The Sonic Hedgehog protein (Shh) has been extensively researched since its discovery in 1980. Its crucial role in early neurogenesis and endogenous stem cells of mature brains, as well as its recently described neuroprotective features, implicate further important effects on neuronal homeostasis. Here, we investigate its potential role in the survival, proliferation, and differentiation of neural precursors cells (NPCs) under inflammatory stress as a potential adjunct for NPC-transplantation strategies in spinal cord injury (SCI) treatment. To this end, we simulated an inflammatory environment in vitro using lipopolysaccharide (LPS) and induced the Shh-pathway using recombinant Shh or blocked it using Cyclopamine, a potent Smo inhibitor. We found that Shh mediates the proliferation and neuronal differentiation potential of NPCs in vitro, even in an inflammatory stress environment mimicking the subacute phase after SCI. At the same time, our results indicate that a reduction of the Shh-pathway activation by blockage with Cyclopamine is associated with reduced NPC-survival, reduced neuronal differentiation and increased astroglial differentiation. Shh might thus, play a role in endogenous NPC-mediated neuroregeneration or even be a potent conjunct to NPC-based therapies in the inflammatory environment after SCI.

Chronic obstructive pulmonary diseases (COPD) is a kind of age-related, airflow-obstruction disease mostly caused by cigarette smoke. However, the relationship between COPD and lung cellular senescence is still not fully understood. Here, we found silencing Pellino-1 could inhibit the protein level of P21. Then, through constructing cell lines expressed ubiquitin-HA, we found that the E3 ubiquitin ligase Pellino-1 could bind to senescence marker p21 and modify p21 by K63-site ubiquitination by co-IP assays. Furthermore, we found that p21-mediated lung cellular senescence could be inhibited by silencing Pellino-1 in a D-galactose senescence mice model. Moreover, by constructing a COPD mouse model with shPellino-1 adenovirus, we found that silencing Pellino-1 could inhibit COPD and inflammation via reduction of SASPs regulated by p21. Taken together, our study findings elucidated that silencing E3 ligase Pellino-1 exhibits therapeutic potential for treatment to attenuate the progression of lung cellular senescence and COPD.

In female mammals, the abnormal apoptosis of ovarian granulosa cells (GCs) impairs follicular development and causes reproductive dysfunction. Many studies have indicated that the FGFR1 gene of the PI3K signaling pathway and the p65 subunit of the transcription factor NF-κB may regulate the proliferation and apoptosis of GCs involved in follicular development. However, little is known about whether p65 regulates the transcription of FGFR1, as well as the biological effects of p65 and FGFR1 on the survival of GCs and follicular development. In porcine follicles and GCs, we found that p65 and FGFR1 were exclusively expressed in the GCs of follicles, and the mRNA and protein levels of p65 and FGFR1 significantly increased from small to large follicles. Both p65 and FGFR1 were found to activate the PI3K signaling pathway, and the expressions of proliferation markers (PCNA and MKI67) and the anti-apoptotic gene BCL2 were significantly increased by p65 and FGFR1. Furthermore, both p65 and FGFR1 were observed to promote cell proliferation and inhibit the cell apoptosis of GCs, and p65 was confirmed to bind at the -348/-338 region of FGFR1 to positively regulate its transcription. Moreover, p65 was further found to enhance the pro-proliferation and anti-apoptotic effects of FGFR1. Taken together, p65 may target the -348/-338 region of FGFR1, promote the transcription of FGFR1, and enhance the pro-proliferation effect and anti-apoptotic effect of FGFR1 to facilitate the growth of follicles. This study will provide useful information for further investigations on the p65-mediated-FGFR1 signaling pathway during folliculogenesis in mammals.

In animals, muscle growth is a quantitative trait controlled by multiple genes. Previously, we showed that the transient receptor potential channel 1 (TRPC1) gene was differentially expressed in muscle tissues between pig breeds with divergent growth traits base on RNA-seq. Here, we characterized TRPC1 expression profiles in different tissues and pig breeds and showed that TRPC1 was highly expressed in the muscle. We found two single nucleotide polymorphisms (SNPs) (C-1763T and C-1604T) in TRPC1 that could affect the promoter region activity and regulate pig growth rate. Functionally, we used RNAi and overexpression to illustrate that TRPC1 promotes myoblast proliferation, migration, differentiation, fusion, and muscle hypertrophy while inhibiting muscle degradation. These processes may be mediated by the activation of Wnt signaling pathways. Altogether, our results revealed that TRPC1 might promote muscle growth and development and plays a key role in Wnt-mediated myogenesis.

Chimeric RNAs (chiRNAs) play many previously unrecognized roles in different diseases including cancer. They can not only be used as biomarkers for diagnosis and prognosis of various diseases but also serve as potential therapeutic targets. In order to better understand the roles of chiRNAs in pathogenesis, we inserted human sequences into mouse genome and established a knockin mouse model of the tamoxifen-inducible expression of ASTN2-PAPPA antisense chimeric RNA (A-PaschiRNA). Mice carrying the A-PaschiRNA knockin gene do not display any apparent abnormalities in growth, fertility, histological, hematopoietic, and biochemical indices. Using this model, we dissected the role of A-PaschiRNA in chemical carcinogen 4-nitroquinoline 1-oxide (4NQO)-induced carcinogenesis of esophageal squamous cell carcinoma (ESCC). To our knowledge, we are the first to generate a chiRNA knockin mouse model using the Cre-loxP system. The model could be used to explore the roles of chiRNA in pathogenesis and potential targeted therapies.

Myo-inositol, a carbocyclic sugar, is believed to be relevant to renal pathobiology since the kidney is the major site for its catabolism. Its role in acute kidney injury (AKI) has not been fully investigated. Ferroptosis, a unique form of regulated cell death, is involved in various types of renal injuries. The relevance of myo-inositol with respect to the process of ferroptosis has not been explored either. Herein, our current exploratory studies revealed that supplementation of myo-inositol attenuates cisplatin-induced injury in cultured Boston University mouse proximal tubular (BUMPT) cells and renal tubules in vivo. Moreover, our studies unraveled that metabolic parameters pertaining to ferroptosis were disrupted in cisplatin-treated proximal tubular cells, which were seemingly remedied by the administration of myo-inositol. Mechanistically, we noted that cisplatin treatment led to the up-regulation of NOX4, a key enzyme relevant to ferroptosis, which was normalized by the administration of myo-inositol. Furthermore, we observed that changes in the NOX4 expression induced by cisplatin or myo-inositol were modulated by carboxy-terminus of Hsc70-interacting protein (CHIP), an E3 ubiquitin ligase. Taken together, our investigation suggests that myo-inositol promotes CHIP-mediated ubiquitination of NOX4 to decelerate the process of ferroptosis, leading to the amelioration of cisplatin-induced AKI.

The malignancy with the greatest global mortality rate is lung cancer. Lung adenocarcinoma (LUAD) is the most common subtype. The evidence demonstrated that voltage-gated potassium channel subunit beta-2 (KCNAB2) significantly participated in the initiation of colorectal cancer and its progression. However, the biological function of KCNAB2 in LUAD and its effect on the tumor immune microenvironment are still unknown. In this study, we found that the expression of KCNAB2 in tissues of patients with LUAD was markedly downregulated, and its downregulation was linked to accelerated cancer growth and poor clinical outcomes. In addition, low KCNAB2 expression was correlated with a deficiency in immune infiltration. The mechanism behind this issue might be that KCNAB2 influenced the immunological process such that the directed migration of immune cells was affected. Furthermore, overexpression of KCNAB2 in cell lines promoted the expression of CCL2, CCL3, CCL4, CCL18, CXCL9, CXCL10, and CXCL12, which are necessary for the recruitment of immune cells. In conclusion, KCNAB2 may play a key function in immune infiltration and can be exploited as a predictive biomarker for evaluating prognosis and a possible immunotherapeutic target.