EVOLUTION: Of Mice . . .

Cyclic nucleotide phosphodiesterases (PDEs) are enzymes that regulate the cellular levels of the second messengers, cAMP and cGMP, by controlling their rates of degradation. There are 11 different PDE families, with each family typically having several different isoforms and splice variants. These unique PDEs differ in their three-dimensional structure, kinetic properties, modes of regulation, intracellular localization, cellular expression, and inhibitor sensitivities. Current data suggest that individual isozymes modulate distinct regulatory pathways in the cell. These properties therefore offer the opportunity for selectively targeting specific PDEs for treatment of specific disease states. The feasibility of these enzymes as drug targets is exemplified by the commercial and clinical successes of the erectile dysfunction drugs, sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra). PDE inhibitors are also currently available or in development for treatment of a variety of other pathological conditions. In this review the basic biochemical properties, cellular regulation, expression patterns, and physiological functions of the different PDE isoforms will be discussed. How these properties relate to the current and future development of PDE inhibitors as pharmacological agents is especially considered. PDEs hold great promise as drug targets and recent research advances make this an exciting time for the field of PDE research.

Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use

PAS domains are newly recognized signaling domains that are widely distributed in proteins from members of the Archaea and Bacteria and from fungi, plants, insects, and vertebrates. They function as input modules in proteins that sense oxygen, redox potential, light, and some other stimuli. Specificity in sensing arises, in part, from different cofactors that may be associated with the PAS fold. Transduction of redox signals may be a common mechanistic theme in many different PAS domains. PAS proteins are always located intracellularly but may monitor the external as well as the internal environment. One way in which prokaryotic PAS proteins sense the environment is by detecting changes in the electron transport system. This serves as an early warning system for any reduction in cellular energy levels. Human PAS proteins include hypoxia-inducible factors and voltage-sensitive ion channels; other PAS proteins are integral components of circadian clocks. Although PAS domains were only recently identified, the signaling functions with which they are associated have long been recognized as fundamental properties of living cells.

PAS Domains: Internal Sensors of Oxygen, Redox Potential, and Light

AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus

The Metabolic Consequences of Sleep Deprivation

A polypeptide that contains an amino acid sequence present in human leptin blocks the inhibitory effect of human C-Reactive Protein on human leptin. Accordingly, such a polypeptide is implicated in an approach to treating or preventing conditions associated with the impact of CRP on leptin.

Human leptin-derived polypeptides and uses thereof

Adiponectin is an adipocyte-secreted cytokine that enhances insulin sensitivity and attenuates inflammation. Although circulating adiponectin level is often inversely associated with several malignancies, its role in the development of nasopharyngeal carcinoma (NPC) remains unclear. Here, we investigated the clinical association between circulating adiponectin level and NPC, and examined the impact of adiponectin, as well as the underlying mechanisms, on NPC growth both in vitro and in vivo.The association between circulating adiponectin level and the risk of developing NPC was assessed in two different cohorts, including a hospital-based case-control study with 152 cases and 132 controls, and a nested case-control study with 71 cases and 142 controls within a community-based NPC screening cohort. Tumor xenograft model, cell proliferation and cycle assays were applied to confirm the effects of adiponectin on NPC growth in cultured cells and in xenograft models. We also investigated the underlying signaling mechanisms with various specific pharmacological inhibitors and biochemistry analysis.High adiponectin levels were associated with a monotonic decreased trend of NPC risk among males in both the hospital-based case-control study and a nested case-control study. In vitro, recombinant human full-length adiponectin significantly inhibited NPC cell growth and arrested cell cycle, which were dependent on AMPK signaling pathway. The growth of xenograft of NPC tumor was sharply accelerated in the nude mice carrying genetic adiponectin deficiency. An adiponectin receptor agonist, AdipoRon, displayed strong anti-tumor activity in human xenograft models.These findings demonstrated for the first time that circulating adiponectin is not only inversely associated with NPC, but also controls the development of NPC via AMPK signaling pathway. Stimulation of adiponectin function may become a novel therapeutic modality for NPC. 

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Adiponectin suppresses tumor growth of nasopharyngeal carcinoma through activating AMPK signaling pathway

Obesity is one of the major risk factors for cancer. Clinical studies have demonstrated that circulating levels of adiponectin are inversely correlated, not only with the extent of adiposity, but also with the incidence of several types of cancer, particularly endometrial cancer (EC). However, thus far, adiponectin remains a correlative factor, without definitive evidence to show a causal effect in EC and the potential mechanism(s) involved. To address this issue, we introduced an Apn‐null mutation into Pten haploid‐deficient (Pten+/−) mice. The Pten heterozygous mutation alone led to the development of EC in less than 30% of female mice; however, when combined with the Apn‐null mutation, the incidence of endometrial lesions rose to at least two‐thirds. Although Apn deficiency did not further potentiate the Akt activation caused by the Pten mutation, it elevated the phosphorylation of mitogen‐activated protein kinase (MAPK) p42/44, indicating activation of the MAPK signaling pathway. Treatment of Apn−/−;Pten+/− mice with a MEK inhibitor blocked the development of EC. Finally, xenografts of a PTEN‐proficient human EC cell line grew faster in Apn‐deficient mice, whereas an adiponectin receptor agonist reduced xenograft growth of a PTEN‐deficient human EC cell line. Thus, reduction of adiponectin activity promotes EC development, at least in the context of Pten mutation, by activating MAPK. © 2022 The Pathological Society of Great Britain and Ireland.

Adiponectin deficiency promotes endometrial carcinoma pathogenesis and development via activation of mitogen‐activated protein kinase

Is leptin an important physiological regulator of CRP

New findings What is the central question of this study? What is the protective benefit of n-3 polyunsaturated fatty acids (PUFAs) on liver fibrosis and what are the relevant signalling pathways in a transgenic mouse model overexpressing the mfat-1 enzyme? What is the main finding and its importance? n-3 PUFA elevation strongly prevented carbon tetrachloride (CCl4 )-induced hepatic damage and inhibited the activation of hepatic stellate cells. n-3 PUFAs suppressed CCl4 -induced activation of mTOR, elevated Bcl-2 expression, and reduced Bax level, suggesting that n-3 PUFAs can render strong protective effects against liver fibrosis and point to the potential of mfat-1 gene therapy as a treatment modality. Abstract Liver fibrosis is a reversible wound healing response with excessive accumulation of extracellular matrix proteins. It is a globally prevalent disease with ultimately severe pathological consequences. However, very few current clinical therapeutic options are available. Nutritional addition of n-3 polyunsaturated fatty acids (PUFAs) can delay and lessen the development of liver fibrosis. Herein, this study examined the protective benefit of n-3 PUFAs on liver fibrosis and the relevant signalling pathways using a transgenic mouse model overexpressing the mfat-1 enzyme that converts n-6 to n-3 PUFAs. Male C57BL/6 wild-type and mfat-1 transgenic mice were administered carbon tetrachloride (CCl4 ) or control corn oil by intraperitoneal injection. Blood alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were subsequently measured. CCl4 -induced hepatic damage and fibrosis were assessed using haematoxylin-eosin and Masson's trichrome staining. Western blot assays were used to detect and quantify fibrosis-related proteins and mechanistic target of rapamycin (mTOR) and B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax) signalling components. The direct effect of docosahexaenoic acid (DHA) on primary hepatic stellate cells (HSCs) was also investigated in a co-culture experiment. n-3 PUFAs, as a result of mfat-1 activity, had a strong protective effect on liver fibrosis. The elevation of ALT and AST induced by CCl4 was significantly lessened in the mfat-1 mice. Histological determination revealed the protective effects of n-3 PUFAs on liver inflammation and collagen deposition. Co-incubation with DHA reduced the expression of profibrogenic factors in the primary HSCs. Moreover, mfat-1 transgenic mice showed significant reduction of proteins that are involved in mTOR and Bcl-2/Bax signalling pathways. Collectively, these results suggest that n-3 PUFA elevation strongly prevents CCl4 -induced hepatic damage by directly inhibiting the activation of HSCs and regulating the basal activity of the mTOR and Bcl-2/Bax signalling pathways. Gene therapy applying mfat-1 and elevating n-3 PUFAs represents a promising treatment strategy to prevent liver fibrosis.

Endogenous production of n-3 polyunsaturated fatty acids protects mice from carbon tetrachloride-induced liver fibrosis by regulating mTOR and Bcl-2/Bax signalling pathways.

Allan Z. Zhao

Papers

Human leptin-derived polypeptides and uses thereof

Adiponectin suppresses tumor growth of nasopharyngeal carcinoma through activating AMPK signaling pathway

Adiponectin deficiency promotes endometrial carcinoma pathogenesis and development via activation of mitogen‐activated protein kinase

Is leptin an important physiological regulator of CRP

Endogenous production of n-3 polyunsaturated fatty acids protects mice from carbon tetrachloride-induced liver fibrosis by regulating mTOR and Bcl-2/Bax signalling pathways.