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PubMed2002

Dust in the Earth system: the biogeochemical linking of land, air and sea.

Understanding the response of the Earth's climate system to anthropogenic perturbation has been a pressing priority for society since the late 1980s. However, recent years have seen a major paradigm shift in how such an understanding can be reached. Climate change demands analysis within an integrated 'Earth-system' framework, taken to encompass the suite of interacting physical, chemical, biological and human processes that, in transporting and transforming materials and energy, jointly determine the conditions for life on the whole planet. This is a highly complex system, characterized by multiple nonlinear responses and thresholds, with linkages often between apparently disparate components. The interconnected nature of the Earth system is wonderfully illustrated by the diverse roles played by atmospheric transport of mineral 'dust', particularly in its capacity as a key pathway for the delivery of nutrients essential to plant growth, not only on land, but perhaps more importantly, in the ocean. Dust therefore biogeochemically links land, air and sea. This paper reviews the biogeochemical role of mineral dust in the Earth system and its interaction with climate, and, in particular, the potential importance of both past and possible future changes in aeolian delivery of the micro-nutrient iron to the ocean. For instance, if, in the future, there was to be a widespread stabilization of soils for the purpose of carbon sequestration on land, a reduction in aeolian iron supply to the open ocean would occur. The resultant weakening of the oceanic carbon sink could potentially offset much of the carbon sequestered on land. In contrast, during glacial times, enhanced dust supply to the ocean could have 'fertilized' the biota and driven atmospheric CO(2) lower. Dust might even play an active role in driving climatic change; since changes in dust supply may affect climate, and changes in climate, in turn, influence dust, a 'feedback loop' is formed. Possible feedback mechanisms are identified, recognition of whose operation could be crucial to our understanding of major climatic transitions over the past few million years.

Carbon↗

PubMed2026

Phenylacetic acid mediates Acinetobacter baumannii entry into a viable but non-culturable state.

Desiccation tolerance is central to the pathogenic success of the opportunistic pathogen Acinetobacter baumannii, allowing its survival on hospital surfaces in the absence of water and nutrients for months at a time, compromising surface decontamination and aiding cross-contamination between staff and patients. Despite the importance of desiccation tolerance, the regulation underpinning this behaviour remains largely elusive. In this work, transcriptomic analyses of desiccated cells revealed phenylacetic acid (PAA) catabolism as an essential mediator of desiccation tolerance. We subsequently demonstrate that deletion of the paa operon abolished the clonogenicity of desiccated cells. Strikingly, these A. baumannii cells remained viable by entering the viable but non-culturable (VBNC) state, a means to survive extreme stressors like antibiotic exposure. Furthermore, we uncover that PAA catabolism is necessary to mediate PAA-driven biofilm regulation. These findings highlight PAA catabolism as a modulator of biofilm formation and a key pathway for entry into the VBNC state in response to desiccation. This reveals PAA catabolism as a target for novel infection prevention strategies.

Phenylacetates↗

PubMed2001

Control of cell division by a retinoblastoma protein homolog in Chlamydomonas.

A key pathway that controls both cell division and differentiation in animal cells is mediated by the retinoblastoma (RB) family of tumor suppressors, which gate the passage of cells from G(1) to S and through S phase. The role(s) of the RB pathway in plants are not yet clearly defined, nor has there been any evidence for its presence in unicellular organisms. Here we have identified an RB homolog encoded by the mat3 gene in Chlamydomonas reinhardtii, a unicellular green alga in the land plant lineage. Chlamydomonas cells normally grow to many times their original size during a prolonged G(1) and then undergo multiple alternating rounds of S phase and mitosis to produce daughter cells of uniform size. mat3 mutants produce small daughter cells and show defects in two size-dependent cell cycle controls: They initiate the cell cycle at a below-normal size, and they undergo extra rounds of S phase/mitosis. Unlike mammalian RB mutants, mat3 mutants do not have a shortened G(1), do not enter S phase prematurely, and can exit the cell cycle and differentiate normally, indicating that the RB pathway in Chlamydomonas has a different role than in animals.

Algal Proteins↗

PubMed2005

Epigenetic changes in cancer and preneoplasia.

Recent studies have identified an increasing number of genes that are inactivated by promoter region methylation in cancer. Some of these genes were initially identified as altered genetically in cancer, but in other tumors they are silenced in association with promoter region CpG island methylation. New approaches for screening the genome add to this list of candidate tumor suppressor genes, and many genes regulated key pathways in cancer, including cell cycle control, DNA repair, and apoptosis. Transcription factors may also be silenced by promoter region methylation, affecting the expression of many downstream target genes and globally altering the cancer phenotype. Determining loss of expression is important in assigning functional importance to promoter region methylation for any gene. Individual cancers have alterations in many different genes, affecting many of these important pathways and contributing to the cancer phenotype. The number of genes targeted for promoter region methylation increases during neoplastic progression. These studies suggest that the epigenetic change of promoter region methylation plays a critical role in neoplastic transformation and progression.

Chromatin↗

PubMed2006

Effect of cocaine on germ cell apoptosis in rats at different ages.

AIM: To investigate the effect of cocaine on apoptosis and caspase-3 activity in germ cells in male rats at different ages. METHODS: Cocaine hydrochloride was given (15 mg/kg body weight s.c.) to male Sprague-Dawley rats of 3 weeks (n = 8), 6 weeks (n = 8) and 12 weeks (n = 8) of age, daily for 28 Days. The serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), testosterone (T) and estrogen (E2) were assayed, and the DNA fragmentation of germ cells was determined by gel eletronphoresis. The cell cycle, apoptosis and caspase-3 activity of germ cells were tested by flow cytometry. RESULTS: After the 28-day cocaine treatment, testes weight of the 3-week-old rats, the testes and body weights of the 6-week-old rats were decreased significantly compared to those of their corresponding controls (P < 0.05). The serum level of T was decreased significantly in the 3-week-old and 6-week-old rats, and the serum level of PRL was also decreased significantly in 12-week-old rats compared to the controls (P < 0.05). In all the three cocaine-treated groups, the isolated DNA displayed a clear ladder pattern, especially in the 6-week old rats. The number of apoptosic germ cells increased significantly in 3- and 6-week-old rats treated with cocaine (P < 0.05). The caspase-3 activity in all three groups increased significantly compared to the controls (P < 0.05), especially in the 6-week-old rats. CONCLUSION: Cocaine exposure for 28 Days leads to significant damage to male gonad and apoptosis elevation in testes of rats of different ages, especially in those of 6 weeks of age. The increase in caspase-3 activity might be a key pathway related to the early stage of apoptosis as the mechanism of cocaine-induced germ cell loss.

Aging↗

PubMed2025

Time-course transcriptome and proteomic dynamics during the de novo shoot organogenesis in Chinese fir (Cunninghamia lanceolata).

De novo shoot organogenesis (DNSO) enables plants to regenerate shoots from various explants, offering valuable opportunities for research and plant biotechnology applications. While significant progress has been made in understanding regeneration in angiosperms, the regulatory mechanisms in gymnosperms, particularly Chinese fir (Cunninghamia lanceolata), remain poorly understood, despite its importance as a key timber species in China. This study successfully established an efficient DNSO protocol for Chinese fir, identifying six distinct stages in the process through cellular-level analysis. Time-course transcriptome and proteomics analyses revealed dynamic changes in mRNA and protein levels during regeneration. Notably, proteins showed more significant alterations across a broad range of biological processes, often independent of corresponding mRNA changes. Key pathways associated with ethylene metabolism and abiotic stress responses were enriched, highlighting their critical roles in regeneration. Further experiments confirmed that moderate osmotic stress treatments (150 mm mannitol) and ethylene treatment (100 μm ACC and 5 μm AgNO3) substantially enhanced DNSO efficiency. In summary, this study uncovers the molecular mechanisms underlying Chinese fir DNSO, providing valuable insights into improving plant regeneration efficiency in this economically important species. These findings contribute to advancements in plant biotechnology and sustainable forestry practices.

Cunninghamia↗

PubMed2026

Topical Donepezil for Cholinergic Modulation in Chronic Wound Repair.

Chronic wounds result from combined defects in vascular perfusion, inflammatory resolution, and epithelial repair. The skin's non-neuronal cholinergic system (NNCS), formed by keratinocytes, endothelial cells, fibroblasts, and immune cells that synthesise and respond to acetylcholine (ACh), helps coordinate these processes through muscarinic and nicotinic receptors. Inhibition of acetylcholinesterase (AChE) increases local ACh concentrations and may engage two key pathways supported by preclinical data: M3 muscarinic receptor (M3 mAChR)-endothelial nitric oxide synthase (eNOS)-nitric oxide (NO)-mediated vasodilation, and α7 nicotinic acetylcholine receptor (α7-nAChR)-mediated suppression of pro-inflammatory cytokines. Donepezil is a reversible, selective AChE inhibitor with physicochemical properties compatible with dermal administration. Low-dose or microneedle dermal delivery has produced dermal exposure with limited systemic uptake in animal and ex vivo skin studies. In preclinical diabetic wound models, nicotinic receptor activation accelerated healing, reduced inflammatory signalling, and improved control of bacterial burden. We hypothesise that topical donepezil formulated for localised dermal delivery could restore cholinergic signalling within the wound microenvironment by increasing local ACh concentrations. This approach may complement metabolic therapies that support arginine-NO coupling and redox balance. Controlled pilot studies should assess local cutaneous pharmacodynamics, perfusion responses, and wound-closure outcomes.

Donepezil↗

PubMed2026

Altered neural electrophysiological properties in the anterior cingulate cortex in a mouse model of Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a neurodevelopmental genetic disease associated with multiple metabolic and behavioural abnormalities converging into a distinctive clinical phenotype characterized by insatiable appetite leading to hyperphagia and eventual morbid obesity. The PWS spectrum results from deficiencies in paternally imprinted chromosome 15q11-13 region clustering around non-coding RNA multiple-repeat gene Snord116. A PWS mouse model with paternal Snord116 deletion (Snord116del) revealed multiple expected behavioural traits but failed to reproduce obesity in experimental paradigms designed to uncover homeostatic hypothalamic mechanisms of hyperphagia, while the possibility for pathologic hedonic overdrive underlying hyperphagic behaviours was not studied. In Snord116del mice, we examined functional properties of pyramidal neurons (PyNs) in the anterior cingulate cortex (ACC), the brain area commonly associated with goal-oriented and choice-outcome processing, including the value assessment of food items. We found indications of higher dendritic complexity and stronger afferent excitatory connectivity compared to controls. A strong excitatory input into Snord116del PyNs was balanced by a more hyperpolarized resting membrane potential, rendering lower soma excitability, improved signal-to-noise discrimination and stronger low-pass filtering. The enhanced excitatory network-tuning ability originating from Snord116 deficiency may explain the previously reported better performance of Snord116del over wild-type mice in working-for-food behavioural tests, whereas in humans it might entail exaggerated reward-seeking behaviour since early childhood when food is the main attractant. Our analysis of previously published genomic databases revealed candidate genes responsible for the abnormal functional neuronal phenotype caused by Snord116 deletion, including K+ and Na+ voltage-dependent ion channels, protein kinases, phosphatases and components of the mechanistic target of rapamycin (mTOR) intracellular signalling pathway. KEY POINTS: Altered biophysical characteristics and parameters of neuronal connectivity in pyramidal neurons in the anterior cingulate cortex (ACC) in Snord116 deletion mice. Alterations include augmented afferent synaptic input, altered resting state and firing properties of ACC pyramidal neurons. Our findings uncover a possible mechanistic basis for altered ACC functionality in Prader-Willi syndrome.

Animals↗

PubMed2006

Opposing role of synaptic and extrasynaptic NMDA receptors in regulation of the extracellular signal-regulated kinases (ERK) activity in cultured rat hippocampal neurons.

The extracellular signal-regulated kinases (ERK) signalling cascade is a key pathway that mediates the NMDA receptor (NMDAR)-dependent neuronal plasticity and survival. However, it is not clear yet how NMDARs regulate ERK activity. Stimulation of the NMDARs induces a complex modification of ERK that includes both ERK activation and inactivation and depends on particular experimental conditions. Here we show that there exists a differential restriction in the regulation of ERK activity that depends on the pool of NMDAR that was activated. The synaptic pool of NMDARs activates ERK whereas the extrasynaptic pool does not; on the contrary, it triggers a signalling pathway that results in the inactivation of ERK. As a result, simultaneous activation of both extrasynaptic and synaptic NMDAR using bath application of NMDA or glutamate (a typical protocol explored in the majority of studies) produced ERK activation that depended on the concentration of agonists and was always significantly weaker than those mediated by synaptic NMDARs. Since the activation of the extrasynaptic NMDA is attributed mainly to global release of glutamate occurring at pathological conditions including hypoxic/ischaemic insults, traumas and epileptic brain damage, the reported differential regulation of ERK cascade by NMDARs provides a unique mechanism for an early identification of the physiological and/or pathophysiological consequences of NMDAR activation. The negative regulation of the ERK activity might be one of the first signalling events determining brain injury and constitutes a putative target of new pharmacological applications.

Action Potentials↗

PubMed2003

Direct and indirect transcriptional targets of DAF-16.

Several genes involved in the determination of life span have been identified by mutation in the free-living soil nematode Caenorhabditis elegans. One of the key pathways studied in the context of life span is the DAF-2 pathway. The daf-2 gene is homologous to the insulin and insulin-like growth factor 1 receptor families. A downstream gene, daf-16, encodes a protein that is homologous to the forkhead transcription factor. A study by McElwee, Bubb, and Thomas, published in the current issue of Aging Cell, used genome-scale gene expression analysis to search for genes that are differentially expressed between long-lived daf-2(e1370) and short-lived daf-16(m27);daf-2(e1370) animals. In doing so, they identified candidate direct and indirect targets of DAF-16. In this Perspective, I discuss the results of this study.

Aging↗

PubMed1995

A meta cleavage pathway for 4-chlorobenzoate, an intermediate in the metabolism of 4-chlorobiphenyl by Pseudomonas cepacia P166.

Bacterial degradation of biphenyl and polychlorinated biphenyls proceeds by a well-studied pathway which produces benzoate and 2-hydroxypent-2,4-dienoate (or, in the case of polychlorinated biphenyls, the chlorinated derivatives of these compounds). Pseudomonas cepacia P166 utilizes 4-chlorobiphenyl for growth and produces 4-chlorobenzoate as a central intermediate. In this study we found that strain P166 further transforms 4-chlorobenzoate to 4-chlorocatechol, which is mineralized by a meta cleavage pathway. Key metabolites which we identified include the meta cleavage product (5-chloro-2-hydroxymuconic semialdehyde), 5-chloro-2-hydroxymuconate, 5-chloro-2-oxopent-4-enoate, 5-chloro-4-hydroxy-2-oxopentanoate, and chloroacetate. Chloroacetate accumulated transiently, and slow but stoichiometric dehalogenation was observed.

Biodegradation, Environmental↗

PubMed2005

Substrate specificity of human ABCC4 (MRP4)-mediated cotransport of bile acids and reduced glutathione.

The multidrug resistance protein ABCC4 (MRP4), a member of the ATP-binding cassette superfamily, mediates ATP-dependent unidirectional efflux of organic anions out of cells. Previous studies showed that human ABCC4 is localized to the sinusoidal membrane of hepatocytes and mediates, among other substrates, the cotransport of reduced glutathione (GSH) with bile acids. In the present study, using inside-out membrane vesicles, we demonstrated that human ABCC4 in the presence of physiological concentrations of GSH has a high affinity for the taurine and glycine conjugates of the common natural bile acids as well as the unconjugated bile acid cholate. Chenodeoxycholyltaurine and chenodeoxycholylglycine were the GSH cosubstrates with the highest affinities for ABCC4, with K(m) values of 3.6 and 5.9 microM, respectively. Ursodeoxycholyltaurine and ursodeoxycholylglycine were cotransported together with GSH by ABCC4 with K(m) values of 7.8 and 12.5 microM, respectively, but no transport of ursodeoxycholate and deoxycholate was observed. The simultaneous transport of labeled GSH and cholyltaurine or cholylglycine was demonstrated in double-labeled cotransport experiments with a bile acid-to-GSH ratio of approximately 1:22. K(m) values of the bile acids for ABCC4 were in a range similar to those reported for the canalicular bile salt export pump ABCB11. Under physiological conditions, the sinusoidal ABCC4 may compete with canalicular ABCB11 for bile acids and thereby play a key role in determining the hepatocyte concentration of bile acids. In cholestatic conditions, ABCC4 may become a key pathway for efflux of bile acids from hepatocytes into blood.

Animals↗

PubMed1997

Cyclin D1 antisense RNA destabilizes pRb and retards lung cancer cell growth.

To investigate the role of cyclin D1 in the regulation of lung cancer cell growth, we created five stably transfected cell lines carrying a cyclin D1 antisense construct. The transfected cells exhibited a marked decrease in the rate of cell growth, in contrast to the original lines (A549 and NCI-H441). The expression of several cell cycle-regulating proteins, including cyclin A, the cyclin-dependent kinases (cdk) 2 and cdk4, in addition to cyclin D1 itself, was markedly decreased. The expression of one cdk inhibitor, p21WAF1/CIP1, increased in the A549-derived cell lines. A specific target of cyclin D1 activity, the growth-suppressing product of the retinoblastoma gene, pRb, exhibited decreased expression and a decreased level of phosphorylation in the transfected cells. Decreased expression of pRb due to a significant increase in its turnover rate suggested that the stability of the protein may depend on phosphorylation by cyclin D1-dependent cdk activity. In addition to the impact on pRb stability, decreased expression of cyclin D1 induced susceptibility to cell death after withdrawal of exogenous growth factors in the antisense transfected cell lines, a response that was not observed in the original cancer cell lines. We conclude that abrogation of cyclin D1 overexpression in lung cancer cells disrupts several key pathways that are required for uncontrolled cell growth and induces those that lead to cell death after growth factor deprivation. Therefore, we speculate that use of antisense cyclin D1 expression in appropriate gene vectors could be a useful method for retarding lung cancer cell growth in accessible tumors such as those of the lung epithelium.

CDC2-CDC28 Kinases↗

PubMed1999

Potassium secretion and the regulation of distal nephron K channels.

K-selective channels in the luminal membranes of distal nephron segments form a key pathway for the secretion of K ions into the urine. This process is important to the control of K balance, particularly under conditions of normal or high K intake. This brief review will cover three issues: 1) the identification of apical K channels, 2) the role of these channels in the maintenance of K homeostasis, and 3) the role of aldosterone in this regulatory process. The large amount of literature on renal K transport has been elegantly summarized in a recent review in this journal [G. Giebisch. Am. J. Physiol. 274 (Renal Physiol. 43): F817-F833, 1998]. Here I will focus on a few prominent unsolved problems.

Aldosterone↗

PubMed2004

Mammalian target of rapamycin inhibition.

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that has been increasingly recognized as key to the regulation of cell growth and proliferation. mTOR either directly or indirectly regulates translation initiation, actin organization, tRNA synthesis, ribosome biogenesis, and many other key cell maintenance functions, including protein degradation and transcription functions. Inhibition of mTOR blocks traverse of the cell cycle from the G1 to S phase. Preclinical data show inhibition of tumor growth in a number of cell lines and xenograft models. Clinical trials are ongoing. In metastatic renal cell cancer, both tumor regression and prolonged stabilization have been noted. mTOR inhibition appears to be a key pathway that may be useful in antitumor therapy. Renal cell cancer may be particularly susceptible through both the translation inhibition pathway and pathways that enhance HIF-1alpha gene expression, a factor believed to stimulate growth in metastatic renal cell cancer. Additional clinical trials that use agents that inhibit mTOR are ongoing.

Carcinoma, Renal Cell↗

PubMed2005

Docetaxel induces cell death through mitotic catastrophe in human breast cancer cells.

Apoptosis has long been considered to be the prevailing mechanism of cell death in response to chemotherapy. Currently, a more heterogeneous model of tumor response to therapy is acknowledged wherein multiple modes of death combine to generate the overall tumor response. The resulting mechanisms of cell death are likely determined by the mechanism of action of the drug, the dosing regimen used, and the genetic background of the cells within the tumor. This study describes a nonapoptotic response to docetaxel therapy in human breast cancer cells of increasing cancer progression (MCF-10A, MCF-7, and MDA-mb-231). Docetaxel is a microtubule-stabilizing taxane that is being used in the clinic for the treatment of breast and prostate cancers and small cell carcinoma of the lung. The genetic backgrounds of these cells were characterized for the status of key pathways and gene products involved in drug response and cell death. Cellular responses to docetaxel were assessed by characterizing cell viability, cell cycle checkpoint arrest, and mechanisms of cell death. Mechanisms of cell death were determined by Annexin V binding and scoring of cytology-stained cells by morphology and transmission electron microscopy. The primary mechanism of death was determined to be mitotic catastrophe by scoring of micronucleated cells and cells undergoing aberrant mitosis. Other, nonapoptotic modes of death were also determined. No significant changes in levels of apoptosis were observed in response to docetaxel.

Antineoplastic Agents, Phytogenic↗

PubMed1997

Role of Ca2+ in metabolic inhibition-induced norepinephrine release in rat brain synaptosomes.

Ischemia and simulated ischemic conditions induce enhanced release of norepinephrine (NE) in the brain and the heart. Although studies with neuronal preparations demonstrated a rise in [Ca2+]i under energy-depleted conditions, such release of NE in the heart appears to be predominantly Ca2+ independent. Since Ca2+ overload occurs in ischemia or energy depletion and since a rise in [Ca2+]i triggers exocytosis without membrane depolarization, we tested the possibility, using brain synaptosomes, that increased NE release could be, at least in part, a consequence of raised [Ca2+]i. Brain synaptosomes were incubated with Krebs-Henseleit medium, and ischemia was mimicked by treatment with metabolic inhibitors. NE content in incubation medium (supernatant) and synaptosomes was analyzed chromatographically. Treatment with metabolic inhibitors reduced ATP content by 75% and increased [Ca2+]i by more than fourfold within minutes. Metabolic inhibition elicited NE release, which started within 10 minutes and reached a maximum after 30 minutes, with a corresponding 55% reduction in synaptosomal NE content after 40 minutes. NE release, together with a marked increase in [Ca2+]i, was also induced in energy-depleted synaptosomes by Ca2+ repletion after incubation with the Ca(2+)-free medium. Effects on NE release of various interventions to prevent Ca2+ overload were tested. Omission of Ca2+ from the incubation medium or loading synaptosomes with the Ca2+ chelator BAPTA-AM (20 and 100 mumol/L) prevented NE release, indicating a Ca(2+)-dependent mechanism. Inhibition of Ca2+ channels with omega-conotoxin, cadmium, or nifedipine had no effect on NE release during energy depletion. In contrast, nickel and 3,4-dichlorobenzamil, Na(+)-Ca2+ exchange inhibitors, dose-dependently inhibited NE release. In conclusion, this study provides evidence that under energy-depleted conditions, Ca2+ overload in synaptosomes of noradrenergic neurons from the brain is an important mechanism for the enhanced release of NE and that a reversal of Na(+)-Ca2+ exchange may be the key pathway leading to intraneuronal Ca2+ overload.

Animals↗

PubMed2004

Immunoglobulins from patients with Graves' disease induce hyaluronan synthesis in their orbital fibroblasts through the self-antigen, insulin-like growth factor-I receptor.

A distinctive histopathological feature associated with thyroid-associated ophthalmopathy is the disordered accumulation of the glycosaminoglycan, hyaluronan, in orbital connective tissues. This often occurs in the context of dramatic inflammation and tissue remodeling. Orbital fibroblasts exhibit a novel phenotype including exaggerated responses to cytokines. Here, we report for the first time the ability of IgG isolated from the sera of patients with Graves' disease (GD-IgG) to provoke in orbital fibroblasts the synthesis of hyaluronan. The effect of GD-IgG can be reproduced by IGF-I, appears to be mediated through the IGF-I receptor, and is abolished with glucocorticoid treatment. TSH failed to influence the synthesis of hyaluronan. In contrast to the effects in GD fibroblasts, cultures derived from donors without known thyroid disease fail to respond to GD-IgG or IGF-I. The observation that hyaluronan production is induced by GD-IgG in fibroblasts suggests that the IGF-I receptor and its activating antibodies may represent a key pathway through which important pathogenic events in thyroid-associated ophthalmopathy are mediated.

Autoantigens↗