Copper is an essential trace metal element that significantly affects human physiology and pathology by regulating various important biological processes, including mitochondrial oxidative ...phosphorylation, iron mobilization, connective tissue crosslinking, antioxidant defense, melanin synthesis, blood clotting, and neuron peptide maturation. Increasing lines of evidence obtained from studies of cell culture, animals, and human genetics have demonstrated that dysregulation of copper metabolism causes heart disease, which is the leading cause of mortality in the US. Defects of copper homeostasis caused by perturbed regulation of copper chaperones or copper transporters or by copper deficiency resulted in various types of heart disease, including cardiac hypertrophy, heart failure, ischemic heart disease, and diabetes mellitus cardiomyopathy. This review aims to provide a timely summary of the effects of defective copper homeostasis on heart disease and discuss potential underlying molecular mechanisms.
Hypothalamic neuropeptide orexin has been implicated in the pathophysiology of psychiatric disorders and accumulating clinical evidence indicates a potential link between orexin and depression. ...However, the exact role of orexin in depression, particularly the underlying neural substrates and mechanisms, remains unknown. In this study, we reveal a direct projection from the hypothalamic orexinergic neurons to the ventral pallidum (VP), a structure that receives an increasing attention for its critical position in rewarding processing, stress responses, and depression. We find that orexin directly excites GABAergic VP neurons and prevents depressive-like behaviors in rats. Two orexin receptors, OX1R and OX2R, and their downstream Na
-Ca
exchanger and L-type Ca
channel co-mediate the effect of orexin. Furthermore, pharmacological blockade or genetic knockdown of orexin receptors in VP increases depressive-like behaviors in forced swim test and sucrose preference test. Intriguingly, blockage of orexinergic inputs in VP has no impact on social proximity in social interaction test between novel partners, but remarkably strengthens social avoidance under an acute psychosocial stress triggered by social rank. Notably, a significantly increased orexin level in VP is accompanied by an increase in serum corticosterone in animals exposed to acute stresses, including forced swimming, food/water deprivation and social rank stress, rather than non-stress situations. These results suggest that endogenous orexinergic modulation on VP is especially critical for protecting against depressive reactions to stressful events. The findings define an indispensable role for the central orexinergic system in preventing depression by promoting stress resilience.
•Intake of resveratrol effectively reduces the risk of diabetes and its related nephropathy.•Resveratrol affords nephroprotective effects in diabetes through regulation of numerous signaling ...pathways.•Resveratrol may be associated with unfavorable pharmacokinetic, conflicting results, and certain side effects.•Long-term follow-up experiments of resveratrol should be considered in clinical settings.
As one of the most common complications of diabetes, nephropathy develops in approximately 40% of diabetic individuals. Although end stage kidney disease is known as one of the most consequences of diabetic nephropathy, the majority of diabetic individuals might die from cardiovascular diseases and infections before renal replacement treatment. Moreover, the routine medical treatments for diabetes hold undesirable side effects. The explosive prevalence of diabetes urges clinicians and scientists to investigate the complementary or alternative therapies. Phytochemicals are emerging as alternatives with a wide range of therapeutic effects on various pathologies, including diabetic kidney disease. Of those phytochemicals, resveratrol, a natural polyphenolic stilbene, has been found to exert a broad spectrum of health benefits via various signaling molecules. In particular, resveratrol has gained a great deal of attention because of its anti-oxidative, anti-inflammatory, anti-diabetic, anti-obesity, cardiovascular-protective, and anti-tumor properties. In the renal system, emerging evidence shows that resveratrol has already been used to ameliorate chronic or acute kidney injury. This review critically summarizes the current findings and molecular mechanisms of resveratrol in diabetic renal damage. In addition, we will discuss the adverse and inconsistent effects of resveratrol in diabetic nephropathy. Although there is increasing evidence that resveratrol affords great potential in diabetic nephropathy therapy, these results should be treated with caution before its clinical translation. In addition, the unfavorable pharmacokinetics and/or pharmacodynamics profiles, such as poor bioavailability, may limit its extensive clinical applications. It is clear that further research is needed to unravel these limitations and improve its efficacy against diabetic nephropathy. Increasing investigation of resveratrol in diabetic kidney disease will not only help us better understand its pharmacological actions, but also provide novel potential targets for therapeutic intervention.
Aim
Endogenous dynorphin signaling via kappa opioid receptors (KORs) plays a key role in producing the depressive and aversive consequences of stress. We investigated the behavioral effects of the ...dynorphin/KOR system in the ventral pallidum (VP) and studied the underlying mechanisms.
Methods
To investigate the effects of dynorphin on the VP, we conducted behavioral experiments after microinjection of drugs or shRNA and brain‐slice electrophysiological recordings. Histological tracing and molecular biological experiments were used to identify the distribution of KORs and the possible sources of dynorphin projections to the VP.
Results
An elevated dynorphin concentration and increased KOR activity were observed in the VP after acute stress. Infusion of dynorphin‐A into the VP produced depressive‐like phenotypes including anhedonia and despair and anxiety behaviors, but did not alter locomotor behavior. Mechanistically, dynorphin had an inhibitory effect on VP neurons—reducing their firing rate and inhibiting excitatory transmission—through direct activation of KORs and modulation of downstream G‐protein‐gated inwardly rectifying potassium (GIRK) channels and high‐voltage gated calcium channels (VGCCs). Tracing revealed direct innervation of VP neurons by dynorphin‐positive projections; potential sources of these dynorphinergic projections include the nucleus accumbens, amygdala, and hypothalamus. Blockade of dynorphin/KOR signaling in the VP by drugs or viral knock‐down of KORs significantly reduced despair behavior in rats.
Conclusions
Endogenous dynorphinergic modulation of the VP plays a critical role in mediating depressive reactions to stress.
Crown ethers demonstrate significant conformational flexibility and rotational symmetry, rendering them invaluable in the realms of supramolecular chemistry and crystal engineering. These unique ...natures facilitate the construction of supramolecular crystals of crown ethers, characterized by disorder‐order phase transitions, imparts unique properties that hold promise for diverse applications across multiple fields. In this study, four supramolecular compounds, namely Na(15‐crown‐5)BF4 (1), Na(18‐crown‐6)BF4⋅H2O (2), K(15‐crown‐5)BF4 (3) and K(18‐crown‐6)BF4⋅H2O (4) were synthesized and characterized by microanalysis, thermogravimetric analysis, differential scanning calorimetry and powder X‐ray diffraction techniques. Herein, 15‐crown‐5 and 18‐crown‐6 correspond to 1,4,7,10,13‐pentaoxacyclopentadecane and 1,4,7,10,13,16‐hexaoxacyclooctadecane, respectively. It was observed that the crystal structure, phase transition, and dielectric properties of these supramolecular compounds are significantly influenced by the size of the crown‐ether rings. The research extensively discussed the correlation between the coordination mode of metal ions of K+ or Na+ with crown ethers, the compatibility between metal ions and crown‐ether rings in terms of size, and the effects of crown‐ether disorder on dielectric permittivity during phase transitions. Our discoveries hold significant implications for the design and development of crown‐ether supramolecular functional materials.
The supramolecular crystals show crown‐ether ring size dependent crystal structure, phase transition and dielectric properties.
Formation subsidence is inevitable during marine hydrate decomposition, and the consequent casing deformation seriously threatens the security of sustainable hydrate production. Owing to insufficient ...observed data of formation subsidence in field, displacement boundary condition of casing is undetermined. Thus the conventional static methods are inapplicable for the calculation of casing deformation in hydrate production well. The present work aims at proposing an approach to investigate dynamic deformation of the casing during hydrate production. In the proposed methodology, based on the movement theory of hydrate decomposition front, hydrate decomposition process can be simulated, in which hydrate reservoir strength formation subsidence showed time-dependent characteristics. By considering the actual interactions among casing, cement and formation, three models of hydrate production well are developed to reveal the static and dynamic deformation mechanisms of the casing. The application of the proposed methodology is demonstrated through a case study. Results show that buckling deformation and bending deformation of casing reduce the passing ability of downhole tools in deformed casing by 4.2% and 7.5%, respectively. With the progress of hydrate production, buckling deformation will increase obviously, while a little increase of bending deformation will occur, as the formation slippage induced by formation inclination is much larger than that caused by hydrate decomposition. The proposed approach can provide theoretical reference for improving casing integrity of marine hydrate production.
The synthesis of medium-sized lactams is a great challenge because of the unfavorable transannular interactions and entropic barriers in the transition state. We have developed a ruthenium-catalyzed ...carbonylation of α-aminoaryl-tethered alkylidenecyclopropanes (ACPs) that allows for the efficient preparation of valuable eight-membered benzolactams under ligand-free conditions. The amino group served a dual role of both directing group and nucleophile to facilitate the metallacycle formation and the carbonylation.
Clostridium difficile toxin B (TcdB) is a critical virulence factor that causes diseases associated with C. difficile infection. Here we carried out CRISPR-Cas9-mediated genome-wide screens and ...identified the members of the Wnt receptor frizzled family (FZDs) as TcdB receptors. TcdB binds to the conserved Wnt-binding site known as the cysteine-rich domain (CRD), with the highest affinity towards FZD1, 2 and 7. TcdB competes with Wnt for binding to FZDs, and its binding blocks Wnt signalling. FZD1/2/7 triple-knockout cells are highly resistant to TcdB, and recombinant FZD2-CRD prevented TcdB binding to the colonic epithelium. Colonic organoids cultured from FZD7-knockout mice, combined with knockdown of FZD1 and 2, showed increased resistance to TcdB. The colonic epithelium in FZD7-knockout mice was less susceptible to TcdB-induced tissue damage in vivo. These findings establish FZDs as physiologically relevant receptors for TcdB in the colonic epithelium.
Rosettes are widely used in epithelial morphogenesis during embryonic development and organogenesis. However, their role in postnatal development and adult tissue maintenance remains largely unknown. ...Here, we show zona glomerulosa cells in the adult adrenal cortex organize into rosettes through adherens junction-mediated constriction, and that rosette formation underlies the maturation of adrenal glomerular structure postnatally. Using genetic mouse models, we show loss of β-catenin results in disrupted adherens junctions, reduced rosette number, and dysmorphic glomeruli, whereas β-catenin stabilization leads to increased adherens junction abundance, more rosettes, and glomerular expansion. Furthermore, we uncover numerous known regulators of epithelial morphogenesis enriched in β-catenin-stabilized adrenals. Among these genes, we show Fgfr2 is required for adrenal rosette formation by regulating adherens junction abundance and aggregation. Together, our data provide an example of rosette-mediated postnatal tissue morphogenesis and a framework for studying the role of rosettes in adult zona glomerulosa tissue maintenance and function.
Abstract
Background
Pancreatic cancer is one of the most lethal human cancers.
N
6
-methyladenosine (m
6
A), a common eukaryotic mRNA modification, plays critical roles in both physiological and ...pathological processes. However, its role in pancreatic cancer remains elusive.
Methods
LC/MS was used to profile m
6
A levels in pancreatic cancer and normal tissues. Bioinformatics analysis, real-time PCR, immunohistochemistry, and western blotting were used to identify the role of m
6
A regulators in pancreatic cancer. The biological effects of methyltransferase-like 14 (METTL14), an mRNA methylase, were investigated using in vitro and in vivo models. MeRIP-Seq and RNA-Seq were used to assess the downstream targets of METTL14.
Results
We found that the m
6
A levels were elevated in approximately 70% of the pancreatic cancer samples. Furthermore, we demonstrated that METTL14 is the major enzyme that modulates m
6
A methylation (frequency and site of methylation). METTL14 overexpression markedly promoted pancreatic cancer cell proliferation and migration both in vitro and in vivo
,
via direct targeting of the downstream
PERP
mRNA (p53 effector related to PMP-22) in an m
6
A-dependent manner. Methylation of the target adenosine lead to increased
PERP
mRNA turnover, thus decreasing PERP (mRNA and protein) levels in pancreatic cancer cells.
Conclusions
Our data suggest that the upregulation of METTL14 leads to the decrease of PERP levels via m
6
A modification, promoting the growth and metastasis of pancreatic cancer; therefore METTL14 is a potential therapeutic target for its treatment.
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