Deficits of the "Good" Eye in Amblyopia: Processing Geometric Properties.

Purpose: Although fellow eyes of amblyopia are typically considered normal, recent studies have revealed impairments in certain aspects of vision. However, it remains unclear at which level of object processing these impairments occur. This study aims to investigate the functional level of visual perception impairment in the fellow eye of children and adults with amblyopia using the geometric functional hierarchy discrimination task based on Klein Mathematics methodology. Methods: Seventy-six patients with amblyopia (40 children and 36 adults) and 77 age-matched healthy controls (40 children and 37 adults) were recruited for this study. The participants completed four sets of geometric hierarchies (in ascending order of stability: Euclidean, affine, projective, and topology) and one set of color discrimination tasks. They were instructed to rapidly and accurately select a distinct shape from the four quadrants. Results: The participants' performance was evaluated using the inverse efficiency (IE) score (IE = response time (RT)/accuracy). The results of IEs show that the fellow eye of children with amblyopia exhibits normal topological processing, yet displays higher IEs in other geometric properties and color processing, suggesting impairments in these specific discrimination abilities. However, adults with amblyopia did not show deficits on any discrimination types compared with adult controls. Conclusions: The lack of compromised topological processing suggests that amblyopia may not have inflicted any damage to the subcortical visual pathways. Furthermore, these deficits observed in the fellow eye tend to diminish significantly during adulthood, implying that amblyopia may potentially hinder the maturation process of the fellow eye.

Females adopt sexual catalepsy to facilitate mating.

Theory predicts that males and females of dioecious species typically engage in an evolutionary sexual conflict over the frequency and choice of mating partner. Female sexual cannibalism, a particularly dramatic illustration of this conflict, is widespread in certain animal taxa including spiders. Nevertheless, females of some funnel weaving spiders that are generally aggressive to conspecifics enter a cataleptic state after male courtship, ensuring the males can mate without risk of attack. In this study, we demonstrated that the physical posture and duration, metabolites, and central neurotransmitters of females of Aterigena aculeata in sexual catalepsy closely resemble females in thanatosis but are distinct from those in anesthesia, indicating that the courted females feign death to eliminate the risk of potentially aggressive responses and thereby allow preferred males to mate. Unlike the taxonomically widespread thanatosis, which generally represents a deceptive visual signal that acts against the interest of the receivers, sexual catalepsy of females in the funnel weaving spiders may deliver a sexual-receptive signal to the courting males and thereby benefit both the signal senders and receivers. Therefore, sexual catalepsy in A. aculeata may not reflect a conflict but rather a confluence of interest between the sexes.

Recent advances of m6A methylation in skeletal system disease.

Skeletal system disease (SSD) is defined as a class of chronic disorders of skeletal system with poor prognosis and causes heavy economic burden. m6A, methylation at the N6 position of adenosine in RNA, is a reversible and dynamic modification in posttranscriptional mRNA. Evidences suggest that m6A modifications play a crucial role in regulating biological processes of all kinds of diseases, such as malignancy. Recently studies have revealed that as the most abundant epigentic modification, m6A is involved in the progression of SSD. However, the function of m6A modification in SSD is not fully illustrated. Therefore, make clear the relationship between m6A modification and SSD pathogenesis might provide novel sights for prevention and targeted treatment of SSD. This article will summarize the recent advances of m6A regulation in the biological processes of SSD, including osteoporosis, osteosarcoma, rheumatoid arthritis and osteoarthritis, and discuss the potential clinical value, research challenge and future prospect of m6A modification in SSD.

Design, synthesis and anti-osteosarcoma activity study of novel pyrido[2,3-d]pyrimidine derivatives by inhibiting DKK1-Wnt/ß-catenin pathway.

Osteosarcoma is a common primary malignant bone tumor in adolescents. Wnt/ß-catenin has been proved to play a pro-oncogenic role and was overactivated in osteosarcoma. Therefore, this pathway has become an interesting therapeutic target for osteosarcoma. Herein we report the design, synthesis and biological activities of a series of novel pyrido[2,3-d]pyrimidine derivatives based on our previous work. Among these, the representative compound 2-{[1,3-dimethyl-7-(4-methylpiperazin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl]amino}-N-[4-(trifluoromethoxy)phenyl]acetamide (7m) has exhibited good antiproliferative activity towards 143B and MG63 cells with good selectivity over non-cancerous HSF cells. In the assay of Ca2+ concentration, the compound 7m increased the intracellular Ca2+ concentration in 143B cells. In addition, the expression of DKK1 increased, and that of p-ß-catenin decreased by 7m treatment. Finally, the Hoechst 33,342 staining, Annexin-FITC/PI staining and mitochondrial fluorescence staining have clearly demonstrated that compound 7m induced apoptosis in 143B cells.

RNA binding proteins in extracellular vesicles and their potential value for cancer diagnosis and treatment (Review).

Extracellular vesicles (EVs) are spherical bilayer membrane vesicles released by cells into extracellular spaces and body fluids, including plasma and synovial fluid. EV cargo comprises various biomolecules, such as proteins, DNA, mRNAs, non­coding RNAs, lipids and metabolites. By delivering these bioactive molecules to recipient cells, EVs mediate intercellular communications and play a critical role in maintaining cellular homeostasis and promoting pathological progression. Of note, cells can selectively sort these bioactive molecules (particularly RNAs) into EVs for secretion, as well as regulate cell­cell communications. RNA­binding proteins (RBPs) are a large class of proteins capable of binding to RNA molecules and function in regulating RNA metabolism. There is increasing evidence to indicate that RBPs can be delivered to receipt cells to influence their cell biology and play a significant role in the sorting of coding and non­coding RNAs in EVs. The present review summarized the current knowledge on EV­associated RBPs, their functions in tumorigenesis and RBP­related exosome engineering. It is hoped that the present review may provide novel insight into RBPs and targeted cancer treatment.

Coptisine Inhibits Influenza Virus Replication by Upregulating p21.

The activation of innate antiviral immunity is a promising approach for combatting viral infections. In this study, we screened Chinese herbs that activated human immunity and identified coptisine as a potent inhibitor of the influenza virus with an EC50 of 10.7 µM in MDCK cells. The time of an addition assay revealed that pre-treatment with coptisine was more effective at reducing viral replication than co-treatment or post-treatment. Our bulk RNA-sequencing data showed that coptisine upregulated the p21 signaling pathway in MDCK cells, which was responsible for its antiviral effects. Specifically, coptisine increased the expression of p21 and FOXO1 in a dose-dependent manner while leaving the MELK expression unchanged. Docking analysis revealed that coptisine likely inhibited MELK activity directly by forming hydrogen bonds with ASP-150 and GLU-87 in the catalytic pocket. These findings suggest that coptisine may be a promising antiviral agent that regulates the p21 signaling pathway to inhibit viral replication.

ADRM1/RPN13 attenuates cartilage extracellular matrix degradation via enhancing UCH37-mediated ALK5 deubiquitination.

Osteoarthritis (OA) is the most common age-related joint disorder with no effective therapy, and its specific pathological mechanism remains to be fully clarified. Adhesion-regulating molecule 1 (ADRM1) has been proven to be involved in OA progression as a favorable gene. However, the exact mechanism of ADRM1 involved in OA were unknown. Here, we showed that the ADRM1 expression decreased in human OA cartilage, destabilization of the medial meniscus (DMM)-induced mouse OA cartilage, and interleukin (IL)-1ß-induced primary mouse articular chondrocytes. Global knockout (KO) ADRM1 in cartilage or ADRM1 inhibitor (RA190) could accelerate the disorders of extracellular matrix (ECM) homeostasis, thereby accelerated DMM-induced cartilage degeneration, whereas overexpression of ADRM1 protected mice from DMM-induced OA development by maintaining the homeostasis of articular cartilage. The molecular mechanism study revealed that ADRM1 could upregulate ubiquitin carboxy-terminal hydrolase 37 (UCH37) expression and bind to UCH37 to activate its deubiquitination activity. Subsequently, increased and activated UCH37 enhanced activin receptor-like kinase 5 (ALK5) deubiquitination to stabilize ALK5 expression, thereby maintaining ECM homeostasis and attenuating cartilage degeneration. These findings indicated that ADRM1 could attenuate cartilage degeneration via enhancing UCH37-mediated ALK5 deubiquitination. Overexpression of ADRM1 in OA cartilage may provide a promising OA therapeutic strategy.

Secoisolariciresinol diglucoside Ameliorates Osteoarthritis via Nuclear factor-erythroid 2-related factor-2/ nuclear factor kappa B Pathway: In vitro and in vivo experiments.

Osteoarthritis (OA) is an age-related joint disease in which inflammation and extracellular matrix (ECM) degradation play a crucial role in the destruction of articular cartilage. Secoisolariciresinol diglucoside (SDG), the main lignan in wholegrain flaxseed, which has been reported to remarkably suppress inflammation and oxidative stress, may have potential therapeutic value in OA. In this study, the effect and mechanism of SDG against cartilage degeneration were verified in the destabilization of the medial meniscus (DMM) and collagen-induced (CIA) arthritis models and interleukin-1ß (IL-1ß)-stimulated osteoarthritis chondrocyte models. From our experiments, SDG treatment downregulated the expression of pro-inflammatory factors induced by IL-1ß in vitro, including inducible nitric oxide synthase (INOS), cyclooxygenase-2 (COX2), tumor necrosis factor (TNF-α), and interleukin 6 (IL-6). Additionally, SDG promoted the expression of collagen II (COL2A1) and SRY-related high-mobility-group-box gene 9(SOX9), while suppressing the expression of a disintegrin and metalloproteinase with thrombospondin motifs 5(ADAMTS5) and matrix metalloproteinases 13(MMP13), which leads to catabolism. Consistently, in vivo, SDG has been identified to have chondroprotective effects in DMM-induced and collagen-induced arthritis models. Mechanistically, SDG exerted its anti-inflammation and anti-ECM degradation effects by activating the Nrf2/HO-1 pathway and inhibiting the nuclear factor kappa B (NF-κB) pathway. In conclusion, SDG ameliorates the progression of OA via the Nrf2/NF-κB pathway, which indicates that SDG may have therapeutic potential for OA.

Identification of several inflammation-related genes based on bioinformatics and experiments.

BACKGROUND: Osteoarthritis (OA) is a common disease of elderly individuals, with an unclear pathogenesis and limited treatment options to date. Inflammation occurs prominently in osteoarthritis, thereby making anti-inflammatory treatments promising in clinical outcomes. Therefore, it is of diagnostic and therapeutic significance to explore more inflammatory genes. METHOD: In this study, appropriate datasets were first acquired through gene set enrichment analysis (GSEA), followed by inflammation-related genes through weighted gene coexpression network analysis (WGCNA). Two machine learning algorithms (random forest-RF and support vector machine-recursive feature elimination, SVM-RFE) were used to capture the hub genes. In addition, two genes negatively associated with inflammation and osteoarthritis were identified. Afterwards, these genes were verified through experiments and network pharmacology. Due to the association between inflammation and many diseases, the expression levels of the above genes in various inflammatory diseases were determined through literature and experiments. RESULT: Two hub genes closely related to osteoarthritis and inflammation were obtained, namely, lysyl oxidase-like 1 (LOXL1) and pituitary tumour-transforming gene (PTTG1), which were shown to be highly expressed in osteoarthritis according to the literature and experiments. However, the expression levels of receptor expression-enhancing protein (REEP5) and cell division cycle protein 14B (CDC14B) remained unchanged in osteoarthritis. This finding was consistent with our verification from the literature and experiments that some genes were highly expressed in numerous inflammation-related diseases, while REEP5 and CDC14B were almost unchanged. Meanwhile, taking PTTG1 as an example, we found that inhibition of PTTG1 expression could suppress the expression of inflammatory factors and protect the extracellular matrix through the microtubule-associated protein kinase (MAPK) signalling pathway. CONCLUSIONS: LOXL1 and PTTG1 were highly expressed in some inflammation-related diseases, while that of REEP5 and CDC14B were almost unchanged. PTTG1 may be a potential target for the treatment of osteoarthritis.

Identification of Andrographolide as a novel FABP4 inhibitor for osteoarthritis treatment.

BACKGROUND AND PURPOSE: Fatty acid binding protein 4 (FABP4) has been identified as a contributor to cartilage degradation in osteoarthritis (OA) patients, and inhibiting FABP4 using small molecules has emerged as a promising approach for developing OA drugs. Our previous research showed that Andrographis paniculata, a medicinal plant, strongly inhibits FABP4 activity. This led us to hypothesize that Andrographis paniculata ingredients might have protective effects on OA cartilage through FABP4 inhibition. METHODS: We analyzed scRNA-seq data from joint tissue of OA patients (GSE152805; GSE145286) using Scanpy 1.9.1 and Single Cell Portal. We conducted docking analysis of FABP4 inhibitors using Autodock Vina v.1.0.2. We evaluated the anti-FABP4 activity using a fluorescence displacement assay and measured the fatty acid oxidation (FAO) activity using the FAOBlue assay. We used H2DCF-DA to measure reactive oxygen species (ROS) levels. We studied signaling pathways using bulk RNA sequencing and western blot analysis in human C28/I2 chondrocytes. We evaluated anti-OA activity in monosodium iodoacetate (MIA)-induced rats. RESULTS: We identified Andrographolide (AP) as a novel FABP4 inhibitor. Bulk RNA-sequencing analysis revealed that FABP4 upregulated FAO and ROS in chondrocytes, which was inhibited by AP. ROS generation activated the NF-κB pathway, leading to overexpression of a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4), which is a responsible factor for cartilage degradation in OA patients. AP inhibited FABP4, thereby reducing the overexpression of ADAMTS4 by inhibiting the NF-κB pathway. In MIA rats, AP treatment reduced the overexpression of ADAMTS4, repaired cartilage and subchondral bone, and promoted cartilage regeneration. CONCLUSION: Our results indicate that the inhibition of FABP4 activity by AP explains the anti-OA properties of Andrographis paniculata by protecting against cartilage degradation in OA patients. Additionally, our findings suggest that AP may be a promising therapeutic agent for OA treatment due to its ability to alleviate cartilage damage and bone erosion.

An Adaptive Dual-Population Collaborative Chicken Swarm Optimization Algorithm for High-Dimensional Optimization.

With the development of science and technology, many optimization problems in real life have developed into high-dimensional optimization problems. The meta-heuristic optimization algorithm is regarded as an effective method to solve high-dimensional optimization problems. However, considering that traditional meta-heuristic optimization algorithms generally have problems such as low solution accuracy and slow convergence speed when solving high-dimensional optimization problems, an adaptive dual-population collaborative chicken swarm optimization (ADPCCSO) algorithm is proposed in this paper, which provides a new idea for solving high-dimensional optimization problems. First, in order to balance the algorithm's search abilities in terms of breadth and depth, the value of parameter G is given by an adaptive dynamic adjustment method. Second, in this paper, a foraging-behavior-improvement strategy is utilized to improve the algorithm's solution accuracy and depth-optimization ability. Third, the artificial fish swarm algorithm (AFSA) is introduced to construct a dual-population collaborative optimization strategy based on chicken swarms and artificial fish swarms, so as to improve the algorithm's ability to jump out of local extrema. The simulation experiments on the 17 benchmark functions preliminarily show that the ADPCCSO algorithm is superior to some swarm-intelligence algorithms such as the artificial fish swarm algorithm (AFSA), the artificial bee colony (ABC) algorithm, and the particle swarm optimization (PSO) algorithm in terms of solution accuracy and convergence performance. In addition, the APDCCSO algorithm is also utilized in the parameter estimation problem of the Richards model to further verify its performance.

Shang-Ke-Huang-Shui and coptisine alleviate osteoarthritis in the knee of monosodium iodoacetate-induced rats through inhibiting CXCR4 signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Shang-Ke-Huang-Shui (SKHS) is a classic traditional Chinese medicine formula originally from the southern China city of Foshan. It has been widely used in the treatment of osteoarthritis (OA) but underlying molecular mechanisms remain unclear. AIM OF STUDY: Recently, activation of C-X-C chemokine receptor type 4 (CXCR4) signaling has been reported to induce cartilage degradation in OA patients; therefore, inhibition of CXCR4 signaling has becoming a promising approach for OA treatment. The aim of this study was to validate the cartilage protective effect of SKHS and test whether the anti-OA effects of SKHS depend on its inhibition on CXCR4 signaling. Additionally, CXCR4 antagonist in SKHS should be identified and its anti-OA activity should also be tested in vitro and in vivo. METHODS: The anti-OA effects of SKHS and the newly identified CXCR4 antagonist was evaluated by monosodium iodoacetate (MIA)-induced rats. The articular cartilage surface was examined by hematoxylin and eosin (H&E) staining and Safranin O-Fast Green (S-F) staining whereas the subchondral bone was examined by micro-CT. CXCR4 antagonist screenings were conducted by molecular docking and calcium response assay. The CXCR4 antagonist was characterized by UPLC/MS/MS. The bulk RNA-Seq was conducted to identify CXCR4-mediated signaling pathway. The expression of ADAMTS4,5 was tested by qPCR and Western blot. RESULTS: SKHS protected rats from MIA-induced cartilage degradation and subchondral bone damage. SKHS also inhibited CXCL12-indcued ADAMTS4,5 overexpression in chondrocytes through inhibiting Akt pathway. Coptisine has been identified as the most potent CXCR4 antagonist in SKHS. Coptisine reduced CXCL12-induced ADAMTS4,5 overexpression in chondrocytes. Furthermore, in MIA-induced OA model, the repaired cartilage and subchondral bone were observed in the coptisine-treated rats. CONCLUSION: We first report here that the traditional Chinese medicine formula SKHS and its predominate phytochemical coptisine significantly alleviated cartilage degradation as well as subchondral bone damage through inhibiting CXCR4-mediated ADAMTS4,5 overexpression. Together, our work has provided an important insight of the molecular mechanism of SKHS and coptisine for their treatment of OA.

The roles of ubiquitin-proteasome system and regulator of G protein signaling 4 in behavioral sensitization induced by a single morphine exposure.

AIMS: Opioid addiction is a major public health issue, yet its underlying mechanism is still unknown. The aim of this study was to explore the roles of ubiquitin-proteasome system (UPS) and regulator of G protein signaling 4 (RGS4) in morphine-induced behavioral sensitization, a well-recognized animal model of opioid addiction. METHODS: We explored the characteristics of RGS4 protein expression and polyubiquitination in the development of behavioral sensitization induced by a single morphine exposure in rats, and the effect of a selective proteasome inhibitor, lactacystin (LAC), on behavioral sensitization. RESULTS: Polyubiquitination expression was increased in time-dependent and dose-related fashions during the development of behavioral sensitization, while RGS4 protein expression was not significantly changed during this phase. Stereotaxic administration of LAC into nucleus accumbens (NAc) core inhibited the establishment of behavioral sensitization. CONCLUSION: UPS in NAc core is positively involved in behavioral sensitization induced by a single morphine exposure in rats. Polyubiquitination was observed during the development phase of behavioral sensitization, while RGS4 protein expression was not significantly changed, indicating that other members of RGS family might be substrate proteins in UPS-mediated behavioral sensitization.

Astragaloside IV as a novel CXCR4 antagonist alleviates osteoarthritis in the knee of monosodium iodoacetate-induced rats.

BACKGROUND AND PURPOSE: C-X-C chemokine receptor type 4 (CXCR4) inhibition protects cartilage in osteoarthritis (OA) animal models. Therefore, CXCR4 has becoming a novel target for OA drug development. Since dietary and herbal supplements have been widely used for joint health, we hypothesized that some supplements exhibit protective effects on OA cartilage through inhibiting CXCR4 signaling. METHODS: The single-cell RNA sequencing data of OA patients (GSE152805) was re-analyzed by Scanpy 1.9.0. The docking screening of CXCR4 antagonists was conducted by Autodock Vina 1.2.0. The CXCR4 antagonistic activity was evaluated by calcium response in THP-1 cells. Signaling pathway study was conducted by bulk RNA sequencing and western blot analysis in human C28/I2 chondrocytes. The anti-OA activity was evaluated in monosodium iodoacetate (MIA)-induced rats. RESULTS: Astragaloside IV (ASN IV), the predominate phytochemical in Astragalus membranaceus, has been identified as a novel CXCR4 antagonist. ASN IV reduced CXCL12-induced ADAMTS4,5 overexpression in chondrocytes through blocking Akt signaling pathway. Furthermore, ASN IV administration significantly repaired the damaged cartilage and subchondral bone in MIA-induced rats. CONCLUSION: The blockade of CXCR4 signaling by ASN IV could explain anti-OA activities of Astragalus membranaceus by protection of cartilage degradation in OA patients. Since ASN IV as an antiviral has been approved by China National Medical Products Administration for testing in people, repurposing of ASN IV as a joint protective agent might be a promising strategy for OA drug development.

Predicting In Vitro and In Vivo Anti-SARS-CoV-2 Activities of Antivirals by Intracellular Bioavailability and Biochemical Activity.

Cellular drug response (concentration required for obtaining 50% of a maximum cellular effect, EC50) can be predicted by the intracellular bioavailability (F ic) and biochemical activity (half-maximal inhibitory concentration, IC50) of drugs. In an ideal model, the cellular negative log of EC50 (pEC50) equals the sum of log F ic and the negative log of IC50 (pIC50). Here, we measured F ic's of remdesivir, favipiravir, and hydroxychloroquine in various cells and calculated their anti-SARS-CoV-2 EC50's. The predicted EC50's are close to the observed EC50's in vitro. When the lung concentrations of antiviral drugs are higher than the predicted EC50's in alveolar type 2 cells, the antiviral drugs inhibit virus replication in vivo, and vice versa. Overall, our results indicate that both in vitro and in vivo antiviral activities of drugs can be predicted by their intracellular bioavailability and biochemical activity without using virus. This virus-free strategy can help medicinal chemists and pharmacologists to screen antivirals during early drug discovery, especially for researchers who are not able to work in the high-level biosafety lab.

An Improved Chicken Swarm Optimization Algorithm for Solving Multimodal Optimization Problems.

To solve the premature convergence problem of the standard chicken swarm optimization (CSO) algorithm in dealing with multimodal optimization problems, an improved chicken swarm optimization (ICSO) algorithm is proposed by referring to the ideas of bacterial foraging algorithm (BFA) and particle swarm optimization (PSO) algorithm. First, in order to improve the depth search ability of the algorithm, considering that the chicks have the weakest optimization ability in the whole chicken swarm, the replication operation of BFA is introduced. In the role update process of the chicken swarm, the chicks are replaced by the same number of chickens with the strongest optimization ability. Then, to maintain the population diversity, the elimination-dispersal operation is introduced to disperse the chicks that have performed the replication operation to any position in the search space according to a certain probability. Finally, the PSO algorithm is integrated to improve the global optimization ability of the algorithm. The experimental results on the CEC2014 benchmark function test suite show that the proposed algorithm has good performance in most test functions, and its optimization accuracy and convergence performance are also better than BFA, artificial fish swarm algorithm (AFSA), genetic algorithm (GA), and PSO algorithm, etc. In addition, the ICSO is also utilized to solve the welded beam design problem, and the experimental results indicate that the proposed algorithm has obvious advantages over other comparison algorithms. Its disadvantage is that it is not suitable for dealing with large-scale optimization problems.

Glycyrrhizin Inhibits SARS-CoV-2 Entry into Cells by Targeting ACE2.

Coronavirus Disease 2019 (COVID-19) is a highly infectious and pathogenic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Early in this epidemic, the herbal formulas used in traditional Chinese medicine (TCM) were widely used for the treatment of COVID-19 in China. According to Venn diagram analysis, we found that Glycyrrhizae Radix et Rhizoma is a frequent herb in TCM formulas against COVID-19. The extract of Glycyrrhizae Radix et Rhizoma exhibits an anti-SARS-CoV-2 replication activity in vitro, but its pharmacological mechanism remains unclear. We here demonstrate that glycyrrhizin, the main active ingredient of Glycyrrhizae Radix et Rhizoma, prevents the coronavirus from entering cells by targeting angiotensin-converting enzyme 2 (ACE2). Glycyrrhizin inhibited the binding of the spike protein of the SARS-CoV-2 to ACE2 in our Western blot-based assay. The following bulk RNA-seq analysis showed that glycyrrhizin down-regulated ACE2 expression in vitro which was further confirmed by Western blot and quantitative PCR. Together, we believe that glycyrrhizin inhibits SARS-CoV-2 entry into cells by targeting ACE2.