Longitudinal assessment of bleomycin-induced pulmonary fibrosis by evaluating TGF-ß1/Smad2, Nrf2 signaling and metabolomic analysis in mice.

INTRODUCTION: Pulmonary fibrosis (PF) is characterized by an increase in collagen synthesis and deposition of extracellular matrix. Several factors, including transforming growth factor-ß1 (TGF-ß1), mothers against decapentaplegic homolog family proteins (Smad), and alpha-smooth muscle actin (α-SMA) trigger extracellular matrix (ECM) accumulation, fibroblast to myofibroblasts conversion, and epithelial-to-mesenchymal-transition (EMT) leading to PF. However, the role of cellular defense mechanisms such as the role of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling during the onset and progression of PF is not understood completely. AIM: The present study aims to analyze the involvement of TGF-ß1/Smad signaling, and Nrf2 in the EMT and metabolic alterations that promote fibrosis in a time-dependent manner using bleomycin (BLM)-induced PF model in C57BL/6 mice. KEY FINDINGS: Histopathological studies revealed loss of lung architecture and increased collagen deposition in BLM-exposed mice. BLM upregulated TGF-ß1/Smad signaling and α-SMA at all time-points. The gradual increase in the accumulation of α-SMA and collagen implied the progression of PF. BLM exposure raises Nrf2 throughout each specified time-point, which suggests that Nrf2 activation might be responsible for TGF-ß1-induced EMT and the development of PF. Further, metabolomic studies linked the development of PF to alterations in metabolic pathways. The pentose phosphate pathway (PPP) was consistently enriched across all the time-points. Additionally, alterations in 22 commonly enriched pathways, associated with fatty acid (FA) and amino acid metabolism were observed in 30- and 60-days. SIGNIFICANCE: This study elucidates the association of TGF-ß1/Smad and Nrf2 signaling in the EMT and metabolic alterations associated with the etiology and progression of PF.

The pharmacological assessment of resveratrol on preclinical models of rheumatoid arthritis through a systematic review and meta-analysis.

Resveratrol/RES (3,5,4'-trihydroxy-trans-stilbene) is a natural compound found in many food items and red wine, which exhibits pleiotropic biological effects. Several preclinical studies evaluating the efficacy of RES in animal models of rheumatoid arthritis (RA) have been conducted, but the diversity of the experimental conditions and of their outcomes preclude definitive conclusions about RES's efficacy. We, therefore, performed a meta-analysis to assess its efficacy in mitigating experimental RA. We searched three databases until January 2021 and used the random-effects model for drawing inferences. Eighteen studies involving 544 animals were used in this study. Pooled analysis showed that experimental RA causes paw swelling (Hedge's g = 9.823, p = 0.000), increases polyarthritis score and arthritis index, and RES administration reduces paw volume (Hedge's g = -2.550, p = 0.000), polyarthritis score, and arthritis index besides amelioration in the histopathological score and cartilage loss. RA is accompanied by increased oxidative stress due to high malondialdehyde (MDA) level (p < 0.001) and low superoxide dismutase (SOD) activity (p = 0.002), and RES reduced MDA level (p < 0.001) and increased SOD activity (p < 0.001). Experimental RA exhibited an increase in pro-inflammatory cytokines viz. tumor necrosis factor (TNF)-α (p < 0.001), interleukin (IL)-6 (p = 0.002), and IL-1 (p < 0.001); however, insufficient quantitative data precluded us from assessing changes in the anti-inflammatory cytokine, IL-10. In experimental RA, RES decreased TNF-α (p < 0.001), IL-6 (p < 0.001) and IL-1 (p = 0.001) and increased IL-10. This meta-analysis suggests that RES can be a clinically effective therapy for RA, pending clinical trials.

A critical assessment of the potential of pharmacological modulation of aldehyde dehydrogenases to treat the diseases of bone loss.

Chronic alcoholism (CA) decreases bone mass and increases the risk of hip fracture. Alcohol and its main metabolite, acetaldehyde impairs osteoblastogenesis by increasing oxidative stress. Aldehyde dehydrogenase (ALDH) is the rate-limiting enzyme in clearing acetaldehyde from the body. The clinical relevance of ALDH in skeletal function has been established by the discovery of single nucleotide polymorphism, SNP (rs671) in the ALDH2 gene giving rise to an inactive form of the enzyme (ALDH2*2) that causes increased serum acetaldehyde and osteoporosis in the affected individuals. Subsequent mouse genetics studies have replicated human phenotype in mice and confirmed the non-redundant role of ALDH2 in bone homeostasis. The activity of ALDH2 is amenable to pharmacological modulation. ALDH2 inhibition by disulfiram (DSF) and activation by alda-1 cause reduction and induction of bone formation, respectively. DSF also inhibits peak bone mass accrual in growing rats. On the other hand, DSF showed an anti-osteoclastogenic effect and protected mice from alcohol-induced osteopenia by inhibiting ALDH1a1 in bone marrow monocytes. Besides DSF, there are several classes of ALDH inhibitors with disparate skeletal effects. Alda-1, the ALDH2 activator induced osteoblast differentiation by increasing bone morphogenic protein 2 (BMP2) expression via ALDH2 activation. Alda-1 also restored ovariectomy-induced bone loss. The scope of structure-activity based studies with ALDH2 and the alda-1-like molecule could lead to the discovery of novel osteoanabolic molecules. This review will critically discuss the molecular mechanism of the ethanol and its principal metabolite, acetaldehyde in the context of ALDH2 in bone cells, and skeletal homeostasis.

Targeted inhibition of sclerostin for post-menopausal osteoporosis therapy: A critical assessment of the mechanism of action.

Promising news in the treatment of osteoporosis is that sequestering sclerostin from circulation with antibodies stimulates robust bone formation. Pre-clinical studies on rodents and monkeys have confirmed that treatment with anti-sclerostin monoclonal antibody (Scl-Ab) increases bone mass, improves bone strength and enhances fracture repair. Clinical trials show that bone gain (anabolic effect) is transient and are primarily at central (spine and hips) than peripheral (wrist) sites. Interestingly Scl-Ab also inhibited bone resorption. Thus Scl-Ab is being regarded as the pharmacologic agent with dual properties - stimulating bone formation and decreasing bone resorption. Sclerostin neutralization transiently increases bone formation markers in post-menopausal women and like parathyroid hormone (PTH) activates osteoblasts and lining cells resulting in bone anabolic effect. However, unlike PTH, sclerostin antibody also decreases bone resorption (anti-catabolic). Although, the U.S. Food and Drug Administration have accepted the Biologics License Application for one of the monoclonal antibodies against sclerostin (romosozumab) for review, many questions remain before romosozumab can be introduced as a skeletal anabolic agent to clinical practice. For example, neutralizing sclerostin alters calcium homeostasis and increases PTH. In addition, sclerostin depletion in preclinical studies has been reported to severely compromises B cell depletion in bone marrow. We have reviewed the currently available evidences that support the use of sclerostin antibody in treating osteoporosis and compare its efficacy and mechanism of action with the currently available anabolic drug, human PTH.