasing attention. Herein, we discovered and evaluated the anti-neuroinflammatory potential of compounds from the Antarctic fungi strain Aspergillus sp. SF-7402 in lipopolysaccharide (LPS)-stimulated BV2 cells. Four metabolites were isolated from the fungi through chemical investigations, namely, 5-methoxysterigmatocystin (1), sterigmatocystin (2), aversin (3), and 6,8-O-dimethylversicolorin A (4). Their chemical structures were elucidated by extensive spectroscopic analysis and HR-ESI-MS, as well as by comparison with those reported in literature. Anti-neuroinflammatory effects of the isolated metabolites were evaluated by measuring the production of nitric oxide (NO), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 in LPS-activated microglia at non-cytotoxic concentrations. Sterigmatocystins (1 and 2) displayed significant effects on NO production and mild effects on TNF-α and IL-6 expression inhibition. The molecular mechanisms underlying this activity were investigated using Western blot analysis. Sterigmatocystin treatment inhibited NO production via downregulation of inducible nitric oxide synthase (iNOS) expression in LPS-stimulated BV2 cells. Additionally, sterigmatocystins reduced nuclear translocation of NF-κB. These results suggest that sterigmatocystins present in the fungal strain Aspergillus sp. are promising candidates for the treatment of neuroinflammatory diseases.

Cytotoxic and nitric oxide inhibitory activities of triterpenoids from Lycopodium clavatum L.

Using combined chromatographic separation techniques, three new triterpenoids named lycomclavatols A-C (1-3), a new natural product, methyl lycernuate-A (4), as well as seven known compounds (5-11), were isolated from the methanol extract of the whole plants of Lycopodium clavatum. Their chemical structures were established based on 1 D/2D NMR and HR-ESI-MS spectroscopic analyses. Among the isolates, compound 1 exhibited inhibitory activity on NO production in LPS-stimulated BV2 cells (IC50 = 36.0 µM). In addition, 1 was cytotoxic against both HepG2 and A549 cancer cell lines, with IC50 values of 40.7 and 87.0 µM, respectively. Compounds 10 and 11 showed cytotoxicity on only HepG2 and A549 cells, with IC50 values of 91.2 and 57.6 µM, respectively. Our results contribute to understanding more the secondary metabolites produced by L. clavatum and provide a scientific rationale for further investigations of anti-inflammatory and anticancer effects for this valuable medicinal plant.

Stem bark of Fraxinus rhynchophylla ameliorates the severity of pancreatic fibrosis by regulating the TGF-ß/Smad signaling pathway.

Chronic pancreatitis (CP) is a pathological fibroinflammatory syndrome of the pancreas. Currently, there are no therapeutic agents available for treating CP-associated pancreatic fibrosis. Fraxinus rhynchophylla (FR) reportedly exhibits anti-inflammatory, antioxidative and antitumor activities. Although FR possesses numerous properties associated with the regulation of diverse diseases, the effects of FR on CP remain unknown. Herein, we examined the effects of FR on CP. For CP induction, mice were intraperitoneally administered cerulein (50 µg/kg) 6 times a day, 4 days per week for 3 weeks. FR extract (100 or 400 mg/kg) or saline (control group) was intraperitoneally injected 1 hour before the first cerulein injection. After 3 weeks, the pancreas was harvested for histological analysis. In addition, pancreatic stellate cells (PSCs) were isolated to examine the antifibrogenic effects and regulatory mechanisms of FR. Administration of FR significantly inhibited histological damage in the pancreas, increased pancreatic acinar cell survival, decreased PSC activation and collagen deposition, and decreased pro-inflammatory cytokines. Moreover, FR treatment inhibited the expression of fibrotic mediators, such as α-smooth muscle actin (α-SMA), collagen, fibronectin 1, and decreased pro-inflammatory cytokines in isolated PSCs stimulated with transforming growth factor (TGF)-ß. Furthermore, FR treatment suppressed the phosphorylation of Smad 2/3 but not of Smad 1/5 in TGF-ß-stimulated PSCs. Collectively, these results suggest that FR ameliorates pancreatic fibrosis by inhibiting PSC activation during CP.

Anti-neuroinflammatory effect of oxaline, isorhodoptilometrin, and 5-hydroxy-7-(2'-hydroxypropyl)-2-methyl-chromone obtained from the marine fungal strain Penicillium oxalicum CLC-MF05.

Penicillium is a rich source of bioactive compounds. Among all Penicillium species, Penicillium oxalicum has been reported to produce various types of secondary metabolites, including alkaloids, phenolics, and tetrahydroxanthone dimeric compounds, exhibiting many pharmacological effects, such as antiviral, antibacterial, and cytotoxic activities. Three secondary metabolites were isolated from a fermented culture of the sponge-associated fungal strain P. oxalicum CLC-MF05: oxaline (1), isorhodoptilometrin (2), and 5-hydroxy-7-(2'-hydroxypropyl)-2-methyl-chromone (3). Their chemical structures were identified by 1D and 2D NMR and high-resolution mass spectroscopic analyses and compared with previously reported data. All three compounds inhibited NO and PGE2 overproduction and iNOS and COX-2 overexpression in both LPS-stimulated BV2 and rat primary microglia. These metabolites also repressed mRNA expression of TNF-α, IL-1ß, IL-6, and IL-12. Further, mechanistic studies revealed that the inhibitory actions of compounds 1-3 were regulated by the inactivation of the NF-κB and MAPK signaling pathways. Furthermore, inactivation of the TLR4/MyD88 pathway contributed to the anti-neuroinflammatory activity of these compounds. These results suggest that compounds 1-3 represent potential anti-inflammatory candidates for the treatment of neurodegenerative diseases; however, further investigation is needed.