IFN-α affects Th17/Treg cell balance through c-Maf and associated with the progression of EBV- SLE.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease, of which the pathogens is remains obscure. Viral infection, particularly Epstein Barr viru (EBV) infection, has been considered a common pathogenic factor. This study suggests that c-Maf may be an important target in T cell differentiation during SLE progression, providing a potentially new perspective on the role of viral infection in the pathogenesis of autoimmune diseases. METHODS: Cytokines of EBV-infected SLE patients were measured by ELISA and assessed in conjunction with their clinical data. IFN-α, c-Maf, and the differentiation of Th17/Treg cells in SLE patients and MRL/LPR mice were analyzed using FCM, WB, RT-PCR, etc. Following the infection of cells and mice with EBV or viral mimic poly (dA:dT), the changes of the aforementioned indicators were investigated. The relationship among IFN-α, STAT3, c-Maf and Th17 cells was determined by si-RNA technique. RESULTS: Many SLE patients are found to be complicated by viral infections; Further, studies have demonstrated that viral infection, especially EBV, is involved in SLE development. This study showed that viral infections might promote IFN-α secretion, inhibit c-Maf expression by activating STAT3, increase Th17 cell differentiation, and lead to the immune imbalance of Th17/Treg cells, thus playing a role in the onset and progression of SLE. CONCLUSION: This study demonstrates that EBV infections may contribute to SLE development by activating STAT3 through IFN-α, inhibiting c-Maf, and causing Th17/Treg immune imbalance. Our work provided a new insight into the pathogenesis and treatment of SLE.

Mitochondrial-dependent oxidative phosphorylation is key for postnatal metabolic adaptation of alveolar macrophages in the lung.

Alveolar macrophages (AMs) seed in lung during embryogenesis and become mature in perinatal period. Establishment of acclimatization to environmental challenges is important, whereas the detailed mechanisms that drive metabolic adaptation of AMs remains to be elucidated. Here, we showed that energy metabolism of AMs was transformed from glycolysis prenatally to oxidative phosphorylation (OXPHOS) postnatally accompanied by up-regulated expression of mitochondrial transcription factor A (TFAM). TFAM deficiency disturbed mitochondrial stability and decreased OXPHOS, which finally impaired AM maintenance and function, but not AM embryonic development. Mechanistically, Tfam-deletion resulted in impaired mitochondrial respiration and decreased ATP production, which triggered endoplasmic reticulum (ER) stress to cause B cell lymphoma 2 ovarian killer (BOK) accumulation and abnormal distribution of intracellular Ca2+, eventually led to induce AM apoptotic death. Thus, our data illustrated mitochondrial-dependent OXPHOS played a key role in orchestrating AM postnatal metabolic adaptation.

Integrated gene co-expression network analysis reveals unique developmental processes of Aurelia aurita.

The typical life cycle of the moon jellyfish (Aurelia aurita) includes the planula, polyp, strobila, ephyra, and medusa developmental stages. These stages exhibit huge differences in both external morphology and internal physiological functions. However, the gene co-expression network involved in these post-embryonic developmental processes has not been studied yet. Here, based on 15 RNA sequencing samples covering all five stages of the A. aurita life cycle, we systematically analyzed the gene co-expression network and obtained 35 relevant modules. Furthermore, we identified the highly correlated modules and hub genes for each stage. These hub genes are implicated to play important roles in the developmental processes of A. aurita, which should help improve our understanding of the jellyfish life cycle.

Hypervirulent FAdV-4 infection induces activation of the NLRP3 inflammasome in chicken macrophages.

Fowl adenovirus serotype 4 (FAdV-4) is the primary causative agent of hepatitis-hydropericardium syndrome (HHS) causing great economic losses to the world poultry industry. The exact factors responsible for the pathogenesis of hypervirulent FAdV-4 have not been completely elucidated. Hypervirulent FAdV-4 infection induces inflammatory damages in accompany with a high level of proinflammatory interleukin-1 beta (IL-1ß) secretion in a variety of organs. Investigation of the mechanisms underlying hypervirulent FAdV-4-induced IL-1ß secretion would contribute to understanding of the pathogenesis of FAdV-4. Here, we investigated whether FAdV-4 infection activates NLRP3 inflammasome in chicken macrophage cell line HD11. The results showed that stimulation of HD11 with hypervirulent FAdV-4 induced NLRP3- and Caspase-1-dependent secretion of IL-1ß. Genetic knockdown of NLRP3 or Caspase-1 expression, a critical component of inflammasome, significantly downregulated IL-1ß expression, indicating that activation of the NLRP3 inflammasome contributed to the FAdV-4-induced IL-1ß secretion. Moreover, ATP signaling and potassium efflux were involved in the process of NLRP3 inflammasome activation. Our data indicated that hypervirulent FAdV-4 infection induces the activation of NLRP3 inflammasome and followed by massive secretion of IL-1ß of macrophages, which thereby contribute to the inflamed lesion of tissues.

The pros and cons of cytokines for fowl adenovirus serotype 4 infection.

Hepatitis-hydropericardium syndrome (HHS), caused by fowl adenovirus serotype 4 (FAdV-4), has spread on chicken farms worldwide, causing huge economic losses. Currently, the exact mechanism of pathogenesis of FAdV-4 remains unknown. Despite the severe inflammatory damage observed in chickens infected with pathogenic FAdV-4, few studies have focused on the host immune system-virus interactions and cytokine secretion. Host immunity acts as one of the most robust defense mechanisms against infection by pathogens, and cytokines are important in their elimination. However, excessive inflammatory cytokine secretion could contribute to the pathogenesis of FAdV-4. Understanding of the roles of cytokines produced during FAdV-4 infection is important for the study of pathogenicity and for developing strategies to control FAdV-4. Several previous studies have addressed the immune responses to FAdV-4 infection, but there has not been a systematic review of this work. The present review provides a detailed summary of the current findings on cytokine production induced by FAdV-4 infection to accelerate our understanding of FAdV-4 pathogenesis.

Epidermal Growth Factor and Tocotrienol-Rich Fraction Cream Formulation Accelerates Burn Healing Process Based on Its Gene Expression Pattern in Deep Partial-Thickness Burn Wound Model.

Our previous study has demonstrated that epidermal growth factor (EGF) with tocotrienol-rich fraction (TRF) cream formulation accelerating postburn wound healing with deep partial-thickness burn in rats. Current study was conducted to determine the gene expression levels related to burn wound healing process. A total of 180 Sprague-Dawley rats were randomly divided into 6 groups: untreated control, treated with Silverdin cream, base cream, base cream with 0.00075% EGF, base cream with 3% TRF or base cream with 0.00075% EGF, and 3% TRF, respectively. Burn wounds were created and the above-mentioned creams were applied once daily. Six animals from each group were sacrificed on days 3, 7, 11, 14, and 21 postburn. RNA was extracted from wound tissues and quantitative real-time polymerase chain reaction was performed to analyze the 9 wound healing-related genes against time postburn. Results demonstrated that topically applied EGF + TRF formulation downregulated the expression levels of IL-6 (interluekin-6), TNF-α (tumor necrosis factor-α) and iNOS (inducible nitric oxide synthase) throughout the whole healing process. TGF-ß1 (transforming growth factor-ß) and VEGF-A (vascular endothelial growth factor-A) were reduced on day 14 postburn. On the contrary, increased expression of Collagen-1 in the early stage of wound healing was observed with no effects on epidemal growth factor receptor (EGFR). The results showed beneficial application of EGF + TRF cream in the treatment of burn wound since it accelerated wound healing by relieving oxidative stress, decreasing inflammation, and promoting proper tissue modelling in the burn wound.

Nucleus-mitochondria positive feedback loop formed by ERK5 S496 phosphorylation-mediated poly (ADP-ribose) polymerase activation provokes persistent pro-inflammatory senescent phenotype and accelerates coronary atherosclerosis after chemo-radiation.

The incidence of cardiovascular disease (CVD) is higher in cancer survivors than in the general population. Several cancer treatments are recognized as risk factors for CVD, but specific therapies are unavailable. Many cancer treatments activate shared signaling events, which reprogram myeloid cells (MCs) towards persistent senescence-associated secretory phenotype (SASP) and consequently CVD, but the exact mechanisms remain unclear. This study aimed to provide mechanistic insights and potential treatments by investigating how chemo-radiation can induce persistent SASP. We generated ERK5 S496A knock-in mice and determined SASP in myeloid cells (MCs) by evaluating their efferocytotic ability, antioxidation-related molecule expression, telomere length, and inflammatory gene expression. Candidate SASP inducers were identified by high-throughput screening, using the ERK5 transcriptional activity reporter cell system. Various chemotherapy agents and ionizing radiation (IR) up-regulated p90RSK-mediated ERK5 S496 phosphorylation. Doxorubicin and IR caused metabolic changes with nicotinamide adenine dinucleotide depletion and ensuing mitochondrial stunning (reversible mitochondria dysfunction without showing any cell death under ATP depletion) via p90RSK-ERK5 modulation and poly (ADP-ribose) polymerase (PARP) activation, which formed a nucleus-mitochondria positive feedback loop. This feedback loop reprogramed MCs to induce a sustained SASP state, and ultimately primed MCs to be more sensitive to reactive oxygen species. This priming was also detected in circulating monocytes from cancer patients after IR. When PARP activity was transiently inhibited at the time of IR, mitochondrial stunning, priming, macrophage infiltration, and coronary atherosclerosis were all eradicated. The p90RSK-ERK5 module plays a crucial role in SASP-mediated mitochondrial stunning via regulating PARP activation. Our data show for the first time that the nucleus-mitochondria positive feedback loop formed by p90RSK-ERK5 S496 phosphorylation-mediated PARP activation plays a crucial role of persistent SASP state, and also provide preclinical evidence supporting that transient inhibition of PARP activation only at the time of radiation therapy can prevent future CVD in cancer survivors.

Vitellogenin from planthopper oral secretion acts as a novel effector to impair plant defenses.

Vitellogenin (Vg) is a well-known nutritious protein involved in reproduction in nearly all oviparous animals, including insects. Recently, Vg has been detected in saliva proteomes of several piercing-sucking herbivorous arthropods, including the small brown planthopper (Laodelphax striatellus, SBPH). Its function, however, remains unexplored. We investigated the molecular mechanism underlying SBPH orally secreted Vg-mediated manipulation of plant-insect interaction by RNA interference, phytohormone and H2 O2 profiling, protein-protein interaction studies and herbivore bioassays. A C-terminal polypeptide of Vg (VgC) in SBPH, when secreted into rice plants, acted as a novel effector to attenuate host rice defenses, which in turn improved insect feeding performance. Silencing Vg reduced insect feeding and survival on rice. Vg-silenced SBPH nymphs consistently elicited higher H2 O2 production, a well-established defense mechanism in rice, whereas expression of VgC in planta significantly hindered hydrogen peroxide (H2 O2 ) accumulation and promoted insect performance. VgC interacted directly with the rice transcription factor OsWRKY71, a protein which is involved in induction of H2 O2 accumulation and plant resistance to SBPH. These findings indicate a novel effector function of Vg: when secreted into host rice plants, this protein effectively weakened H2 O2 -mediated plant defense through its association with a plant immunity regulator.

CASC15 Polymorphisms are Correlated With Breast Cancer Susceptibility in Chinese Han Women.

INTRODUCTION: Breast cancer (BC) is a prevalent malignant tumor among women. Numerous studies have been reported that long noncoding RNAs (lncRNAs) were associated with various human diseases. MATERIALS AND METHODS: In the current study, 681 patients with BC and 680 unrelated controls were recruited to investigate the correlation between lncRNA cancer susceptibility candidate 15 (CASC15) polymorphisms and BC risk in Chinese Han women. We performed single-nucleotide polymorphism genotyping using the Agena MassARRAY platform. The relationship between lncRNA CASC15 polymorphisms and the risk of BC were evaluated through odds ratios and 95% confidence intervals. RESULTS: Our results suggested that the lncRNA CASC15 rs7740084 "G/G" genotype and rs1928168 "T/C" genotype significantly reduced BC risk in different genetic models (P = .045, P = .029, and P = .047, respectively). However, rs9393266 "C/T" and "C/T-T/T" genotypes were correlated with the risk of BC (P = .021 and P = .048). In addition, we also observed that rs1928168 was related to the risk of BC in patients with age > 50 years (P = .025), body mass index > 24 (P = .006), and tumor size (P = .035). For rs9393266, it was revealed that the "C/T" and "C/T-T/T" genotypes were related to BC risk in people with age ≤ 50 years (P = .005) and body mass index > 24 (P = .023). CONCLUSION: In summary, our results revealed a potential interaction between lncRNA CASC15 polymorphisms and BC susceptibility. The results provided an important insight into lncRNA CASC15 function in the development of BC.

Expression, purification and functional identification of the modified hEGF protein.

Human epidermal growth factor (hEGF) plays an important role in the growth and division of epithelial cells and has good application prospects in skin-related injuries and diseases. Weak skin penetration and rapid clearance of hEGF in skin via the mononuclear phagocyte system have restricted the application of hEGF. To overcome these shortcomings, the recombinant gene TAT-hEGF-CD47 was constructed in our experiments, and the fusion protein TAT-hEGF-CD47 was expressed, purified and renatured. The cell proliferation-promoting function, skin penetration and concentration of TAT-hEGF-CD47 in skin after its application were determined. The results showed that TAT-hEGF-CD47 effectively promoted human skin fibroblast and skin epithelial cell proliferation, and the proliferation-promoting effect was positively correlated with the TAT-hEGF-CD47 concentration. After administration to the skin, TAT-hEGF-CD47 effectively penetrated the epidermal layer of the skin because of the TAT domain and stayed in the skin for a long time because the CD47 fragment slowed its clearance via the mononuclear phagocytic system. In conclusion, TAT-hEGF-CD47 exhibits high cell proliferation-promoting activity, high skin penetration efficiency and long retention time in skin and has laid the foundation for its wide application in skin repair, ulcer, diabetes and even cancer treatments.

Immunomodulatory and Antiviral Activity of Metformin and Its Potential Implications in Treating Coronavirus Disease 2019 and Lung Injury.

The pandemic of coronavirus disease 2019 (COVID-19), a disease which causes severe lung injury and multiple organ damage, presents an urgent need for new drugs. The case severity and fatality of COVID-19 are associated with excessive inflammation, namely, a cytokine storm. Metformin, a widely used drug to treat type 2 diabetes (T2D) mellitus and metabolic syndrome, has immunomodulatory activity that reduces the production of proinflammatory cytokines using macrophages and causes the formation of neutrophil extracellular traps (NETs). Metformin also inhibits the cytokine production of pathogenic Th1 and Th17 cells. Importantly, treatment with metformin alleviates various lung injuries in preclinical animal models. In addition, a recent proteomic study revealed that metformin has the potential to directly inhibit SARS-CoV-2 infection. Furthermore, retrospective clinical studies have revealed that metformin treatment reduces the mortality of T2D with COVID-19. Therefore, metformin has the potential to be repurposed to treat patients with COVID-19 at risk of developing severe illness. This review summarizes the immune pathogenesis of SARS-CoV-2 and addresses the effects of metformin on inhibiting cytokine storms and preventing SARS-CoV-2 infection, as well as its side effects.

Leukocyte immunoglobulin-like receptor subfamily B member 1 potentially acts as a diagnostic and prognostic target in certain subtypes of adenocarcinoma.

BACKGROUND: Leukocyte immunoglobulin (Ig)-like receptor subfamily B member 1 (LILRB1) involves in the occurrence and development of various tumors through transmitting immune inhibitory signals. However, the regulatory mechanism of LILRB1 underlying the disease progression of adenocarcinoma remains vague. This study is aimed to disclose the expression pattern of LILRB1 on adenocarcinoma and its indicative roles on the diagnosis and prognosis of adenocarcinoma patients. METHODS: LILRB1 level in microarray was measured using immunohistochemistry (IHC) staining. Expression analysis of LILRB1 gene were based on the Gene Expression Profiling Interactive Analysis 2.0 (GEPIA2) and Oncomine databases. Survival and correlation analyses were analyzed using The Cancer Genome Atlas (TCGA) database (Breastinvasivecarcinoma, TCGA-BRCA). RESULTS: The IHC results showed that the number of LILRB1-positive cells were robustly elevated in some common subtypes of adenocarcinoma including thyroid gland papillary carcinoma, gastric mixed adenocarcinoma, colon and rectal mucinous adenocarcinoma, pancreatic ductal adenocarcinoma and invasive ductal breast carcinoma compared to their corresponding para-carcinoma. Although the enhancement of LILRB1 expression was only observed in pancreaticadenocarcinoma (PAAD) by using GEPIA2, its expression presented a significant increase in the above subtypes of adenocarcinoma by analyzing using Oncomine database. Besides, there had a significant positive association between LILRB1 expression status and pathological stages, and a negative association between LILRB1 status and Overall Survival (OS) probability in the above certain subtypes of adenocarcinoma. CONCLUSION: LILRB1 is abnormally upregulated in certain subtypes of adenocarcinoma. Patients with low LILRB1 possibly portend a good prognosis in adenocarcinoma. These findings imply that LILRB1 may act as a diagnostic and prognostic target in some subtypes of adenocarcinoma.

Nestin protects podocyte from injury in lupus nephritis by mitophagy and oxidative stress.

Podocyte injury is the main cause of proteinuria in lupus nephritis (LN). Nestin, an important cytoskeleton protein, is expressed stably in podocytes and is associated with podocyte injury. However, the role of nestin in the pathogenesis of proteinuria in LN remains unclear. The correlations among nestin, nephrin and proteinuria were analyzed in LN patients and MRL/lpr lupus-prone mice. The expression of nestin in mouse podocyte lines (MPCs) and MRL/lpr mice was knocked down to determine the role of nestin in podocyte injury. Inhibitors and RNAi method were used to explore the role of mitophagy and oxidative stress in nestin protection of podocyte from damage. There was a significantly negative correlation between nestin and proteinuria both in LN patients and MRL/lpr mice, whereas the expression of nephrin was positively correlated with nestin. Knockdown of nestin resulted in not only the decrease of nephrin, p-nephrin (Y1217) and mitophagy-associated proteins in cultured podocytes and the podocytes of MRL/lpr mice, but also mitochondrial dysfunction in podocytes stimulated with LN plasma. The expression and phosphorylation of nephrin was significantly decreased by reducing the level of mitophagy or production of reactive oxygen species (ROS) in cultured podocytes. Our findings suggested that nestin regulated the expression of nephrin through mitophagy and oxidative stress to protect the podocytes from injury in LN.

Clinical significance of progranulin correlated with serum soluble Oxford 40 ligand in primary Sjögren's syndrome.

The present study aimed to investigate the association between the expressions of serum progranulin (PGRN) and serum soluble Oxford 40 ligand (sOX40L) and determine their clinical significances in primary Sjögren's syndrome (pSS).The present study included a total of 68 patients with pSS and 50 healthy controls. Demographic data and clinical basic information were collected. Enzyme-linked immunosorbent assay (ELISA) was performed to determine serum levels of PGRN, sOX40L and interleukins. Spearman's correlation coefficient and Mann-Whitney U test were used to determine the correlation between PGRN, and sOX40L and the association between PGRN and sOX40L and disease activity and disease severity.Serum interleukin (IL)-4, IL-6, IL-10, PGRN, and sOX40L levels were significantly higher in pSS patients as compared to the healthy controls. A positive correlation was observed between PGRN and sOX40L. Patients with elevated levels of PGRN or sOX40L exhibited higher disease activity compared to those with lower levels. Patients with III to IV stages of pSS or multiple system damage showed higher serum levels of PGRN and sOX40L.Elevated serum PGRN, and sOX40L levels were relevant with disease activity and severity in patients with pSS.

The increased virulence of hypervirulent fowl adenovirus 4 is independent of fiber-1 and penton.

Hepatitis-hydropericardium syndrome (HHS) caused by hypervirulent fowl adenovirus 4 (FAdV-4) have been causing great economic losses to Chinese poultry industry since 2015. Elucidation of the pathogenesis of FAdV-4 will lay solid foundation for developing attenuated FAdV-4 vaccine and vaccine vector. Our previous study has demonstrated that the increased virulence of hypervirulent FAdV-4 was associated with fiber-2 and hexon genes. However, the roles of fiber-1 and penton in virulence of FAdV-4 have never been elucidated. To further investigate the roles of the major structural proteins fiber-1 and penton in the virulence of hypervirulent FAdV-4, the fiber-1- and penton-replaced mutant viruses were constructed based on the FAdV-4 infectious clones of hypervirulent strain HNJZ using Redαß recombineering techniques. The pathogenicity of the rescued viruses was evaluated in 3-week-old SPF chickens. Chickens infected with the rescued recombinant viruses carrying the fiber-1 or penton base gene from a nonpathogenic strain ON1 developed similar clinical signs to the natural hypervirulent FAdV-4 infection, including HHS-indicative gross lesions and histopathological changes in sick/dead chickens. Our results suggested that the increased virulence of hypervirulent FAdV-4 was independent of fiber-1 and penton. The detailed pathogenesis of FAdV-4 and the roles of fiber-1 and penton in the viral replication and infection process need to be further explored.

Effect of (m)RVD-hemopressin against Aß1-42-induced apoptosis and inhibition of neurite outgrowth in SH-SY5Y cells.

Alzheimer's disease (AD) is a serious neurodegenerative disease. Senile plaques (SPs) in the extracellular space and neurofibrillary tangles (NFTs) in the intracellular areas of the brain are two typical features of AD. SPs and NFTs are composed of amyloid-ß (Aß) aggregates and hyperphosphorylated Tau, respectively. (m)RVD-hemopressin (RVD), which is derived from mouse brain peptide, binds to the cannabinoid 1 receptor (CB1R) as an agonist. Our previous study indicated that RVD reversed Aß1-42-induced memory impairment in mice. Here, we investigated the underlying molecular mechanism of RVD on Aß1-42-induced neurotoxicity in retinoic acid-differentiated human neuroblastoma SH-SY5Y cells. Cell viability and neurite outgrowth were investigated by live cell imaging and analysis instrument. We found that RVD reversed Aß1-42-induced Tau phosphorylation, apoptosis and suppression of neurite outgrowth and the synapse-associated protein postsynaptic density protein 95 (PSD-95) by inhibiting the activity of protein kinase A (PKA) and glycogen synthase kinase 3ß (GSK-3ß). Combined treatment with AM251 (a CB1R antagonist) blocked the effects of RVD. In conclusion, RVD may be a potential therapeutic agent for the treatment of cognitive dysfunctions, such as Alzheimer's disease.

Protection of chickens against hepatitis-hydropericardium syndrome and Newcastle disease with a recombinant Newcastle disease virus vaccine expressing the fowl adenovirus serotype 4 fiber-2 protein.

Newcastle disease (ND) is one of the most important and devastating avian diseases with considerable threat to the global poultry industry. Hepatitis-hydropericardium syndrome (HHS), caused by virulent fowl adenovirus serotype 4 (FAdV-4), is another highly infectious disease in chickens with severe economic impact. The effective way to combat ND and HHS is by vaccinating the poultry. In the present study, a recombinant NDV LaSota vaccine strain expressing full length fiber-2 gene of FAdV-4 (rLaSota-fiber2) was generated using reverse genetics. The FAdV-4 fiber-2 protein was expressed as a soluble form rather than NDV membrane-anchored form. The rLaSota-fiber2 was genetically stable, and it showed growth patterns in embryonated eggs comparable to that of parental rLaSota virus. Since our unpublished data demonstrated that delivery of live rLaSota-fiber2 in drinking water or ocular delivery of the vaccine didn't produce protection against hypervirulent FAdV-4 challenge, even though the vaccine provide full protection against NDV challenge, the efficacy of the rLaSota-fiber2 was evaluated by delivering the vaccine intramuscularly in this study. Single-dose intramuscular vaccination of 2-week-old SPF White Leghorn chicks with the live or inactivated rLaSota-fiber2 provided complete protection against virulent NDV challenge. However, single-dose intramuscular vaccination with the live rLaSota-fiber2 vaccine provided better protection against virulent FAdV-4 challenge and significantly reduced faecal viral shedding comparing to the inactivated vaccine. These results indicate that the NDV-vectored FAdV-4 vaccine is a promising bivalent vaccine candidate to control both HHS and ND.

Risk factors for the formation of double-contour sign and tophi in gout.

BACKGROUND: This study aimed to confirm the diagnostic accuracy of ultrasound (US) on gout and explore the potential risk factors for double-contour sign and tophi formation in gout patients. METHODS: The US analyses were performed on all knee, ankle, and first metatarsophalangeal (MTP 1) joints to reveal the type and location of lesions. While a questionnaire and blood biochemical index were used to explore the potential risk factors for double-contour sign and tophi in gout, the SPSS17.0 software was used for statistical analysis in the present study. RESULTS: Totally, 117 gout patients with 702 joints (38 lesions in knee joint, 93 lesions in ankle joint, and 112 lesions in MTP 1 joint) were enrolled in current analyses. Double-contour sign and joint effusion were the two most outstanding lesion manifestations in knee joints and ankle joints. Tophi and double-contour sign were the two most outstanding lesion manifestations in TMP 1 joints. Moreover, factors including uric acid (UA) level and the highest blood UA were potential risk factors of the double-contour sign, while age and history of US were potential risk factors for tophi. CONCLUSION: US was effective on the joints of gout patients. There was US sensitivity for tophi and double-contour sign in MTP 1 joints. The double-contour sign was a potential specific manifestation in knee joints and ankle joints. Furthermore, UA and highest blood UA level were potential risk factors for double-contour sign, while age and US history were potential risk factors for tophi.

Improvement on Natural Enemies of Bemisia tabaci (Hemiptera: Aleyrodidae) Using Extracts of Agrimonia pilosa.

Compared with the numerous natural enemies against insect pests that have been identified, the commercialization of natural biological control resources remains very limited. To increase the use of natural enemies for biological control, determining how to improve the low efficacy, slow speed, and high cost of natural enemies is very important. Mediterranean species of The whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodoidea), increasingly threatens many crops in China, and control primarily depends on chemical insecticides. Here, the effect of ethanol extracts from two plants, Agrimonia pilosa (Ledeb) (Rosales: Rosaceae) and Melia azedarach (Linn) (Meliaceae: Melia), on predominant natural enemies of B. tabaci was investigated using a leaf dipping or spraying method. The results showed that the ethanol extract of A. pilosa significantly improved the infectivity of the fungus Isaria javanica (Friedrichs & Bally) (Ascomycota: Hypocreales), and the mortality of whiteflies caused by the combination of fungus (105 spores/mL) with the extract of A. pilosa (2 mg/mL dried powder of A. pilosa containing 0.0942 mg/mL total polyphenols) was 81.6%, which was significantly higher than that caused by the fungus only. However, the ethanol extract of M. azedarach had no effect on fungus infectivity. Additionally, insecticide tolerance of the predator Pardosa pseudoannulata was also significantly improved by the extract of A. pilosa. The longevity of the parasitoid Encarsia formosa was not affected by the extracts. These findings indicate that the extract of A. pilosa played a dual role that included improving pathogenic fungi infectivity and insecticidal tolerance of a predator and thus could be a synergist in the biological control of B. tabaci.

Novel cathepsin K inhibitors block osteoclasts in vitro and increase spinal bone density in zebrafish.

Cathepsin K (Cat K) is a predominant cysteine protease and highly potent collagenase expressed in osteoclasts. Cat K inhibitors are anti-resorptive agents to treat osteoporosis. A novel scaffold of cathepsin K inhibitors, exemplified by lead compound 1x, was used as the template for designing and synthesizing a total of 61 derivatives that have not been reported before. An exploratory structure-activity relationship analysis identified the potent Cat K inhibitor A22, which displayed an IC50 value of 0.44 µM against Cat K. A22 was very specific for Cat K and caused a significantly higher in vitro inhibition of the enzyme as compared to that of lead compound 1x. A surface plasmon resonance analysis confirmed in vitro binding of A22 to Cat K. Molecular docking studies indicated several favourable interaction sites for A22 within the active pocket of Cat K. Furthermore, A22 also blocked active osteoclasts in vitro and increased spinal bone density in zebrafish, in which it showed an activity that was higher than that of the marketed therapeutic bone metabolizer etidronate disodium. A22 represents a very promising lead compound for the development of novel antiresorptive agents functioning as orthosteric inhibitors of Cat K.