Volume 102 Issue 9, September 2022

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with no curative therapy. Liquid-liquid phase separation (LLPS) is a biophysical phenomenon in which a homogeneous mixture of solutions separates into two phases. Recently LLPS has gained attention in ALS research because many ALS-causing proteins undergo LLPS, which eventually contribute to protein aggregates. This review summarizes the molecular mechanisms underlying the LLPS of ALS-causing proteins and discusses strategies to develop therapeutics targeting LLPS.

In nasopharyngeal carcinoma (NPC) CREB1 and SRGN are increased while miR-148a-5p is decreased. Silencing of SRGN and CREB1, and miR-148a-5p overexpression represses NPC tumor progression. The authors show that CREB1 promotes SRGN expression by targeting its promoter. In NPC, FoxO1 binds to miR-148a-5p, and miR-148a-5p targets CREB1. FoxO1 knockdown abolishes the downregulation of CREB1 and SRGN induced by STAT3 silencing. In summary, STAT3 regulates SRGN and promotes the growth and metastasis of NPC through the FoxO1-miR-148a-5p-CREB1 axis.

This study describes how HOTAIRM1 transferred by alveolar epithelial cell (AEC)-derived Exos promotes proliferation and transdifferentiation of lung fibroblasts. The authors reveal the mechanism by which HOTAIRM1 competitively binds to miR-30d-3p and YY1 to upregulate the expression of HSF1. Furthermore, AEC-Exosomes harboring HOTAIRM1 accelerates interstitial pulmonary fibrosis through disrupting miR-30d-3p-mediated HSF1 inhibition and inducing HSF1.

Circular RNAs (circRNAs) play important roles in many lung diseases. This study investigated the role of circHECTD1 in acute lung injury (ALI). circHECTD1 attenuates the apoptosis of alveolar epithelial cells in lipopolysaccharide-induced ALI through the miR-320a/PIK3CA and miR-136/Sirt1 pathways, indicating a novel therapeutic target for ALI.

The authors carried out a comparative genetic and histopathological study of 15 patient-derived xenografts (PDX) that were newly established from patients with various types of aggressive non-Hodgkin lymphomas. We have demonstrated that despite keeping the same genetic profiles the PDX models do not recapitulate microenvironmental heterogeneity of the original lymphomas. These findings have implications on the relevance of PDX models in the context of preclinical research.

The expression of circRTN4 is significantly enhanced in lupus nephritis. Downregulation of circRTN4 expression alleviates extracellular matrix deposition by targeting the miR-513a-5p/FN axis in cultured human renal mesangial cells and pristane-induced BALB/c mice or MRL/lpr mice. In addition, monocyte circRTN4 participates in mesangial cell dysfunction in an exosome-dependent manner. Exosomal circRTN4 mzytherefore be an effective biomarker for lupus nephritis detection and a novel therapeutic target.

When skeletal muscles undergo ischemia/reperfusion injury, fibroblast growth factor 21 (FGF21), a stress regulator, is upregulated and reduces Drp1 levels, which consequently alleviates abnormal mitochondrial fission and apoptosis. This work provides new insight into relationship between FGF21 and mitochondria and provides a possible therapeutic target for amelioration of muscle ischemia/reperfusion injury.

WISP-2, a recently identified adipokine, plays a role in modulating the turnover of extracellular matrix in the cartilage, and its downregulation may detrimentally alter the inflammatory environment in osteoarthritic cartilage. The authors also show the participation of Wnt/β-catenin signaling pathway in these processes. Thus, targeting WISP-2 might represent a potential therapeutical approach for degenerative and/or inflammatory diseases of musculoskeletal system, such as osteoarthritis.

Leukemia/lymphoma-related factor (LRF) in mouse and osteoclast zinc finger protein (OCZF) in rats are members of the zinc finger and BTB domain-containing protein (zBTB) family of transcriptional regulators and are highly expressed in mature osteoclasts, and enhance the expression of Bcl-xl mRNA. OCZF overexpression significantly promotes bone loss in ovariectomy-induced osteolytic mice. Protein levels of RNA binding splicing regulator of Bcl-x mRNA and Src substrate associated in mitosis of 68 kDa (Sam68) protein were markedly decreased in OCZF-Tg mouse-derived osteoclasts, suggesting that OCZF promotes osteoclast survival via Sam68.

GTSE1 performs oncogenic functions in various tumors; however, its role in clear cell renal cell carcinoma (ccRCC) remains unknown. Here, the authors found that GTSE1 is overexpressed in ccRCC, and its high expression was positively relation with advanced clinical stages and worse prognosis. In additional, GTSE1 knockdown inhibited ccRCC cell malignant phenotype in vitro and vivo. Mechanistically, GTSE1 promotes ccRCC malignance progression by attenuating KLF4 expression.

Current treatments, which mostly aim to restore bowel habits, are ineffective for intestinal pain in irritable bowel syndrome (IBS). Abnormal gut-derived serotonin metabolism and mucosal neurite outgrowth are linked to visceral hypersensitivity. Enhanced mucosal innervation dependent on 5-HT₇ contributes to hyperalgesia in two IBS-like mouse models. A positive-feedback loop between serotonin and neurotrophin is involved in intensifying nerve fiber elongation. A novel 5-HT₇ receptor antagonist may be administered orally as an intestinal analgesic for IBS-related pain.

Rare tumors, such as mesenchymal chondrosarcoma (MCS) lack effective treatments partly due to unavailability of research models. The authors developed novel in vitro and in vivo MCS models and validated them at the single-cell RNA level. MCS dependencies were identified and coupled with clinically available therapies. Imatinib showed the highest selectivity and cytotoxicity in both models.