Targeted inhibition of osteoclastogenesis reveals the pathogenesis and therapeutics of bone loss under sympathetic neurostress

Sympathetic cues via the adrenergic signaling critically regulate bone homeostasis and contribute to neurostress-induced bone loss,but the mechanisms and therapeutics remain incompletely elucidated.Here,we reveal an osteoclastogenesis-centered functionally important osteopenic pathogenesis under sympatho-adrenergic activation with characterized micro RNA response and efficient therapeutics.We discovered that osteoclastic mi R-21 was tightly regulated by sympatho-adrenergic cues downstream theβ2-adrenergic receptor(β2AR)signaling,critically modulated osteoclastogenesis in vivo by inhibiting programmed cell death 4(Pdcd4),and mediated detrimental effects of both isoproterenol(ISO)and chronic variable stress(CVS)on bone.Intriguingly,without affecting osteoblastic bone formation,bone protection against ISO and CVS was sufficiently achieved by a(D-Asp8)-lipid nanoparticle-mediated targeted inhibition of osteoclastic mi R-21 or by clinically relevant drugs to suppress osteoclastogenesis.Collectively,these results unravel a previously underdetermined molecular and functional paradigm that osteoclastogenesis crucially contributes to sympatho-adrenergic regulation of bone and establish multiple targeted therapeutic strategies to counteract osteopenias under stresses.

Magnesium metal and its corrosion products:Promising materials for tumor interventional therapy

Magnesium is generally known to degrade in aqueous environments by an electrochemical reaction.The corrosion products of magnesium include hydrogen gas,Mg^(2+),and Mg(OH)_(2).Here,we summarize the published literature describing the corrosion characteristics of magnesium,and the antitumor properties of magnesium-associated corrosion products,aiming to induce the therapeutic properties of magnesium and magnesium alloys in solid tumors.The therapeutic potential of corrosion products of magnesium is enormous.Hydrogen gas exhibits antioxidant and anti-inflammatory properties,which amount to potential anti-tumor characteristics.Mg(OH)_(2),which creates a localized alkaline microenvironment,represents a second approach for anti-tumor therapy with magnesium metal.Upregulated concentrations of Mg^(2+)ions in the local tumor microenvironment remodelling are considered a third approach for anti-tumor therapy.Therefore,we speculate about the different physical forms of magnesium that could create an anti-tumor microenvironment upon tumor interventional therapy,a technique that precisely places anti-tumor implants like particles and stents.Finally,we present our viewpoints on the potential use of magnesium in diverse solid tumor therapies to inhibit tumor progression.

Oxidative stress,epigenetic regulation and pathological processes of lens epithelial cells underlying diabetic cataract

Background:Cataract is a blinding disease worldwide.It is an age-related disease that mainly occurs in people over 65 years old.Cataract is also prevalent in patients with diabetes mellites(DM).The pathological mechanisms underlying diabetic cataract(DC)are more complex than that of age-related cataract.Studies have identified that polyol pathway,advanced glycation end products(AGEs)and oxidative stress are the primary pathogenesis of DC.In recent years,molecular-level regulations and pathological processes of lens epithelial cells(LECs)have been confirmed to play roles in the initiation and progression of DC.A comprehensive understanding and elucidation of how chronic hyperglycemia drives molecular-level regulations and cytopathological processes in the lens will shed lights on the prevention,delay and treatment of DC.Main text:Excessive glucose in the lens enhances polyol pathway and AGEs formation.Polyol pathway causes imbalance in the ratio of NADPH/NADPt and NADH/NADt.Decrease in NADPH/NADPt ratio compromises antioxidant enzymes,while increase in NADH/NADt ratio promotes reactive oxygen species(ROS)overproduction in mitochondria,resulting in oxidative stress.Oxidative stress in the lens causes oxidation of DNA,proteins and lipids,leading to abnormalities in their structure and functions.Glycation of proteins by AGEs decreases solubility of proteins.High glucose triggered epigenetic regulations directly or indirectly affect expressions of genes and proteins in LECs.Changes in autophagic activity,increases in fibrosis and apoptosis of LECs destroy the morphological structure and physiological functions of the lens epithelium,disrupting lens homeostasis.Conclusions:In both diabetic animal models and diabetics,oxidative stress plays crucial roles in the formation of cataract.Epigenetic regulations,include lncRNA,circRNA,microRNA,methylation of RNA and DNA,histone acetylation and pathological processes,include autophagy,fibrosis and apoptosis of LECs also involved in DC.