New insight into enhanced carbon recovery from anaerobic fermentation of waste activated sludge with cation exchange resin coupled with NaCl pretreatment.

Carbon recovery from waste activated sludge has been attracting considerable attention. However, the migration and transformation patterns of carbon sources between the phases have rarely been reported. In this study, a novel strategy using cation exchange resin (CER) coupled with sodium chloride (NaCl) to enhance carbon recovery through anaerobic fermentation (AF) was proposed. The results demonstrated that CER coupled with NaCl destroyed OH and CO stretching in amide I while promoting the formation of ß-sheet and random coil structures, leading to sludge disintegration. This significantly improved the kinetics of endogenous carbon release, resulting in the release of 1146.33 mg/L of carbon from the solid sludge into the liquid phase. Approximately 75.61 % of the initial carbon source was bio-transformed into short-chain fatty acids. Correspondingly, carbon recovery was significantly increased up to 852.23 mg C/L, 4.57 times that of the control. Mechanism exploration revealed that carbon source recovery was significantly elevated by the synergistic effect of CER and NaCl. CER effectively removed high-valence cations from extracellular polymeric substance (EPS), weakening its bridging and adsorption-electro neutralization capabilities, promoting protein deflocculation, and triggering EPS disruption to release extracellular carbon sources. NaCl disrupted the ionic strength and distribution inside and outside microbial cells, creating an osmotic pressure difference that resulted in cell plasmolysis and lysis, ultimately inducing the release of intracellular carbon sources. Economic and carbon emission reduction benefit analyses verified that the CER coupled with NaCl pretreatment is a cost-effective sludge treatment strategy. This study illustrates the carbon source migration and transformation pathways in the CER coupled with NaCl-assisted AF process, providing guidance for sustainable sludge management.

Mitochondrial transplantation: A promising therapy for mitochondrial disorders.

As a vital energy source for cellular metabolism and tissue survival, the mitochondrion can undergo morphological or positional change and even shuttle between cells in response to various stimuli and energy demands. Multiple human diseases are originated from mitochondrial dysfunction, but the curative succusses by traditional treatments are limited. Mitochondrial transplantation therapy (MTT) is an innovative therapeutic approach that is to deliver the healthy mitochondria either derived from normal cells or reassembled through synthetic biology into the cells and tissues suffering from mitochondrial damages and finally replace their defective mitochondria and restore their function. MTT has already been under investigation in clinical trials for cardiac ischemia-reperfusion injury and given an encouraging performance in animal models of numerous fatal critical diseases including central nervous system disorders, cardiovascular diseases, inflammatory conditions, cancer, renal injury, and pulmonary damage. This review article summarizes the mechanisms and strategies of mitochondrial transfer and the MTT application for types of mitochondrial diseases, and discusses the potential challenge in MTT clinical application, aiming to exhibit the good therapeutic prospects of MTTs in clinics.

Photoresponsive Hydrogels for Tissue Engineering.

Hydrophilic and biocompatible hydrogels are widely applied as ideal scaffolds in tissue engineering. The "smart" gelation material can alter its structural, physiochemical, and functional features in answer to various endo/exogenous stimuli to better biomimic the endogenous extracellular matrix for the engineering of cells and tissues. Light irradiation owns a high spatial-temporal resolution, complete biorthogonal reactivity, and fine-tunability and can thus induce physiochemical reactions within the matrix of photoresponsive hydrogels with good precision, efficiency, and safety. Both gel structure (e.g., geometry, porosity, and dimension) and performance (like conductivity and thermogenic or mechanical properties) can hence be programmed on-demand to yield the biochemical and biophysical signals regulating the morphology, growth, motility, and phenotype of engineered cells and tissues. Here we summarize the strategies and mechanisms for encoding light-reactivity into a hydrogel and demonstrate how fantastically such responsive gels change their structure and properties with light irradiation as desired and thus improve their applications in tissue engineering including cargo delivery, dynamic three-dimensional cell culture, and tissue repair and regeneration, aiming to provide a basis for more and better translation of photoresponsive hydrogels in the clinic.

Selective inhibition of glycolysis in hepatic stellate cells and suppression of liver fibrogenesis with vitamin A-derivative decorated camptothecin micelles.

The persistent transformation of quiescent hepatic stellate cells (HSCs) into myofibroblasts (MFs) and the excessive proliferation of MF-HSCs in the liver contribute to the pathogenesis of liver fibrosis, cirrhosis, and liver cancer. Glycolysis inhibition of MF-HSCs can reverse their MF phenotype and suppress their abnormal expansion. Here, we have developed vitamin A-derivative (VA) decorated PEG-PCL polymeric micelles to encapsulate the labile and hydrophobic camptothecin (CPT) and direct its active attack on HSCs, selectively inhibiting of HIF-1α and cellular glycolysis, ultimately repressing hepatic fibrogenesis. The obtained micelles exhibited a good stability, biocompatibility, pH sensitivity, and exceptional HSC-targetability, allowing an efficient accumulation of their carried CPT in acutely and chronically injured livers. On their intracellular release of CPT specifically in MF-HSCs, these CPT micelles nicely inhibited the HIF-1α and a series of glycolytic players in MF-HSCs and prominently suppressed their proliferation and MF phenotypic characteristics. Accordingly, on in vitro administration to the mice challenged by CCl4 or subjected to bile duct ligation, these VA-decorated CPT micelles ameliorated the pathological symptoms of the livers, as evidenced by the significant reduction in serum levels of ALT and AST, infiltration of inflammatory cells, and collagen accumulation, the drastic down-regulation of multiple fibrotic genes, and the good recovery of attenuated hepatocyte CYP2E1 and lipogenesis regulator PPARγ. Overall, the CPT carried by VA-decorated PEG-PCL polymeric micelles can selectively inhibit the glycolysis and expansion of HSCs and thus suppress fibrogenesis, providing an original and effective approach for anti-fibrotic therapy. STATEMENT OF SIGNIFICANCE: Our work introduces an innovative antifibrotic drug system that is developed upon the active targeting of CPT and aims for the fate reversal of HSCs. Through HSC-targeted delivery achieved by PEG-PCL polymeric micelles decorated with vitamin A-derivatives, CPT significantly suppressed the expressions of HIF-1α and glycolytic enzymes in MF-HSCs, as well as their pathologic expansion in mouse livers. It effectively ameliorated chronic liver fibrosis in mice induced by CCl4 injection or BDL and restored the damaged liver structure and function. These compelling findings demonstrate the therapeutic potential of glycolytic HSC-targeting in combating fibrosis and related disorders and thus provide new promise for future clinical management of such prevalent and life-threatening conditions.

Folate Decoration Supports the Targeting of Camptothecin Micelles against Activated Hepatic Stellate Cells and the Suppression of Fibrogenesis.

As the central cellular player in fibrogenesis, activated hepatic stellate cells (aHSCs) are the major target of antifibrotic nanomedicines. Based on our finding that activated HSCs increase the expression of folate receptor alpha (FRα), we tried to apply folic acid (FA) decoration to generate an active drug-targeting at aHSCs and suppress hepato-fibrogenesis. FA-conjugated poly(ethylene glycol)-poly(ε-caprolactone) copolymers (PEG-PCL) were synthesized and self-assembled into the spherical micelles that owned a uniform size distribution averaging at 60 nm, excellent hemo- and cyto-compatibility, and pH-sensitive stability. These FA-modified micelles were preferentially ingested by aHSCs as expected and accumulated more in acutely CCl4 injured mouse livers compared to nondecorated counterparts. Such an aHSC targetability facilitated the loaded medicinal camptothecin (CPT) to achieve a greater therapeutic efficacy and inhibition of MF phenotypic genes in aHSCs. Encouragingly, though free CPT and nontargeting CPT micelles produced negligible curative outcomes, FA-decorated CPT micelles yielded effectively remedial effects in chronically CCl4-induced fibrotic mice, as represented by a significant shrinkage of aHSC population, suppression of fibrogenesis, and recovery of liver structure and function, clearly indicating the success of the folate decoration-supported aHSC-targeted strategy for antifibrotic nanomedicines in fibrosis resolution.

Targeting endoplasmic reticulum stress-the responder to lipotoxicity and modulator of non-alcoholic fatty liver diseases.

INTRODUCTION: Endoplasmic reticulum (ER) stress occurs with aberrant lipid accumulation and resultant adverse effects and widely exists in nonalcoholic fatty liver disease (NAFLD). It triggers the unfolded protein response (UPR) to restore ER homeostasis and actively participates in NAFLD pathological processes, including hepatic steatosis, inflammation, hepatocyte death, and fibrosis. Such acknowledges drive the discovery of novel NAFLD biomarker and therapeutic targets and the development of ER-stress targeted NAFLD drugs. AREAS COVERED: This article discusses and updates the role of ER stress and UPR in NAFLD, the underlying action mechanism, and especially their full participation in NAFLD pathophysiology. It characterizes key molecular targets useful for the prevention and treatment of NAFLD and highlights the recent ER stress-targeted therapeutic strategies for NAFLD. EXPERT OPINION: Targeting ER Stress is a valuable and promising strategy for NAFLD treatment, but its smooth translation into clinical application still requires better clarification of the different UPR patterns in diverse NAFLD physiological states. Further understanding of the distinct effects of these various patterns on NAFLD, the thresholds deciding their final impacts, and their actions via non-liver tissues and cells would be of great help to develop a precise and effective therapy for NAFLD. [Figure: see text].