Wear particle-induced inflammatory osteoclast activation is a master contributor to periprosthetic osteolysis, which can cause pathological bone loss and destruction. Hence, inhibiting inflammation and osteoclastogenesis is an important strategy for preventing wear particle-induced osteolysis. To date, there are no FDA-approved non-surgical pharmacotherapies for arresting periprosthetic osteolysis. Kaempferol (KAE), a natural flavonol abundant in many traditional Chinese herbal medicines, has been shown to have protective effects against inflammatory bone diseases such as rheumatoid arthritis, but no previous study has evaluated the effects of KAE on wear particle-induced osteolysis.The study aimed to investigate the effects of KAE on wear particle-induced inflammatory osteolysis and osteoclast activation, and further explore the underlying mechanisms.TiAl6V4 metal particles (TiPs) were retrieved from the prosthesis of patients who underwent revision hip arthroplasty due to aseptic loosening. A mouse calvarial osteolysis model was used to investigate the effects of KAE on wear particle-induced inflammatory osteolysis in vivo. Primary bone marrow-derived macrophages (BMMs) were used to explore the effects of KAE on osteoclast differentiation and bone-resorbing activity as well as the underlying mechanisms in vitro.In the present study, we found that KAE alleviated wear particle-induced inflammatory bone loss in vivo and inhibited osteoclast differentiation and function in vitro. Furthermore, we revealed that KAE exerted anti-osteoclastogenic effects by downregulating JNK and p38-MAPK signaling as well as the downstream NFATc1 expression.KAE is an alternative therapeutic agent for preventing and treating periprosthetic osteolysis and aseptic loosening. 

Kaempferol attenuates wear particle-induced inflammatory osteolysis via JNK and p38-MAPK signaling pathways

Abstract The inference of gene regulatory networks (GRNs) from gene expression profiles has been a key issue in systems biology, prompting many researchers to develop diverse computational methods. However, most of these methods do not reconstruct directed GRNs with regulatory types because of the lack of benchmark datasets or defects in the computational methods. Here, we collect benchmark datasets and propose a deep learning-based model, DeepFGRN, for reconstructing fine gene regulatory networks (FGRNs) with both regulation types and directions. In addition, the GRNs of real species are always large graphs with direction and high sparsity, which impede the advancement of GRN inference. Therefore, DeepFGRN builds a node bidirectional representation module to capture the directed graph embedding representation of the GRN. Specifically, the source and target generators are designed to learn the low-dimensional dense embedding of the source and target neighbors of a gene, respectively. An adversarial learning strategy is applied to iteratively learn the real neighbors of each gene. In addition, because the expression profiles of genes with regulatory associations are correlative, a correlation analysis module is designed. Specifically, this module not only fully extracts gene expression features, but also captures the correlation between regulators and target genes. Experimental results show that DeepFGRN has a competitive capability for both GRN and FGRN inference. Potential biomarkers and therapeutic drugs for breast cancer, liver cancer, lung cancer and coronavirus disease 2019 are identified based on the candidate FGRNs, providing a possible opportunity to advance our knowledge of disease treatments.

DeepFGRN: inference of gene regulatory network with regulation type based on directed graph embedding

Grain refinement strengthening is crucial for Mg alloys. However, refined grains can facilitate grain boundary migration during high-temperature creep, usually unfavorably affecting high-temperature creep properties. Al was incorporated into Mg-Y alloy to address this trade-off between fine-grained structures and creep properties, causing the refinement of the Mg-Y alloy (average grain size of 73.2 ± 2.9 μm) while maintaining excellent creep resistance. At 300 °C/50 MPa, the Al-refined alloy exhibited the minimum creep rate of 1.31 × 10-8 s-1, representing a 62% reduction compared to that of the Mg-Y alloy without Al refinement. During high-temperature creep, the thermally stable Al2Y and long-period stacking ordered (LPSO)/stacking faults (SFs) phases introduced by Al addition effectively pin grain boundaries and impede dislocation movement, which could thus enhance the alloy's creep resistance. Meanwhile, Al addition reduces stacking fault energy (SFE), rendering dislocation climb more challenging and further enhancing the alloy's creep resistance. This study employs Al to refine Mg-Y alloys, achieving grain refinement while enhancing creep resistance, providing a novel method for developing Mg-RE alloys with both refined grains and creep resistance. 

Grain refinement and exceptional creep resistance achieved in an as-cast Mg-Y alloy with Al addition

Over the last couple of decades, three highly pathogenic and deadly human coronaviruses have posed dreadful impacts on human life, namely SARS-CoV, MERS-CoV and SARS-CoV-2. In addition, many other viral diseases also affect various aspects of human well-being such as lifestyles and socio-economic conditions. Therefore, research on developing antiviral drugs should be progressively carried out to rapidly prevent or reduce the severity of infection for the current and future emerging infection with pandemic potential. Conventional antiviral drugs have been associated with high cost, toxicity and resistance issues. The use of medicinal plants and their secondary metabolites (SMs) with potential anti-inflammatory properties garners attention as a safer alternative for treating viral diseases. This review discussed various plant SMs with therapeutic potential for treating viral diseases. Due to various factors including low concentrations of the phytocompounds produced, relying on natural systems for producing medically important SMs is not sustainable. Thus, several biotechnology strategies such as metabolic engineering and genetic modification, in vitro production as well as gene editing to enhance the phytochemical compounds are also highlighted. Future perspectives on the potential of plant-based antiviral drugs as well as other strategies to treat viral diseases in humans are also elaborated. Altogether, this review gives a comprehensive view of the pharmaceutical importance of plant SMs as an alternative approach against viral diseases. 

Biotechnological approaches in the production of plant secondary metabolites for treating human viral diseases: Prospects and challenges.

Inflammatory cascades of the dysregulated inflammatory pathways in COVID-19 can cause excessive production of pro-inflammatory cytokines and chemokines leading to cytokine storm syndrome (CSS). The molecular cascades involved in the pathways may be targeted for discovery of new anti-inflammatory agents. Many plant extracts have been used clinically in the management of COVID-19, however, their immunosuppressive activities were mainly investigated based on in silico activity. Dietary flavonoids of the extracts such as quercetin, luteolin, kaempferol, naringenin, isorhamnetin, baicalein, wogonin, and rutin were commonly identified as responsible for their inhibitory effects. The present review critically analyzes the anti-inflammatory effects and mechanisms of phytochemicals, including dietary compounds against cytokine storm (CS) and hyperinflammation via inhibition of the altered inflammatory pathways triggered by SARS-CoV-2, published since the emergence of COVID-19 in December 2019. Only a few phytochemicals, mainly dietary compounds such as nanocurcumin, melatonin, quercetin, 6-shagoal, kaempferol, resveratrol, andrographolide, and colchicine have been investigated either in in silico or preliminary clinical studies to evaluate their anti-inflammatory effects against COVID-19. Sufficient pre-clinical studies on safety and efficacy of anti-inflammatory effects of the phytochemicals must be performed prior to proper clinical studies to develop them into therapeutic adjuvants in the prevention and treatmemt of COVID-19 symptoms.

Inhibitory effect of food-functioned phytochemicals on dysregulated inflammatory pathways triggered by SARS-CoV-2: a mechanistic review.

Effect of Zr grain refinement on solidification behavior of Mg–3Nd alloy by cooling curve thermal analysis

We propose a link-disjoint path computation and resource pre-locking scheme for hierarchical controlled multi-domain PTN, in order to decrease the path setup delay and improve resource utilization, as well as eliminate concurrent reservation conflicts. Simulations show its better performance in terms of disjoint path setup delay and blocking rate.

End-to-End Link-Disjoint Path Computation and Resource Pre-Locking Scheme for Multi-Domain Packet Transport Networks

COVID‐19 has infected 272 million patients and caused 5.33 million deaths around the world, and it remains the main global threat. Previous studies revealed that Chinese traditional medicine is an effective treatment for COVID‐19 infection. This study aims to reveal the pharmacological effects of kaempferol, which is the active component of Radix Bupleuri and Tripterygii Radix, and potential mechanisms for the treatment of COVID‐19. Here, we employed the bioinformatics methods to filter the anti‐COVID‐19 candidate genes of kaempferol, which mainly enriched in inflammation (TNF, JUN, etc.) and virus infection (AKT1, JNK, etc.). The Transcription levels of AKT1, JNK and JUN were significantly reduced by kaempferol treatment in the LPS‐activated macrophages. In addition, kaempferol reduced the secretion of inflammatory factors by LPS‐stimulated macrophages, inhibited MAPK/NF‐κB signaling and regulated macrophage polarization to M2 type in vitro, and suppressed endotoxin‐induced cytokine storm and improved survival in mice. Molecular docking analysis demonstrated that kaempferol was probable to bind the COVID‐19 protein 5R84 and formatted hydrogen bond with the residues, the free binding energy of which was lower than the original ligand. In summary, our current work indicates that kaempferol has anti‐COVID‐19 potential through the reduction of COVID‐19‐induced body dysfunction and molecule–protein interaction, and bioinformatics results clarify that some of these key target genes might serve as potential molecular markers for detecting COVID‐19.

Kaempferol has potential anti‐coronavirus disease 2019 (COVID‐19) targets based on bioinformatics analyses and pharmacological effects on endotoxin‐induced cytokine storm

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Effect of Zr grain refinement on solidification behavior of Mg–3Nd alloy by cooling curve thermal analysis

End-to-End Link-Disjoint Path Computation and Resource Pre-Locking Scheme for Multi-Domain Packet Transport Networks

Kaempferol has potential anti‐coronavirus disease 2019 (COVID‐19) targets based on bioinformatics analyses and pharmacological effects on endotoxin‐induced cytokine storm