Downregulation of microRNA-129-2 by Hepatitis B Virus Promotes Cell Proliferation in Hepatocellular Carcinoma.

Objective: MicroRNA-192-2 has been shown to have a role in the early diagnosis of hepatocellular carcinoma (HCC), but the relationship between microRNA-192-2 and hepatitis B virus (HBV) in HCC patients remains unclear.

Methods: Specimens were collected from 56 HCC patients diagnosed with HBV infection and 56 HCC patients without viral infection. HBV and miR-129-2 levels in HCC tissues, adjacent tissues, and cell lines were analyzed by RT‒PCR.

Homeostatic regulation of NAD(H) and NADP(H) in cells.

Nicotinamide adenine dinucleotide (NAD)/reduced NAD (NADH) and nicotinamide adenine dinucleotide phosphate (NADP)/reduced NADP (NADPH) are essential metabolites involved in multiple metabolic pathways and cellular processes. NAD and NADH redox couple plays a vital role in catabolic redox reactions, while NADPH is crucial for cellular anabolism and antioxidant responses. Maintaining NAD(H) and NADP(H) homeostasis is crucial for normal physiological activity and is tightly regulated through various mechanisms, such as biosynthesis, consumption, recycling, and conversion between NAD(H) and NADP(H).

Acetyl-NPKY of integrin-β1 binds KINDLIN2 to control endothelial cell proliferation and junctional integrity.

Integrin-dependent crosstalk between cell-matrix adhesions and cell-cell junctions is critical for controlling endothelial permeability and proliferation in cancer and inflammatory diseases but remains poorly understood. Here, we investigated how acetylation of the distal NPKY-motif of Integrin-β1 influences endothelial cell physiology and barrier function. Expression of an acetylation-mimetic β1-K794Q-GFP mutant led to the accumulation of immature cell-matrix adhesions accompanied by a transcriptomic reprograming of endothelial cells, involving genes associated with cell adhesion, proliferation, polarity, and barrier function.

The ATP-bound inward-open conformation of ABCC4 reveals asymmetric ATP binding for substrate transport.

The multidrug resistance-associated protein (MRP) ABCC4 facilitates substrate transport across the cytoplasmic membrane, crucial for normal physiology and mediating multidrug resistance in tumor cells. Despite intensive studies on MRPs, ABCC4's transport mechanism remains incompletely understood. In this study, we unveiled an inward-open conformation with an ATP bound to degenerate NBD1.

Emerging roles of FOXK2 in cancers and metabolic disorders.

FOXK2, a member of the Forkhead box K (FOXK) transcription factor family, is widely expressed in various tissues and organs throughout the body. FOXK2 plays crucial roles in cell proliferation, differentiation, autophagy, nucleotide biosynthesis, DNA damage response, and aerobic glycolysis. Although FOXK2 is recognized as an oncogene in colorectal cancer and hepatocellular carcinoma, it acts as a tumor suppressor in breast cancer, cervical cancer, and non-small cell lung cancer (NSCLC).

Structural insights into the transporting and catalyzing mechanism of DltB in LTA D-alanylation.

DltB, a model member of the Membrane-Bound O-AcylTransferase (MBOAT) superfamily, plays a crucial role in D-alanylation of the lipoteichoic acid (LTA), a significant component of the cell wall of gram-positive bacteria. This process stabilizes the cell wall structure, influences bacterial virulence, and modulates the host immune response. Despite its significance, the role of DltB is not well understood.

Deacylases-structure, function, and relationship to diseases.

Reversible S-acylation plays a pivotal role in various biological processes, modulating protein functions such as subcellular localization, protein stability/activity, and protein-protein interactions. These modifications are mediated by acyltransferases and deacylases, among which the most abundant modification is S-palmitoylation. Growing evidence has shown that this rivalrous pair of modifications, occurring in a reversible cycle, is essential for various biological functions.

Multilevel thresholding with divergence measure and improved particle swarm optimization algorithm for crack image segmentation.

Crack formation is a common phenomenon in engineering structures, which can cause serious damage to the safety and health of these structures. An important method of ensuring the safety and health of engineered structures is the prompt detection of cracks. Image threshold segmentation based on machine vision is a crucial technology for crack detection.

Palmitoylation alters LDHA activity and pancreatic cancer response to chemotherapy.

Lactate dehydrogenase A (LDHA) serves as a key regulator of the Warburg Effect by catalyzing the conversion of pyruvate to lactate in the final step of glycolysis. Both the expression level and enzyme activity of LDHA are upregulated in cancers, however, the underlying mechanism remains incompletely understood. Here, we show that LDHA is post-translationally palmitoylated by ZDHHC9 at cysteine 163, which promotes its enzyme activity, lactate production, and reduces reactive oxygen species (ROS) generation.

ZDHHC5-mediated NLRP3 palmitoylation promotes NLRP3-NEK7 interaction and inflammasome activation.

The nucleotide-binding domain (NBD), leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome is a critical mediator of the innate immune response. How NLRP3 responds to stimuli and initiates the assembly of the NLRP3 inflammasome is not fully understood. Here, we found that a cellular metabolite, palmitate, facilitates NLRP3 activation by enhancing its S-palmitoylation, in synergy with lipopolysaccharide stimulation.

Fantastic voyage: The journey of NLRP3 inflammasome activation.

NLRP3 inflammasome, an intracellular multiprotein complex, can be activated by a range of pathogenic microbes or endogenous hazardous chemicals. Its activation results in the release of cytokines such as IL-1β and IL-18, as well as Gasdermin which eventually causes pyroptosis. The activation of NLRP3 inflammasome is under strict control and regulation by numerous pathways and mechanisms.

Inhibition of talin-induced integrin activation by a double-hit stapled peptide.

Integrins are ubiquitously expressed cell-adhesion proteins. Activation of integrins is triggered by talin through an inside-out signaling pathway, which can be driven by RAP1-interacting adaptor molecule (RIAM) through its interaction with talin at two distinct sites. A helical talin-binding segment (TBS) in RIAM interacts with both sites in talin, leading to integrin activation.

Direct stimulation of de novo nucleotide synthesis by O-GlcNAcylation.

O-linked β-N-acetyl glucosamine (O-GlcNAc) is at the crossroads of cellular metabolism, including glucose and glutamine; its dysregulation leads to molecular and pathological alterations that cause diseases. Here we report that O-GlcNAc directly regulates de novo nucleotide synthesis and nicotinamide adenine dinucleotide (NAD) production upon abnormal metabolic states. Phosphoribosyl pyrophosphate synthetase 1 (PRPS1), the key enzyme of the de novo nucleotide synthesis pathway, is O-GlcNAcylated by O-GlcNAc transferase (OGT), which triggers PRPS1 hexamer formation and relieves nucleotide product-mediated feedback inhibition, thereby boosting PRPS1 activity.

Effect of birth asphyxia on neonatal blood glucose during the early postnatal life: A multi-center study in Hubei Province, China.

Background: Birth asphyxia causes hypoxia or inadequate perfusion to the organs of newborns, leading to metabolism dysfunctions including blood glucose disorders.

Methods: Neonates with and without birth asphyxia were retrospectively recruited from 53 hospitals in Hubei Province from January 1 to December 31, 2018. In summary, 875, 1139, and 180 cases in the control group, the mild asphyxia group, and the severe asphyxia group were recruited, respectively.

Downregulation of TRIM27 alleviates hypoxic-ischemic encephalopathy through inhibiting inflammation and microglia cell activation by regulating STAT3/HMGB1 axis.

TRIM27 expression was increased in the Parkinson's disease (PD), and knockdown of TRIM27 in PC12 cells significantly inhibited cell apoptosis, indicating that downregulation of TRIM27 exerts a neuroprotective effect. Herein, we investigated TRIM27 role in hypoxic-ischemic encephalopathy (HIE) and the underlying mechanisms. HIE models were constructed in newborn rats using hypoxic ischemic (HI) treatment and PC-12/BV2 cells with oxygen glucose deprivation (OGD), respectively.

nucleotide biosynthetic pathway and cancer.

nucleotide biosynthetic pathway is a highly conserved and essential biochemical pathway in almost all organisms. Both purine nucleotides and pyrimidine nucleotides are necessary for cell metabolism and proliferation. Thus, the dysregulation of the nucleotide biosynthetic pathway contributes to the development of many human diseases, such as cancer.

Diagnostic Value of Tumor Markers in Peritoneal Lavage Fluid for Peritoneal Metastasis from Colorectal Cancer.

Objective: To investigate the diagnostic value of tumor markers in peritoneal lavage fluid in the diagnosis of peritoneal metastasis from colorectal cancer.

Methods: One hundred eighty-six patients with colorectal cancer and 15 patients with benign disease who underwent surgical treatment were included. The abdominal cavity and pelvis of the patients were lavaged with 200 ml of normal saline immediately after abdominal cavity incision or pneumoperitoneum establishment.

Metabolic Modifications, Inflammation, and Cancer Immunotherapy.

Cancer immunotherapy has accomplished significant progresses on treatment of various cancers in the past decade; however, recent studies revealed more and more heterogeneity in tumor microenvironment which cause unneglectable therapy resistance. A central phenomenon in tumor malignancy is metabolic dysfunctionality; it reprograms metabolic homeostasis in tumor and stromal cells thus affecting metabolic modifications on specific proteins. These posttranslational modifications include glycosylation and palmitoylation, which usually alter the protein localization, stability, and function.

Crystal structure of the FERM-folded talin head reveals the determinants for integrin binding.

Binding of the intracellular adapter proteins talin and its cofactor, kindlin, to the integrin receptors induces integrin activation and clustering. These processes are essential for cell adhesion, migration, and organ development. Although the talin head, the integrin-binding segment in talin, possesses a typical FERM-domain sequence, a truncated form has been crystallized in an unexpected, elongated form.

Phosphorylation of RIAM by src promotes integrin activation by unmasking the PH domain of RIAM.

Integrin activation controls cell adhesion, migration, invasion, and extracellular matrix remodeling. RIAM (RAP1-GTP-interacting adaptor molecule) is recruited by activated RAP1 to the plasma membrane (PM) to mediate integrin activation via an inside-out signaling pathway. This process requires the association of the pleckstrin homology (PH) domain of RIAM with the membrane PIP2.

Structural basis for the inhibition of HSP70 and DnaK chaperones by small-molecule targeting of a C-terminal allosteric pocket.

The stress-inducible mammalian heat shock protein 70 (HSP70) and its bacterial orthologue DnaK are highly conserved nucleotide binding molecular chaperones. They represent critical regulators of cellular proteostasis, especially during conditions of enhanced stress. Cancer cells rely on HSP70 for survival, and this chaperone represents an attractive new therapeutic target.

Crystal structure of the stress-inducible human heat shock protein 70 substrate-binding domain in complex with peptide substrate.

The HSP70 family of molecular chaperones function to maintain protein quality control and homeostasis. The major stress-induced form, HSP70 (also called HSP72 or HSPA1A) is considered an important anti-cancer drug target because it is constitutively overexpressed in a number of human cancers and promotes cancer cell survival. All HSP70 family members contain two functional domains: an N-terminal nucleotide binding domain (NBD) and a C-terminal protein substrate-binding domain (SBD); the latter is subdivided into SBDα and SBDβ subdomains.

Architectural organization of the metabolic regulatory enzyme ghrelin O-acyltransferase.

Ghrelin O-acyltransferase (GOAT) is a polytopic integral membrane protein required for activation of ghrelin, a secreted metabolism-regulating peptide hormone. Although GOAT is a potential therapeutic target for the treatment of obesity and diabetes and plays a key role in other physiologic processes, little is known about its structure or mechanism. GOAT is a member of the membrane-bound O-acyltransferase (MBOAT) family, a group of polytopic integral membrane proteins involved in lipid-biosynthetic and lipid-signaling reactions from prokaryotes to humans.

Crystal structure studies on sulfur oxygenase reductase from Acidianus tengchongensis.

Sulfur oxygenase reductase (SOR) simultaneously catalyzes oxidation and reduction of elemental sulfur to produce sulfite, thiosulfate, and sulfide in the presence of molecular oxygen. In this study, crystal structures of wild type and mutants of SOR from Acidianus tengchongensis (SOR-AT) in two different crystal forms were determined and it was observed that 24 identical SOR monomers form a hollow sphere. Within the icosatetramer sphere, the tetramer and trimer channels were proposed as the paths for the substrate and products, respectively.