Factor VIIa (AryoSeven)

Case Report: Effectiveness of Abatacept for Palindromic Rheumatism Followed by Rheumatoid Factor-Positive Polyarticular Juvenile Idiopathic Arthritis.

Fujita Yuji Y, Suzuki Shotaro S, Maezawa Reika R, Ikeda Kei K et al.

Plant-specific and conserved mechanisms of the polymerase-associated factor 1 complex in replication stress responses.

Li Cunliang C, Guo Yuyu Y, Wang Ziying Z, Zheng Haowei H et al.

DNA replication stress threatens genome stability, but how plants respond to this challenge remains unclear. Here we show that the evolutionarily conserved polymerase-associated factor 1 complex (PAF1C) is required for the replication stress response in Arabidopsis. Plants lacking functional PAF1C are hypersensitive to replication stress-inducing agents. Mechanistically, we reveal a plant-specific pathway in which the stress-activated kinase WEE1 phosphorylates PAF1 to prevent its protein degradation, a regulatory mechanism absent in yeast. By contrast, we uncover a conserved pathway in which the replication factor C (RFC) complex recruits PAF1C to stalled replication forks, where PAF1C in turn recruits the E2 ubiquitin-conjugating enzymes UBC1/2 and the E3 ubiquitin ligases HUB1/2 to promote histone H2B monoubiquitination, thereby stabilizing the forks. Collectively, our findings suggest that PAF1 regulates replication stress responses by integrating a plant-specific protein stability control mechanism (WEE1-PAF1) with a conserved recruitment mechanism (RFC-PAF1-UBC1/2-HUB1/2). This work establishes a new function for PAF1C and expands the mechanistic understanding of WEE1 and the RFC complex in the replication stress response.

Jianchang No. 1 (1) formula alleviates irritable bowel syndrome with diarrhea improving gut microbiota and regulating toll-like receptors/nuclear factor-kappa B signaling pathway in bowel syndrome with diarrhea rats.

Yutong Liu L, Yan Yang Y, Huiying X U XU, Lei L I LI et al.

To evaluate the therapeutic efficacy of Jianchang No. 1 (1) in treating irritable bowel syndrome with diarrhea (IBS-D) and to explore its underlying mechanisms of action. IBS-D rat models were established through a combination of chronic restraint stress, water avoidance stress, and the administration of senna decoction. Body weight, fecal water content (FWC), and intestinal capacity threshold in IBS-D rats were monitored before and after treatment. Pathological alterations in colon tissue were examined using hematoxylin and eosin staining. Serum levels of lipopolysaccharide (LPS), along with LPS content in colon tissue were measured using the enzyme-linked immunosorbent assay. 16S rRNA sequencing technology was employed to assess the abundance and compositional shifts within the gut microbiota. Quantitative real-time polymerase chain reaction, Western blot, and immunofluorescence were employed to determine gene and protein expression in colonic samples. Jianchang No. 1 treatment restored body weight, lowered FWC, and raised the intestinal capacity threshold in IBS-D rats. Meanwhile, Jianchang No. 1 enhanced both the richness and composition of the gut microbiota. Moreover, Jianchang No. 1 markedly upregulated the tight-junction proteins zonula occludens-1 and occludin together with the anti-inflammatory cytokine interleukin-10, while simultaneously downregulating the LPS-toll-like receptor (TLR) 2/4- myeloid differentiation factor 88- nuclear factor kappa B (NF-κB) axis and the downstream pro-inflammatory mediators interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, together with interleukin-4 and interferon-gamma. Jianchang No. 1 maintains intestinal barrier integrity by reshaping gut-microbial diversity and composition, dampening the TLR/NF-κB signaling cascade, and thereby alleviating low-grade colonic inflammation and its attendant clinical symptoms in IBS-D rats.

Astragaloside IV mitigates mitochondrial damage and neurological symptoms in rats with cervical spondylotic myelopathy by inhibiting IL-17/TRAF6/NF-κB pathway.

Han Xin X, Li Xianlin X, Bu Xianzhong X

Astragaloside IV (AS-IV) exhibits pharmacological effects like antioxidant, anti-inflammatory, and neuroprotective properties. Interleukin (IL)-17 and the tumor necrosis factor receptor-associated factor 6/nuclear factor-κB (TRAF6/NF-κB) pathway are closely associated with nerve injury, but whether AS-IV improves cervical spondylotic myelopathy (CSM)-related nerve injury through this pathway remains unclear. The aim of this study is to investigate whether AS-IV ameliorates nerve injury in CSM rats by regulating the IL-17/TRAF6/NF-κB axis. Primary spinal cord neurons were obtained from newborn rats, and neuronal injury was induced using lipopolysaccharide (LPS). The optimal concentration of AS-IV was determined by Cell Counting Kit-8 assay. Inflammatory cytokines, neuronal apoptosis, and mitochondrial function were detected by ELISA, Western Blot, flow cytometry, and fluorescence staining. The CSM rat model was constructed, and the motor function and pathological damage of spinal cord tissue were evaluated by behavioral score and pathological staining. The pathway-related proteins levels were assessed using Western Blot, and mitochondrial morphology in spinal cord tissue was viewed through transmission electron microscopy. LPS reduced neuronal viability, ATP production, and mitochondrial membrane potential levels and promoted apoptosis and pro-inflammatory factor secretion. AS-IV treatment reversed the above effects. IL-17 was highly expressed in LPS-induced neurons. IL-17 antibody inhibited TRAF6/NF-κB signaling pathway and reduced LPS-induced neuronal damage. AS-IV downregulated IL-17, and TRAF6 overexpression reversed the pathway inhibition of AS-IV, while silencing TRAF6 has the opposite effect. In vivo AS-IV improved behavioral score in CSM rats, restored lower limb electrophysiological potentials, mitigated pathological spinal cord damage, inhibited the IL-17/TRAF6/NF-κB pathway, preserved mitochondrial morphology, increased surviving neurons, reduced apoptosis, and promoted axon regeneration. AS-IV effectively improves mitochondrial dysfunction and associated damage in neurons by inhibiting IL-17 to hinder the TRAF6/NF-κB axis, thereby alleviating neurological symptoms in CSM rats.