TGF-β isoforms inhibit hepatitis C virus propagation in transforming growth factor beta/SMAD protein signalling pathway dependent and independent manners

Transforming growth factor beta (TGF-β) plays an important role in the viral liver disease progression via controlling viral propagation and mediating inflammation-associated responses. However, the antiviral activities and mechanisms of TGF-β isoforms, including TGF-β1, TGF-β2 and TGF-β3, remain unclear. Here, we demonstrated that all of the three TGF-β isoforms were increased in Huh7.5 cells infected by hepatitis C virus (HCV), but in turn, the elevated TGF-β isoforms could inhibit HCV propagation with different potency in infectious HCV cell culture system. TGF-β isoforms suppressed HCV propagation through interrupting several different stages in the whole HCV life cycle, including virus entry and intracellular replication, in TGF-β/SMAD signalling pathway–dependent and TGF-β/SMAD signalling pathway–independent manners. TGF-β isoforms showed additional anti-HCV activities when combined with each other. However, the elevated TGF-β1 and TGF-β2, not TGF-β3, could also induce liver fibrosis with a high expression of type I collagen alpha-1 and α-smooth muscle actin in LX-2 cells. Our results showed a new insight into TGF-β isoforms in the HCV-related liver disease progression.     

Molecular regulation of autophagy in a pro-inflammatory tumour microenvironment: New insight into the role of serum amyloid A

Chronic inflammation, systemic or local, plays a vital role in tumour progression and metastasis. Dysregulation of key physiological processes such as autophagy elicit unfavourable immune responses to induce chronic inflammation. Cytokines, growth factors and acute phase proteins present in the tumour microenvironment regulate inflammatory responses and alter crosstalk between various signalling pathways involved in the progression of cancer. Serum amyloid A (SAA) is a key acute phase protein secreted by the liver during the acute phase response (APR) following infection or injury. However, cancer and cancer-associated cells produce SAA, which when present in high levels in the tumour microenvironment contributes to cancer initiation, progression and metastasis. SAA can activate several signalling pathways such as the PI3K and MAPK pathways, which are also known modulators of the intracellular degradation process, autophagy. Autophagy can be regarded as having a double edged sword effect in cancer. Its dysregulation can induce malignant transformation through metabolic stress which manifests as oxidative stress, endoplasmic reticulum (ER) stress and DNA damage. On the other hand, autophagy can promote cancer survival during metabolic stress, hypoxia and senescence. Autophagy has been utilised to promote the efficiency of chemotherapeutic agents and can either be inhibited or induced to improve treatment outcomes. This review aims to address the known mechanisms that regulate autophagy as well as illustrating the role of SAA in modulating these pathways and its clinical implications for cancer therapy.     

Resveratrol effects in bladder cancer: A mini review

Bladder cancer has a high incidence worldwide and is the most common genitourinary cancer. The treatment of bladder cancer involves surgery and chemotherapy; however high failure rates and toxicity are observed. In this context, the search of new drugs aiming a more effective treatment is extremely necessary. Natural products are an important source of compounds with antiproliferative effects. Resveratrol is a naturally occurring plant polyphenol whose anticancer activity has been demonstrated in different types of cancer. This review summarizes the in vitro and in vivo studies using models of bladder cancer treated with resveratrol and discusses its different mechanisms of action.     

Unconventional signalling in tunicates

The zooids in colonial tunicates do not appear to be directly interconnected by nerves, but this has not prevented the evolution of coordinated behaviour in several groups. In Botryllus and other colonial styelid asci‐dians the endothelium lining the blood vessels is excitable and transmits action potentials from cell to cell via gap junctions. These signals mediate protective contractions of the zooids and synchronize contractions of the vascular ampullae. In didemnid ascidians such as Diplosoma a network of myocytes in the tunic serves to transmit excitation and to cause contractions of the cloacal apertures. Individual zooids of Pyrosoma protect themselves by closing their siphons and arresting their branchial cilia when stimulated. At the same time a flash of light is emitted. Neighbouring zooids sense the flash with their photoreceptors and respond in turn with protective responses and light emission. Protective responses thus spread by photic signalling and propagate from zooid to zooid through the colony in a saltatory manner. In chains of Salpafusifortnis, changes in the direction and/or speed of swimming are transmitted from zooid to zooid via adhesion plaques. When a zooid is stimulated, its body‐wall epithelium conducts action potentials to the plaque connecting it to the next zooid, exciting receptor neurons in that zooid. These receptors have sensory processes that bridge the gap between the two zooids. The sensory neurons so excited in the second zooid conduct impulses to the brain where they alter the motor output pattern, and at the same time generate epithelial action potentials that travel to the next zooid in line, where the same thing happens.

It is not clear why these unconventional signalling methods have evolved but the tunic may be an inhospitable environment for nerves, making conventional nervous links impossible.     

Corticosterone regulates multiple colour traits in Lacerta [Zootoca] vivipara males

Ornamental colours usually evolve as honest signals of quality, which is supported by the fact that they frequently depend on individual condition. It has generally been suggested that some, but not all types of ornamental colours are condition dependent, indicating that different evolutionary mechanisms underlie the evolution of multiple types of ornamental colours even when these are exhibited by the same species. Stress hormones, which negatively affect condition, have been shown to affect colour traits based on different pigments and structures, suggesting that they mediate condition dependence of multiple ornament types both among and within individuals. However, studies investigating effects of stress hormones on different ornament types within individuals are lacking, and thus, evidence for this hypothesis is scant. Here, we investigated whether corticosterone mediates condition dependence of multiple ornaments by manipulating corticosterone levels and body condition (via food availability) using a two‐factorial design and by assessing their effect on multiple colour traits in male common lizards. Corticosterone negatively affected ventral melanin‐ and carotenoid‐based coloration, whereas food availability did not affect coloration, despite its significant effect on body condition. The corticosterone effect on melanin‐ and carotenoid‐based coloration demonstrates the condition dependence of both ornaments. Moreover, corticosterone affected ventral coloration and had no effect on the nonsexually selected dorsal coloration, showing specific effects of corticosterone on ornamental ventral colours. This suggests that corticosterone simultaneously mediates condition dependence of multiple colour traits and that it therefore accounts for covariation among them, which may influence their evolution via correlational selection.     

Redox biology of the intestine

Abstract

The intestinal tract, known for its capability for self-renew, represents the first barrier of defence between the organism and its luminal environment. The thiol/disulfide redox systems comprising the glutathione/glutathione disulfide (GSH/GSSG), cysteine/cystine (Cys/CySS) and reduced and oxidized thioredoxin (Trx/TrxSS) redox couples play important roles in preserving tissue redox homeostasis, metabolic functions, and cellular integrity. Control of the thiol-disulfide status at the luminal surface is essential for maintaining mucus fluidity and absorption of nutrients, and protection against chemical-induced oxidant injury. Within intestinal cells, these redox couples preserve an environment that supports physiological processes and orchestrates networks of enzymatic reactions against oxidative stress. In this review, we focus on the intestinal redox and antioxidant systems, their subcellular compartmentation, redox signalling and epithelial turnover, and contribution of luminal microbiota, key aspects that are relevant to understanding redox-dependent processes in gut biology with implications for degenerative digestive disorders, such as inflammation and cancer.     

Mitochondrial reactive oxygen species originating from Romo1 exert an important role in normal cell cycle progression by regulating p27Kip1 expression

Reactive oxygen species (ROS) steady-state levels are required for entry into the S phase of the cell cycle in normal cells, as well as in tumour cells. However, the contribution of mitochondrial ROS to normal cell proliferation has not been well investigated thus far. A previous report showed that Romo1 was responsible for the high ROS levels in tumour cells. Here, we show that endogenous ROS generated by Romo1 are indispensable for cell cycle transition from G1 to S phase in normal WI-38 human lung fibroblasts. The ROS level in these cells was down-regulated by Romo1 knockdown, resulting in cell cycle arrest in the G1 phase. This arrest was associated with an increase in the level of p27^Kip1. These results demonstrate that mitochondrial ROS generated by Romo1 expression is required for normal cell proliferation and it is suggested that Romo1 plays an important role in redox signalling during normal cell proliferation.     

Role of high-mobility group box-1 protein in disruption of vascular barriers and regulation of leukocyte–endothelial interactions

Abstract

High-mobility group box-1 protein (HMGB1) is a highly conserved non-histone DNA-binding protein present in the nuclei and cytoplasm of nearly all cell types. The results from recent research provide evidence that HMGB1 is secreted into the extracellular milieu and acts as a pro-inflammatory cytokine and exhibits angiogenic effects to fire the immunological response against the pathological effects. Recently, a great deal of evidence has indicated the critical importance of HMGB1 in mediating vascular barriers dysfunction by modulating the expression of adhesion molecules, such as intercellular adhesion molecule-1, vascular cell adhesion protein 1 and E-selectin on the surface of endothelial cells. Such process promotes the adhesion and migration of leukocytes across the endothelium, leading to breakdown of vascular barriers (blood–brain barrier and blood–retinal barrier) via modulating the expression, content, phosphorylation, and distribution of tight junction proteins. Therefore, here we give an abridged review to understand the mechanistic link between HMGB1 and vascular barriers dysfunction, including interaction with cell-surface receptors and intracellular signaling pathways.