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PubMed2025

Preserving centromere identity: right amounts of CENP-A at the right place and time.

Four decades ago, the discovery of centromere protein-A (CENP-A) marked a pivotal breakthrough in chromosome biology, revealing the epigenetic foundation of centromere identity. CENP-A, a histone H3 variant, directs the formation of the microtubule-binding kinetochore complex, designating the chromosomal site for its assembly and underpins the accurate partitioning of genetic material during cell division. Errors in cell division can give rise to DNA instability and aneuploidy, implicated in human diseases such as cancer. Therefore, discovering the underlying pathways and mechanisms responsible for the formation, regulation and maintenance of the centromere is important to our understanding of genome stability, epigenetic inheritance, and in providing the knowledge to help generate possible treatments and therapeutics. Here, we review various molecular pathways and mechanisms implicated in maintaining centromere identity and highlight some of the key outstanding questions with a focus on the human centromere.

Humans↗
PubMed1975

Interactions of the third component of complement (C3) with cross-linked dextran. II. Demonstration of an alternate pathway activation as binding mechanism of C3 to cross-linked dextran.

In previous investigations we could show that incubation of cross-linked dextran (Sephadex) with normal human serum results in the binding of the third component of complement to the Sephadex beads. In this paper, data are presented which demonstrate that not only human but also guinea pig C3 reacts with Sephadex and that this binding is due to an alternate pathway of C3 activation. This conclusion was drawn, since a) C3 is bound also from guinea pig serum with total deficiency of C4, b) the reaction can be completely blocked by EDTA but only diminished by EGTA and c) the reaction turned out to be temperature dependent with an optimum at 37 degrees C and could be abolished by diluting the serum more than 1:16. The ability of cross-linked dextran to activate C3 via the alternate pathway seems to be due to conformational changes, since in our experiments soluble dextran of the same source was found to be ineffective in this respect. Implications from these findings and possible applications are discussed.

Animals↗
PubMedDate not supplied

Low-threshold mechanisms and cortical activation pathways.

In chronic experiments with alert cats, stimulation with electrical current of moderate strength at various points on the lateral surface of the cerebral hemispheres leads to activation of various brain regions. In addition to high-threshold cortical points, low-threshold points have been discovered which are located in the sensorimotor region and in the Ep field of the auditory zone. The latter possess the same low thresholds for evoking an activation response as do points in the mesencephalic RF and the thalamic CM, VPL, and GM. Connections have been discovered (in the morphological part of the study) between the auditory Ep field and the intralaminar nuclei of the thalamus and the brain-stem part of the RF; the major projections run from the dorsal part of the Ep field into the lateral zone of the tegmentum. It is proposed that the role of the cortical low-threshold foci could involve the triggering of the nonspecific activation apparatus in accord with the biological significance of the signals being analyzed.

Animals↗
PubMed2026

Transcriptomic analysis reveals the molecular mechanisms underlying the inhibition of Mytilus edulis attachment by biofouling control agents.

This study combined acute toxicity assays, phenotypic quantification, and transcriptomic profiling to systematically investigate the inhibitory effects and molecular regulatory mechanisms of a novel alkylamine-based antifouling agent on survival, byssus secretion, and attachment behavior of juvenile Mytilus edulis. The 96 h-LC50 of the agent to juvenile M. edulis was 8.84 mg/L, and 10 mg/L of the agent completely inhibited mussel attachment within 24 h, significantly reducing byssal thread number, length, and diameter while increasing detachment frequency, resulting in irreversible attachment failure. Transcriptomic analysis identified 2746 differentially expressed genes, which were mainly enriched in pathways including signal transduction, immune defense, stress response, cytoskeleton organization, and protein binding. KEGG and GSEA enrichment revealed that the antifouling agent activated the MAPK stress signaling pathway, disturbed transcriptional regulation, and impaired intracellular homeostasis and cytoskeletal stability, thereby synergistically suppressing the expression of key byssal protein genes including mfp-1 and mfp-3 and ultimately blocking byssus synthesis and adhesion. This study clarifies the multi-pathway molecular mechanism underlying antifouling agent-induced attachment inhibition in M. edulis, and provides core molecular targets and theoretical support for developing efficient, specific antifouling activity, and potentially applicable marine antifouling technologies.

Animals↗
PubMed2026

Multi-omics dynamic profiling reveals predictive biomarkers for first-line immunochemotherapy in extensive-stage small-cell lung cancer.

BACKGROUND: Extensive-stage small-cell lung cancer (ES-SCLC) is associated with a poor prognosis. Although first-line immunochemotherapy improves clinical outcomes, robust prognostic biomarkers for this treatment modality remain unavailable. The aim of this study was to identify non-invasive, easily accessible, and dynamically monitored biomarkers of ES-SCLC by machine learning integrating serum metabolomics, lipidomics, and proteomics at multiple time points. METHODS: A total of 816 serum samples were collected from ES-SCLC patients receiving first-line immunotherapy combined with chemotherapy or first-line chemotherapy for metabolomics, lipidomics, and proteomics analysis. The immunochemotherapy cohort was randomly divided into training and validation subsets at a 6:4 ratio. Biomarkers were identified using machine learning algorithms, and their prognostic significance was evaluated through receiver operating characteristic (ROC) analysis, Kaplan–Meier survival analysis, and multivariate Cox regression. Potential metabolic pathways and mechanisms were further explored via integrated multi-omic analysis. RESULTS: The immunochemotherapy exhibited a prolonged median progression-free survival (PFS) and higher objective response rate (ORR) compared to the chemotherapy group. A total of 5 serum metabolites (uric acid, L-aspartate-semialdehyde, dimethisterone, xanthine, L-cysteine), 6 lipids (Cer d18:1/26:0, Cer d18:2/25:0, SM d18:1/20:1, SM d17:1/25:1, DG O-18:1_16:0, PS 18:0_24:0), and 3 proteins (ACIN1, ACSL4, PHGDH) were identified and constructed into independent prognostic models. Among patients receiving immunochemotherapy, those categorized as low-risk based on the model demonstrated significantly longer PFS compared with those in the high-risk group. These prognostic signatures also retained predictive value in patients who underwent second-line treatment with anlotinib plus immunochemotherapy. Integrated analysis revealed that glycine, serine, and threonine metabolism was the commonly enriched pathway across all three omics layers. Notably, PHGDH (protein), L-aspartate-semialdehyde and L-cysteine (metabolites), and PS (18:0_24:0) (lipid), key elements in this pathway, were all incorporated in the predictive model. In addition, models of the composition of these substances after one cycle of treatment can still predict the prognosis of patients. CONCLUSION: In this study, we constructed and validated a set of non-invasive, dynamically monitorable prognostic models (containing 5 metabolites, 6 lipids, and 3 proteins) using machine learning by integrating multiple time point data from the serum metabolome, lipid panel, and proteome to accurately distinguish the prognostic risk of patients with ES-SCLC receiving immunochemotherapy. PFS was significantly prolonged in patients in the low-risk group, and this model remains predictive in the subsequent second-line treatment with anlotinib in combination with immunochemotherapy. Glycine-serine-threonine metabolic pathway may be the key mechanism, of which PHGDH, L-aspartate semialdehyde, L-cysteine and PS (18:0_24:0) are the core predictors. This study provides the first multi-omics dynamic prognostic tool for ES-SCLC immunochemotherapy and reveals potential therapeutic targets.

Humans↗
PubMed1975

Stimulation of neutrophil oxidative metabolism by the alternate pathway of complement activation: a mechanism for the spontaneous NBT test.

The reduction of nitroblue tetrazolium dye by human neutrophils was measured in the presence of serum in which the complement system had been activated through the alternate pathway by interaction with inulin. Neutrophils incubated with serum inulin supernatants reduced the dye and showed a general increase in oxidative metabolism. The oxidation of glucose-1-14-C by supernatant prepared from selectively depleted sera indicated that the neutrophil-stimulating factor(s) was generated through the alternate pathway of complement activation. The possibility that inulun had been ingested as a particle was ruled out by light microscopy and radiolabeling studies. The failure of neutrophils stimulated by the serum-inulun supernatants to migrate after exposure to a chemotactic agent suggested that the site of neutrophil-complement interaction was on the cell membrane. It is concluded from these results that biologically active fragments generated through the alternative pathway of complement activation can stimulate neutrophil metabolism in the absence of phagocytosis. Interaction of such fragments with circulating neutrophils in vivo and the subsequent metabolic activation of these cells is one explanation for the spontaneous reduction of nitroblue tetrazolium dye in vitro by neutrophils from patients with certain infections and inflammatory disorders.

Absorption↗
PubMed1978

Iodide and thiocyanate efflux from brain following injection into rat caudate nucleus.

Mechanisms and pathways of 125I and 35SCN efflux from the brain were investigated in anesthetized rats. Tracers were injected into the caudate nucleus through a guide cannula implanted 1 wk previously and concentrations of isotope in brain and cerebrospinal fluid (CSF) were determined at various times after injection. 125I clearance from the brain followed a single exponential curve. In control rats 36.2% of the 125I remained in the brain 30 min after injection and 60.4% in rats pretreated with perchlorate. Comparable values for 35SCN were 25.8% in control rats, 41.0% with perchlorate, and 39.7% with iodide loading. Estimates of 125I and 35SCN effluxes from the brain via the blood-brain barrier and CSF pathways suggest that greater than 95% of efflux crosses the blood-brain barrier. These results indicate that 1)iodide and thiocyanate are transported across the blood-brain barrier by a common mechanism, and 2) this efflux system is an important factor in the control of the distributions of iodide and thiocyanate in the central nervous system.

Animals↗
PubMed1978

Mechanism of iron chelation in the hypertransfused rat: definition of two alternative pathways of iron mobilization.

The mechanism of action of two recently identified iron-chelating drugs, RA and CHA, was compared with that of two well-known chelating agents, DF and DTPA, in hypertransfused rats labeled with selective parenchymal and RE cell radioiron probes. The existence of two alternative pathways for the in vivo chelation of iron has been indicated by the present findings. The first of these pathways involves the extracellular chelation of RE cell iron and its subsequent excretion in the urine. The second pathway is concerned with the intracellular binding of hepatic parenchymal cell iron and its subsequent excretion in the bile. Iron chelation by DTPA is restricted to the first pathway, whereas iron chelation by CHA is confined to the second pathway. DF and RA have a dual effect and are able to enhance the urinary excretion of RE cell iron as well as the biliary excretion of hepatic parenchymal iron. Hypertransfused rats are a simple and useful experimental model for the study of iron mobilization by chelating agents of potential clinical usefulness. However, further studies are required to show whether the pathways of iron chelation identified in rats may represent the mechanism of iron chelation in patients with transfusional iron overload.

Animals↗
PubMed1979

Principles of pain management. A short review.

Information that contributes to our understanding of the processes that participate in the perception of and responses to pain has expanded rapidly in the last decade. Much of this information and many clinical observations demand new conceptual frameworks within which to modify and expand classical teachings of pain pathways and mechanisms. In this brief review, some of these new dimensions are considered. The limited references serve as an introduction to more comprehensive original and review material.

Afferent Pathways↗
PubMed2026

miR-191 affects skeletal muscle differentiation by regulating Wwp1 in mouse myoblasts.

Skeletal muscle atrophy is a key complication of various diseases, such as chronic obstructive pulmonary disease (COPD) and cancer. The mechanisms by which these diseases affect skeletal muscle metabolism need to be deeply explored. By analyzing the miRNA expression profiles in the plasma of patients with COPD, we found that miR-191 expression was significantly altered and it may influence skeletal muscle metabolism by regulating ubiquitination and the mTOR pathway. Using a mouse model of skeletal muscle injury induced by cardiotoxin, we found that miR-191 and Wwp1 showed a dynamic negative correlation in injury repair. Transfection with miR-191 mimics significantly inhibited the expression of myogenic regulatory factor Myog and differentiation markers Myh1/7/8, while downregulating key genes in the mTOR pathway. Molecular mechanism studies showed that miR-191 could directly act on the 3' untranslated region of the Wwp1 gene to inhibit its expression. This study reveals the important role of the miR-191/Wwp1 axis in skeletal muscle differentiation and provides a novel theoretical basis for research on muscle atrophy induced by COPD, cancer cachexia, and other diseases.

Animals↗
PubMed2026

The Mechanism of Celosiae Semen in the Treatment of Diabetic Cataract: Based on Network Pharmacology.

INTRODUCTION: Diabetes mellitus can be complicated by a variety of ocular diseases, among which the postoperative complications of diabetic cataract (DC) are significantly higher than those of non-DC patients. Therefore, finding drugs with natural active ingredients is an urgent challenge in the prevention and treatment of DC. Discovering the potential molecular mechanism of celosiae semen (CS) for the treatment of DC and providing new ideas and programs for the treatment and prevention of DC. METHODS: In this study, network pharmacology, molecular docking, and molecular dynamics simulations were utilized to predict the binding and functional enrichment of the main active ingredients of CS with DC-related targets, and to explore the potential pathways and mechanisms of CS for the treatment of DC. RESULTS: Through database searching and screening, a total of 45 potential targets of CS for the treatment of DC were identified, functionally enriched, and a protein-protein interaction network was constructed, and the key target, SRC, was finally found. The results of molecular docking and molecular dynamics simulation showed that the main active ingredient of CS, stigmasterol, could bind stably to the key target SRC protein. DISCUSSION: This study not only elucidates the phyto-pharmacological basis of CS in DC management but also provides a framework for developing natural product-derived targeted therapies against diabetic ocular complications. The integration of modern genomics and computational chemistry to deconstruct the therapeutic effects of traditional Chinese herbal medicines has great clinical significance in expanding the scope of traditional Chinese medicines for the treatment of DC and promoting precision targeting. However, this requires verification through basic experiments. CONCLUSION: These computational findings suggest that CS may exert its anti-cataract effects through the multi-target modulation of diabetic metabolic pathways and SRC-mediated signaling cascades.

Humans↗
PubMed2024

Multi-omics association study of hexadecane degradation in haloarchaeal strain Halogranum rubrum RO2-11.

Haloarchaea with the capacity to degrade alkanes is promising to deal with petroleum pollution in hypersaline environments. However, only a limited number of haloarchaeal species are investigated, and their pathway and mechanism for alkane degradation remain unclear. In this study, Halogranum rubrum RO2-11, a haloarchaeal strain, verified the ability to degrade kerosene and hexadecane in 184 g/L NaCl, with 53% and 52% degradation rates after 9 and 4 days, respectively. Genome sequencing and gene annotation indicated that strain RO2-11 possesses a complete potential alkane-degrading pathway, of which alkane hydroxylases may include CYP450, AlmA, and LadA. Transcriptome and metabolome analyses revealed that the upregulation of related genes in TCA cycle, lysine biosynthesis, and acetylation may help improve hexadecane degradation. Additionally, an alternative degrading pathway of hexadecane based on dual-terminal β-oxidation may occur in strain RO2-11. It is likely to be the first report of alkane degradation by the genus Halogranum, which may be helpful for applications of oil-pollution bioremediation under high-salt conditions.

Alkanes↗
PubMed1976

Alternative pathway complement activation:a possible mechanism inducing skin lesions in benign gonococcal spesis.

In order to elucidate the pathogenesis of the skin lesions in 'benign gonococcal sepsis' direct immunofluorescence of an early macular lesion and routine histopathology of a mature papulopustular lesion in a patient with septic gonococcal dermatitis have been performed. Histopathology of the mature skin lesion revelaed a pattenr of 'allergic vasculitis'. Direct immunofluorescence showed exclusively deposits of C3 around and within the capillaries and in the basement membrane zone. No specific IgG, IgM, IgA or C4 deposits could be demonstrated. This, together with serological findings and reports from the literature, suggests an important pathogenetic function for complement, activated through the alternative pathway by means of gonococcal endotoxic lipopolysaccharide, in the pathogenesis of the skin lesions in benign gonococcal sepsis.

Adult↗