counteract perturbations by urea (eg in elasmobranchs and mammalian kidney), inorganic ions, and hydrostatic pressure in deep-sea animals Trehalose and proline in overwintering insects stabilize membranes at subzero temperatures Trehalose in insects and yeast, and anionic polyols in microorganisms around hydrothermal vents, can protect proteins from denaturation by high temperatures Third, stabilizing solutes appear to be used in nature only to counteract perturbants of macromolecules, perhaps because stabilization is detrimental in the absence of perturbation Some of these solutes have applications in biotechnology, agriculture and medicine, including in vitro rescue of the misfolded protein of cystic fibrosis However, caution is warranted if high levels cause overstabilization of proteins

/pdf/organic-osmolytes-as-compatible-metabolic-and-counteracting-3nlnu54927.pdf

Organic osmolytes as compatible, metabolic and counteracting cytoprotectants in high osmolarity and other stresses

Danshen, the dried root of Salvia miltiorrhiza, has been widely used in China and, to a lesser extent, in Japan, the United States, and other European countries for the treatment of cardiovascular and cerebrovascular diseases. In China, the specific clinical use is angina pectoris, hyperlipidemia, and acute ischemic stroke. The current review covers its traditional uses, chemical constituents, pharmacological activities, pharmacokinetics, clinical applications, and potential herb-drug interactions based on information obtained in both the English and Chinese literature. Although numerous clinical trials have demonstrated that certain Danshen products in China are effective and safe for the treatment of cardiovascular diseases, most of these lack sufficient quality. Therefore, large randomized clinical trials and further scientific research to determine its mechanism of actions will be necessary to ensure the safety, effectiveness, and better understanding of its action.

Danshen: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use.

https://www.cell.com/trends/cell-biology/pdf/S0962-8924(00)01898-5.pdf

Coiled coils: a highly versatile protein folding motif.

Cells in the renal inner medulla are normally exposed to extraordinarily high levels of NaCl and urea. The osmotic stress causes numerous perturbations because of the hypertonic effect of high NaCl and the direct denaturation of cellular macromolecules by high urea. High NaCl and urea elevate reactive oxygen species, cause cytoskeletal rearrangement, inhibit DNA replication and transcription, inhibit translation, depolarize mitochondria, and damage DNA and proteins. Nevertheless, cells can accommodate by changes that include accumulation of organic osmolytes and increased expression of heat shock proteins. Failure to accommodate results in cell death by apoptosis. Although the adapted cells survive and function, many of the original perturbations persist, and even contribute to signaling the adaptive responses. This review addresses both the perturbing effects of high NaCl and urea and the adaptive responses. We speculate on the sensors of osmolality and document the multiple pathways that signal activation of the transcription factor TonEBP/OREBP, which directs many aspects of adaptation. The facts that numerous cellular functions are altered by hyperosmolality and remain so, even after adaptation, indicate that both the effects of hyperosmolality and adaptation to it involve profound alterations of the state of the cells.

https://www.physiology.org/doi/pdf/10.1152/physrev.00056.2006

Cellular Response to Hyperosmotic Stresses

https://genie.weizmann.ac.il/pubs/2015_maayan.pdf

Microbiota-Modulated Metabolites Shape the Intestinal Microenvironment by Regulating NLRP6 Inflammasome Signaling.

Taurine regulates an unusual number of biological phenomena, including heart rhythm, contractile function, blood pressure, platelet aggregation, neuronal excitability, body temperature, learning, motor behavior, food consumption, eye sight, sperm motility, cell proliferation and viability, energy metabolism and bile acid synthesis. Many of these actions are associated with alterations in either ion transport or protein phosphorylation. Although the effects on ion transport have been attributed to changes in membrane structure, they could be equally affected by a change in the activity of the affected transporters. Three common ways of altering transporter activity is enhanced expression, changes in the phosphorylation status of the protein and cytoskeletal changes. Interestingly, all three events are altered by osmotic stress. Since taurine is a key organic osmolyte in most cells, the possibility that the effects of taurine on ion transport could be related to its osmoregulatory activity was considered. This was accomplished by comparing the effects of taurine, cell swelling and cell shrinkage on the activities of key ion channels and ion transporters. The review also compares the phosphorylation cascades initiated by osmotic stress with some of the phosphorylation events triggered by taurine depletion or treatment. The data reveal that certain actions of taurine are probably caused by the activation of osmotic-linked signaling pathways. Nonetheless, some of the actions of taurine are unique and appear to be correlated with its membrane modulating and phosphorylation regulating activities.

Role of osmoregulation in the actions of taurine.

The concept that taurine exhibits cytoprotective activity was introduced in 1981. Although several studies at the time had supported the notion that taurine was capable of modulating Ca2+movement, most of those studies focused on the transporter affected by taurine. It was only after taurine was found to prevent Ca2+-induced cellular necrosis that its cytoprotective activity was recognized1. Since that date, numerous reports have documented that high levels of extracellular taurine render cells resistant to an array of damaging stimuli, including ischemia-reperfusion, hyperglycemia, reactive oxygen species, heat shock, toxic xenobiotics, cellular excitotoxicity and osmotic derangements. The ability of taurine to counteract these toxic stimuli has been attributed to four actions of taurine: (1) osmoregulation, (2) anti-oxidant/membrane stabilizing activity, (3) conjugation and (4) regulation of [Ca2+]i. Indeed, osmotic stress, oxidative stress and Ca2+overload are major causes of cellular necrosis and apoptosis. Nonetheless, cell death is a complex phenomenon, involving interactions between these and several other factors. For example, oxidative stress can damage membranes leading to changes in [Ca21. Conversely, high [Ca2+]ican cause enhanced free radical generation by the mitochondria. It is also known that osmotic stress affects the activity of ion transporters that regulate [Ca2+]i. Despite these and other interactions, it is clear that taurine affects each of the four factors individually. Thus, the aim of this review is to discuss the importance of each factor in the cytoprotective actions of taurine.

Why is taurine cytoprotective

Cardiomyocyte apoptosis contributes to cell death during myocardial infarction. One of the factors that regulate the degree of apoptosis during ischemia is the amino acid taurine. To study the mechanism underlying the beneficial effect of taurine, we examined the interaction between taurine and mitochondria-mediated apoptosis using a simulated ischemia model with cultured rat neonatal cardiomyocytes sealed in closed flasks. Exposure to medium containing 20 mM taurine reduced the degree of apoptosis following periods of ischemia varying from 24 to 72 h. In the untreated group, simulated ischemia for 24 h led to mitochondrial depolarization accompanied by cytochrome c release. The apoptotic cascade was also activated, as evidenced by the activation of caspase-9 and -3. Taurine treatment had no effect on mitochondrial membrane potential and cytochrome c release; however, it inhibited ischemia-induced cleavage of caspase-9 and -3. Taurine loading also suppressed the formation of the Apaf-1/caspase-9 apoptosome and the interaction of caspase-9 with Apaf-1. These findings demonstrate that taurine effectively prevents myocardial ischemia-induced apoptosis by inhibiting the assembly of the Apaf-1/caspase-9 apoptosome.

Taurine inhibits apoptosis by preventing formation of the Apaf-1/caspase-9 apoptosome

In hypertonic environment, taurine accumulates in cells via activation of TauT (taurine transporter) as an adaptive regulation. Recent studies revealed that TonE (tonicity-responsive element)/TonEBP (TonE-binding protein) pathway regulated the expression of various molecules which protect cells against hypertonic stress. In the present study, we investigated the osmoregulatory mechanisms of TauT expression. TauT was up-regulated at both functional and transcriptional levels in HepG2 under hypertonic condition. The TonE site was identified in the promoter region of TauT gene. Reporter gene assay revealed that promoter activity was increased under hypertonic conditions, whereas deletion or mutation of TonE sequence abolished the induction of the promoter activity in response to hypertonicity. By using the reporter gene plasmids containing a TonE site of TauT promoter (p2xTonE-Luc), it was demonstrated that a TonE site was sufficient for the hypertonicity-mediated activation of TauT promoter. Importantly, co-transfection of TauT promoter gene plasmid with wild-type TonEBP expression vector enhanced promoter activity under isotonic conditions, whereas dominant-negative TonEBP abrogated the TauT promoter activity induced by hypertonicity. Finally, treatment with taurine prevented HepG2 cells from cell death induced by hypertonic medium. These findings suggested that induction of TauT by hypertonicity is mediated by the activation of the TonE/TonEBP pathway and confers resistance to hypertonic stress.

/pdf/expression-of-taurine-transporter-is-regulated-through-the-2uqmgmzyre.pdf

Expression of taurine transporter is regulated through the TonE (tonicity-responsive element)/TonEBP (TonE-binding protein) pathway and contributes to cytoprotection in HepG2 cells.

Sodium tanshinone IIA sulfonate derived from Danshen (Salvia miltiorrhiza) attenuates hypertrophy induced by angiotensin II in cultured neonatal rat cardiac cells.

Kyoko Takahashi

Papers

Role of osmoregulation in the actions of taurine.

Why is taurine cytoprotective

Taurine inhibits apoptosis by preventing formation of the Apaf-1/caspase-9 apoptosome

Expression of taurine transporter is regulated through the TonE (tonicity-responsive element)/TonEBP (TonE-binding protein) pathway and contributes to cytoprotection in HepG2 cells.

Sodium tanshinone IIA sulfonate derived from Danshen (Salvia miltiorrhiza) attenuates hypertrophy induced by angiotensin II in cultured neonatal rat cardiac cells.