MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

MicroRNAs: Target Recognition and Regulatory Functions

The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative review.

Macrophage M1/M2 polarization and rheumatoid arthritis: A systematic review.

The ATLANTIC trial reported that higher PD-L1 expression in tumors was involved in a higher objective response in patients with EGFR+/ALK+ non-small cell lung cancer (NSCLC), indicating the possibility of anti-PD-1/PD-L1 therapy as a third-line (or later) treatment for advanced NSCLC. Therefore, the determination of status and regulatory mechanisms of PD-L1 in EGFR mutant NSCLC before and after acquired EGFR-TKIs resistance are meaningful. The correlation among PD-L1, c-MET, and HGF was analyzed based on TCGA datasheets and paired NSCLC specimens before and after acquired EGFR-TKI resistance. EGFR-TKI resistant NSCLC cells with three well-known mechanisms, c-MET amplification, hepatocyte growth factor (HGF), and EGFR-T790M, were investigated to determinate PD-L1 expression status and immune escape ability. PD-L1-deleted EGFR-TKIs sensitive and resistant cells were used to evaluate the immune escape ability of tumors in mice xenograft models. Positive correlations were found among PD-L1, c-MET, and HGF, based on TCGA datasheets and paired NSCLC specimens. Moreover, the above three resistant mechanisms increased PD-L1 expression and attenuated activation and cytotoxicity of lymphocytes in vitro and in vivo, and downregulation of PD-L1 partially restored the cytotoxicity of lymphocytes. Both MAPK and PI3K pathways were involved in the three types of resistance mechanism-induced PD-L1 overexpression, whereas the NF-kappa B pathway was only involved in T790M-induced PD-L1 expression. HGF, MET-amplification, and EGFR-T790M upregulate PD-L1 expression in NSCLC and promote the immune escape of tumor cells through different mechanisms.

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EGFR-TKI resistance promotes immune escape in lung cancer via increased PD-L1 expression

Pathological pain can be initiated after inflammation and/or peripheral nerve injury. It is a consequence of the pathological functioning of the nervous system rather than only a symptom. In fact, pain is a significant social, health, and economic burden worldwide. Flavonoids are plant derivative compounds easily found in several fruits and vegetables and consumed in the daily food intake. Flavonoids vary in terms of classes, and while structurally unique, they share a basic structure formed by three rings, known as the flavan nucleus. Structural differences can be found in the pattern of substitution in one of these rings. The hydroxyl group (-OH) position in one of the rings determines the mechanisms of action of the flavonoids and reveals a complex multifunctional activity. Flavonoids have been widely used for their antioxidant, analgesic, and anti-inflammatory effects along with safe preclinical and clinical profiles. In this review, we discuss the preclinical and clinical evidence on the analgesic and anti-inflammatory proprieties of flavonoids. We also focus on how the development of formulations containing flavonoids, along with the understanding of their structure-activity relationship, can be harnessed to identify novel flavonoid-based therapies to treat pathological pain and inflammation.

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Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development.

PI3K/AKT signaling is essential in regulating pathophysiology of osteoarthritis (OA). However, its potential modulatory role in early OA progression has not been investigated yet. Here, a mouse destabilization OA model in the tibia was used to investigate roles of PI3K/AKT signaling in the early subchondral bone changes and OA pathological process. We revealed a significant increase in PI3K/AKT signaling activation which was associated with aberrant bone formation in tibial subchondral bone following destabilizing the medial meniscus (DMM), which was effectively prevented by treatment with PI3K/AKT signaling inhibitor LY294002. PI3K/AKT signaling inhibition attenuated articular cartilage degeneration. Serum and bone biochemical analyses revealed increased levels of MMP-13, which was found expressed mainly by osteoblastic cells in subchondral bone. However, this MMP-13 induction was attenuated by LY294002 treatment. Furthermore, PI3K/AKT signaling was found to enhance preosteoblast proliferation, differentiation, and expression of MMP-13 by activating NF-κB pathway. In conclusion, inhibition of PI3K/AKT/NF-κB axis was able to prevent aberrant bone formation and attenuate cartilage degeneration in OA mice.

Blocking PI3K/AKT signaling inhibits bone sclerosis in subchondral bone and attenuates post-traumatic osteoarthritis.

Hesperidin inhibits synovial cell inflammation and macrophage polarization through suppression of the PI3K/AKT pathway in complete Freund's adjuvant-induced arthritis in mice.

Background: It is generally thought that the occurrence and progression of osteoarthritis (OA) results from multiple causes, including degradation and destruction of the cartilage matrix and aging of chondrocytes. Metformin is a first-line drug for the treatment of diabetes, and has great potential for the treatment of other disorders. However, the role of metformin in OA is unknown.

Results: Metformin displayed a protective effect against OA. There were lower OARSI scores and fewer MMP-13-positive cells in DMM mice and cartilage explants after treatment with metformin. In addition, metformin treatment decreased p16INK4a levels in OA chondrocytes, and enhanced polarization of AMPK and inhibition of mTORC1 in OA mice and chondrocytes in a dose-dependent manner.

Conclusions: Metformin effectively alleviated cartilage degradation and aging through regulation of the AMPK/mTOR signaling pathways, suggesting that it could be an effective treatment for OA.

Methods: The effects of metformin on cartilage degradation and chondrocyte aging was determined in a destabilization of the medial meniscus (DMM)-induced OA mouse model and in IL-1β-treated mouse chondrocytes and cartilage explants. Articular cartilage degeneration was graded using the Osteoarthritis Research Society International (OARSI) criteria. Immunostaining, RT-PCR, and western blot analyses were conducted to detect the relative expressions of protein and RNA.

Metformin attenuates cartilage degeneration in an experimental osteoarthritis model by regulating AMPK/mTOR.

Osteoarthritis (OA) is an aging-related chronic degenerative disease characterized by the degradation of chondrocyte extracellular matrix (ECM). Previous studies have suggested that microRNAs (miRNAs) are associated with OA, but the role of miR-146b in OA remains unclear. The aim of this study was to determine the role of miR-146b in OA progression. The effect of miR-146b on ECM degradation were studied in mouse chondrocytes transfected with miRNA and treated with IL-1β. Cell viability and the expression levels of proteolytic enzymes in the transfected cells were assessed by real-time RT-PCR, ELISA and Western blots. We found downregulation of miR-146b expression in chondrocytes dramatically inhibited IL-1β-induced caspase activation and proteolytic enzyme expression via influencing its targeted Alpha-2-macroglobulin (A2M). Luciferase reporter assays confirmed that A2M mRNA was negatively regulated by miR-146b in chondrocytes. Intra-articular injection of antago-miR-146b against miR-146b effectively protected mice from the progression of DMM-induced osteoarthritis by inhibiting cartilage proteoglycan degradation. Our study indicates that miR-146b plays a critical role in the progression of injury-induced osteoarthritis by directly targeting A2M expression to elevate the proteolytic enzyme production and stimulate chondrocytes apoptosis, and miR-146b as well as A2M could be therapeutic targets.

/pdf/mir-146b-accelerates-osteoarthritis-progression-by-targeting-y9jbzwf15v.pdf

Xiaofeng Feng

Papers

Blocking PI3K/AKT signaling inhibits bone sclerosis in subchondral bone and attenuates post-traumatic osteoarthritis.

Hesperidin inhibits synovial cell inflammation and macrophage polarization through suppression of the PI3K/AKT pathway in complete Freund's adjuvant-induced arthritis in mice.

Metformin attenuates cartilage degeneration in an experimental osteoarthritis model by regulating AMPK/mTOR.

MiR-146b accelerates osteoarthritis progression by targeting alpha-2-macroglobulin.