Cyanobacterial NDH-1 complexes use a conserved Type-I energy-transducing core for respiratory electron transfer, photosystem I cyclic electron flow, and, in specialized isoforms, active CO2 uptake. This review examines how the common structural and energetic principles of respiratory Complex I may be adapted to these distinct physiological functions. Building on current mechanistic models, this review frames quinone reduction as producing a distributed, metastable "tense state" in the membrane arm. This state is represented not by a single strained conformation, but by coupled changes in proton affinity, ion-pair geometry, hydration, and local electrostatics. This framework is then applied to the cyanobacterial CO2-uptake complexes NDH-13 and NDH-14, in which the distal NdhF3/NdhF4-CupA/B module appears to repurpose part of the canonical proton-coupling machinery for Zn-dependent CO2 hydration. Bioenergetic estimates indicate that ferredoxin-dependent plastoquinone reduction could, in principle, support three-proton translocation together with CO2 hydration and bicarbonate accumulation. The model connects Complex I energy transduction pathways to cyanobacterial CO2 hydration chemistry and identifies testable predictions regarding coupling at the Zn-site to distant plastoquinone reduction and proton transfer.
Skeletal muscle wasting is a multifactorial syndrome that contributes to weakness, reduced physical function, loss of independence, and poor clinical outcomes across aging, cancer, obesity, heart failure, disuse, and rare neuromuscular diseases. Although major advances have illuminated much of the molecular signaling for skeletal muscle, effective pharmacologic therapy remains extremely limited. This narrative review examines current and emerging drug-development strategies for muscle wasting with an emphasis on mechanistic rationale, translational evidence, and the barriers that continue to impede clinical success. The focus is on four major therapeutic areas: myostatin/activin pathway inhibition, selective androgen receptor modulators, ghrelin-related appetite-directed therapies, and mitochondria-targeted approaches. Across these classes, preclinical studies have shown that pharmacologic manipulation of anabolic or catabolic signaling, energy intake, and mitochondrial function can preserve or increase muscle mass and, in some settings, improve survival or selected functional measures. However, clinical translation has been inconsistent. A recurring theme is that favorable effects on muscle mass or muscle size do not translate into improvements in strength, mobility, fatigue, or patient-centered outcomes. Additional barriers include disease heterogeneity, limitations of preclinical models, muscle maintenance after therapy, safety concerns, regulatory demands for clinically meaningful endpoints, as well as the complexity of rare-disease development. Future progress will depend on biomarker-guided and phenotype-enriched trial design, multimodal interventions, and outcome measures that capture muscle function.
Water oxidation in photosynthesis occurs through a four-electron redox reaction that is catalyzed by the oxygen-evolving complex (OEC) in Photosystem II (PS II), that consists of the Mn4CaO5 cluster. Among the four stable intermediates in the water oxidation reaction, it has been reported that the paramagnetic S2 state with the formal oxidation of Mn(III)Mn(IV)3 has multiple spin states, that include high spin (HS, 5/2, g≥4.1) and low spin (LS, 1/2, g = 2) forms. Previous computational studies proposed that these two forms differ in their structure and the high spin form may represent an intermediate form of the OEC during the S2 to S3 transition, the step in which the first substrate water binds to the last open coordination site of the cluster. In the current study, we examined the pH-induced HS-S2 state of T. vestitus PS II with MnK edge extended X-ray absorption fine structure (EXAFS) and X-ray absorption near edge spectroscopy (XANES). Small, but notable differences were observed in the EXAFS and XANES between the HS and LS S2 states. EXAFS data and the fits indicate that the basic geometry of the cluster remains the same between these two states. Therefore, we hypothesize that the difference between the HS and LS S2 state may be due to chemical differences such as different protonation states of the oxo and/or water ligands, or its surroundings. We also examined the detailed oxygen positions of the S2 states in the XFEL-based room temperature crystal structures, and confirmed that at neutral pH at room temperature, the structure is consistent with that of the LS-S2 model with open cubane-like geometry.
The central mechanism of cholestatic liver fibrosis (CLF) is the accumulation of extracellular matrix caused by the activation of hepatic stellate cells (HSCs), which is reversible in the early to mid-stages. Therefore, this study characterized the underlying molecular mechanisms involved. In this study, the liver and spleen indexes of the CLF model markedly increased and continued to rise over time. There were significant differences in ALP, TBIL, AST, DBIL, ALT, IBIL, AST/ALT, and GGT levels among rats in the CLF and SHAM groups at different time points. Histological staining revealed that the CLF had progressed to cirrhosis by week 5. Importantly, relative to the SHAM group, the CLF-2, CLF-3, CLF-4, and CLF-5 groups contained 2886, 3472, 5297, and 4586 differentially expressed genes (DEGs), respectively. The four comparisons identified 1848 shared DEGs that regulate cell growth, chemotaxis, inflammation, apoptosis, and fibrosis. Pxdn and Gpx1 are the hub genes for these shared DEGs. Pxdn knockdown reversed the TGF-β-induced increase in HSC activity and markers (Col I, α-SMA, and FN), an effect that was rescued by Gpx1 knockdown. Pxdn knockdown increased GPX1 levels in HSCs, whereas Gpx1 knockdown had no effect on PXDN. In conclusion, Pxdn knockdown attenuated TGF-β-induced activation of HSC by upregulating GPX1. These findings nominate the PXDN-GPX1 axis as a mechanistic candidate warranting in vivo interrogation.
Gastric cardia adenocarcinoma (GCA) is an aggressive malignancy in which immune microenvironment remodeling contributes to tumor progression. This study investigated whether Tat interactive protein, 60 kDa (TIP60)-mediated acetylation of ubiquitin-like with PHD and RING Finger domains 1 (UHRF1) regulates GCA progression and tumor cell-dependent M2-like macrophage polarization. Transcriptomic screening identified UHRF1 as a candidate oncogenic regulator, and UHRF1 was upregulated in GCA tissues and cell lines. Functional assays showed that UHRF1 promoted GCA cell proliferation, migration, invasion, cell-cycle progression, and epithelial-mesenchymal transition. Single-cell RNA sequencing and immune infiltration analyses revealed enrichment of M2 macrophages in GCA tissues and a positive association between UHRF1 expression and M2 macrophage abundance. Co-culture and conditioned-medium experiments demonstrated that tumor cell-derived UHRF1 enhanced macrophage polarization toward an M2-like phenotype, reflected by increased CD206, CD163, Arg-1, and Mrc-2 expression. Mechanistically, TIP60 interacted with UHRF1 and promoted its acetylation at K644, K646, K648, and K650. The acetylation-defective UHRF1 4KR mutant showed reduced capacity to promote GCA cell aggressiveness and tumor cell-dependent M2-like macrophage polarization. In vivo, TIP60 inhibition suppressed tumor growth, metastatic potential, and M2-like macrophage infiltration, whereas UHRF1 overexpression partially restored these effects. These findings indicate that the TIP60/UHRF1 acetylation axis promotes GCA progression by linking tumor-intrinsic epigenetic regulation with macrophage-associated immune remodeling, suggesting a potential therapeutic target for GCA.
