Hepatocellular carcinoma (HCC) is the most familiar primary hepatic malignancy with a poor prognosis. The incidence of HCC and the associated deaths have risen in recent decades. Sorafenib is the first drug to be approved by the Food and Drug Administration (FDA) for routine use in the first-line therapy of patients with advanced HCC. However, only about 30% of patients with HCC will be benefited from sorafenib therapy, and drug resistance typically develops within 6 months. In recent years, the mechanisms of resistance to sorafenib have gained the attention of a growing number of researchers. A promising field of current studies is ferroptosis, which is a novel form of cell death differing from apoptosis, necroptosis, and autophagy. This process is dependent on the accumulation of intracellular iron and reactive oxygen species (ROS). Furthermore, the increase in intracellular iron levels and ROS can be significantly observed in cells resistant to sorafenib. This article reviews the mechanisms of resistance to sorafenib that are related to ferroptosis, evaluates the relationship between ferroptosis and sorafenib resistance, and explores new therapeutic approaches capable of reversing sorafenib resistance in HCC through the modulation of ferroptosis. Graphical Abstract

/pdf/mechanism-of-sorafenib-resistance-associated-with-3chj6wv5.pdf

Mechanism of sorafenib resistance associated with ferroptosis in HCC

Abstract Chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are associated with bile stasis and gradually progress to fibrosis, cirrhosis, and liver failure, which requires liver transplantation. Although ursodeoxycholic acid is effective in slowing the disease progression of PBC, it has limited efficacy in PSC patients. It is challenging to develop effective therapeutic agents due to the limited understanding of disease pathogenesis. During the last decade, numerous studies have demonstrated that disruption of bile acid (BA) metabolism and intrahepatic circulation promotes the progression of cholestatic liver diseases. BAs not only play an essential role in nutrition absorption as detergents but also play an important role in regulating hepatic metabolism and modulating immune responses as key signaling molecules. Several excellent papers have recently reviewed the role of BAs in metabolic liver diseases. This review focuses on BA-mediated signaling in cholestatic liver disease. 

Bile acid-mediated signaling in cholestatic liver diseases

Pulmonary surfactant is a critical component of lung function in healthy individuals. It functions in part by lowering surface tension in the alveoli, thereby allowing for breathing with minimal effort. The prevailing thinking is that low surface tension is attained by a compression-driven squeeze-out of unsaturated phospholipids during exhalation, forming a film enriched in saturated phospholipids that achieves surface tensions close to zero. A thorough review of past and recent literature suggests that the compression-driven squeeze-out mechanism may be erroneous. Here, we posit that a surfactant film enriched in saturated lipids is formed shortly after birth by an adsorption-driven sorting process and that its composition does not change during normal breathing. We provide biophysical evidence for the rapid formation of an enriched film at high surfactant concentrations, facilitated by adsorption structures containing hydrophobic surfactant proteins. We examine biophysical evidence for and against the compression-driven squeeze-out mechanism and propose a new model for surfactant function. The proposed model is tested against existing physiological and pathophysiological evidence in neonatal and adult lungs, leading to ideas for biophysical research, that should be addressed to establish the physiological relevance of this new perspective on the function of the mighty thin film that surfactant provides.

Pulmonary Surfactant: A Mighty Thin Film.

Simple Summary Aberrant Wnt/β-catenin signaling has been reported to play crucial role in pathogenesis of hepatocellular carcinoma (HCC). In this review, we focus on the regulatory role of Wnt/β-catenin signaling in cancer stemness and metabolic reprogramming, which are two emerging hallmarks of cancer. Understanding the role of Wnt/β-catenin signaling in regulation of the above processes reveals novel therapeutic strategy against this deadly disease. Abstract Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide due to its high rates of tumor recurrence and metastasis. Aberrant Wnt/β-catenin signaling has been shown to play a significant role in HCC development, progression and clinical impact on tumor behavior. Accumulating evidence has revealed the critical involvement of Wnt/β-catenin signaling in driving cancer stemness and metabolic reprogramming, which are regarded as emerging cancer hallmarks. In this review, we summarize the regulatory mechanism of Wnt/β-catenin signaling and its role in HCC. Furthermore, we provide an update on the regulatory roles of Wnt/β-catenin signaling in metabolic reprogramming, cancer stemness and drug resistance in HCC. We also provide an update on preclinical and clinical studies targeting Wnt/β-catenin signaling alone or in combination with current therapies for effective cancer therapy. This review provides insights into the current opportunities and challenges of targeting this signaling pathway in HCC.

/pdf/wnt-b-catenin-signaling-as-a-driver-of-stemness-and-10orpzwn.pdf

Wnt/β-Catenin Signaling as a Driver of Stemness and Metabolic Reprogramming in Hepatocellular Carcinoma

Cancer chemoresistance is a problematic dilemma that significantly restrains numerous cancer management protocols. It can promote cancer recurrence, spreading of cancer, and finally, mortality. Accordingly, enhancing the responsiveness of cancer cells towards chemotherapies could be a vital approach to overcoming cancer chemoresistance. Tumour cells express a high level of sphingosine kinase-1 (SphK1), which acts as a protooncogenic factor and is responsible for the synthesis of sphingosine-1 phosphate (S1P). S1P is released through a Human ATP-binding cassette (ABC) transporter to interact with other phosphosphingolipids components in the interstitial fluid in the tumor microenvironment (TME), provoking communication, progression, invasion, and tumor metastasis. Also, S1P is associated with several impacts, including anti-apoptotic behavior, metastasis, mesenchymal transition (EMT), angiogenesis, and chemotherapy resistance. Recent reports addressed high levels of S1P in several carcinomas, including ovarian, prostate, colorectal, breast, and HCC. Therefore, targeting the S1P/SphK signaling pathway is an emerging therapeutic approach to efficiently attenuate chemoresistance. In this review, we comprehensively discussed S1P functions, metabolism, transport, and signaling. Also, through a bioinformatic framework, we pointed out the alterations of SphK1 gene expression within different cancers with their impact on patient survival, and we demonstrated the protein-protein network of SphK1, elaborating its sparse roles. Furthermore, we made emphasis on different machineries of cancer resistance and the tight link with S1P. We evaluated all publicly available SphK1 inhibitors and their inhibition activity using molecular docking and how SphK1 inhibitors reduce the production of S1P and might reduce chemoresistance, an approach that might be vital in the course of cancer treatment and prognosis. 

The emerging roles of sphingosine 1-phosphate and SphK1 in cancer resistance: a promising therapeutic target

Sphingosine 1-phosphate receptor, a new therapeutic direction in different diseases.

It is well known that the enzyme catalyzes the first step of branched-chain amino acid (BCAA) catabolism is branched-chain amino transferase (BCAT), which is involved in the synthesis and degradation of leucine, isoleucine and valine. There are two main subtypes of human branched chain amino transferase (hBCAT), including cytoplasmic BCAT (BCAT1) and mitochondrial BCAT (BCAT2). In recent years, the role of BCAT in tumors has attracted the attention of scientists, and there have been continuous research reports that BCAT plays a role in the tumor, Alzheimer’s disease, myeloid leukaemia and other diseases. It plays a significant role in the growth and development of diseases, and new discoveries about this gene in some diseases are made every year. BCAT usually promotes cancer proliferation and invasion by activating the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway and activating Wnt/β-catenin signal transduction. This article reviews the role and mechanism of BCAT in different diseases, as well as the recent biomedical research progress. This review aims to make a comprehensive summary of the role and mechanism of BCAT in different diseases and to provide new research ideas for the treatment, prognosis and prevention of certain diseases. Graphical Abstract The mechanism of branched chain amino transferases (BCATs) in related diseases.There are two main subtypes of human branched chain amino transferase (hBCAT), including cytoplasmic BCAT (BCAT1) and mitochondrial BCAT (BCAT2). High expression of BCAT1 promotes gastric cancer, lung cancer, breast cancer, prostate cancer, glioma, hepatocellular carcinoma, urothelial cancer, melanoma, lymphoma, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, and nasopharyngeal carcinoma. It also aggravates liver disease, inflammatory disease, myeloid leukaemia, and Alzheimer’s disease. Low expression of BCAT1 exacerbates Parkinson’s disease. In contrast, high levels of BCAT1 protect the heart and help treat acute myocardial infarction. BCAT2 overexpression aggravates pancreatic ductal adenocarcinoma. Inhibiting the expression of BCAT can treat the above diseases. BCATs: branched chain amino transferases; hBCAT: human branched chain amino transferase; BCAT1: cytoplasmic BCAT; BCAT2: mitochondrial BCAT. “+” stands for promotion and “-” for inhibition.

https://www.frontiersin.org/articles/10.3389/fonc.2022.988290/pdf

The mechanism of branched-chain amino acid transferases in different diseases: Research progress and future prospects

LCAT- targeted therapies: Progress, failures and future.

Recent update on application of dihydromyricetin in metabolic related diseases.

ABSTRACT With the aim of increasing protein productivity of Chinese hamster ovary (CHO) cells, we sought to generate new CHO hosts with favorable biomanufacturing phenotypes and improved functionality. Here, we present an innovative approach of enriching the CHO host cells with a high mitochondrial membrane potential (MMP). Stable transfectant pools and clonal cell lines expressing difficult-to-express bispecific molecules generated from the MMP-enriched host outperformed the parental host by displaying (1) improved fed-batch productivity; (2) enhanced long-term cell viability of pools; (3) more favorable lactate metabolism; and (4) improved cell cloning efficiency during monoclonal cell line generation. Proteomic analysis together with Western blot validation were used to investigate the underlying mechanisms by which high MMP influenced production performance. The MMP-enriched host exhibited multifaceted protection against mitochondrial dysfunction and endoplasmic reticulum stress. Our findings indicate that the MMP-enriched host achieved an overall “fitter” phenotype that contributes to the significant improvement in biomanufacturing capability.

Mitochondrial membrane potential-enriched CHO host: a novel and powerful tool for improving biomanufacturing capability

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