scholarly journals Interstitial Fluid and Lymph Formation and Transport: Physiological Regulation and Roles in Inflammation and Cancer

2012 ◽  
Vol 92 (3) ◽  
pp. 1005-1060 ◽  
Author(s):  
Helge Wiig ◽  
Melody A. Swartz
Keyword(s):  
Interstitial Fluid ◽  
Cell Function ◽  
Biological Effects ◽  
Lymphatic Vessels ◽  
Peripheral Tolerance ◽  
Cellular Microenvironment ◽  
Physiological Regulation ◽  
Functional Implications ◽  
Biological Aspects ◽  
Lymph Fluid

The interstitium describes the fluid, proteins, solutes, and the extracellular matrix (ECM) that comprise the cellular microenvironment in tissues. Its alterations are fundamental to changes in cell function in inflammation, pathogenesis, and cancer. Interstitial fluid (IF) is created by transcapillary filtration and cleared by lymphatic vessels. Herein we discuss the biophysical, biomechanical, and functional implications of IF in normal and pathological tissue states from both fluid balance and cell function perspectives. We also discuss analysis methods to access IF, which enables quantification of the cellular microenvironment; such methods have demonstrated, for example, that there can be dramatic gradients from tissue to plasma during inflammation and that tumor IF is hypoxic and acidic compared with subcutaneous IF and plasma. Accumulated recent data show that IF and its convection through the interstitium and delivery to the lymph nodes have many and diverse biological effects, including in ECM reorganization, cell migration, and capillary morphogenesis as well as in immunity and peripheral tolerance. This review integrates the biophysical, biomechanical, and biological aspects of interstitial and lymph fluid and its transport in tissue physiology, pathophysiology, and immune regulation.

Statins: A Conceivable Remedial Role for the Regulation of Cancer Progression

2019 ◽  
Vol 15 (2) ◽  
pp. 131-145
Author(s):  
Gajanan V. Sherbet
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Tumour Growth ◽  
Cell Function ◽  
Mevalonate Pathway ◽  
Biological Effects ◽  
Vegf Receptor ◽  
Mesenchymal Transition ◽  
Cancer Management ◽  
Metabolic Role

The mevalonate pathway (also known as the cholesterol biosynthesis pathway) plays a crucial metabolic role in normal cell function as well as in the pathological environment. It leads to the synthesis of sterol and non-sterol isoprenoid biomolecules which subserve a variety of cellular functions. It is known to be deregulated in many disease processes. Statins and bisphosphonates are prominent inhibitors of the mevalonate pathway. They inhibit cell proliferation and activate apoptotic signalling and suppress tumour growth. Statins subdue metastatic spread of tumours by virtue of their ability to suppress invasion and angiogenesis. The induction of autophagy is another feature of statin effects that could contribute to the suppression of metastasis. Herein highlighted are the major signalling systems that statins engage to generate these biological effects. Statins can constrain tumour growth by influencing the expression and function of growth factor and receptor systems. They may suppress epithelial mesenchymal transition with resultant inhibition of cell survival signalling, together with the inhibition of cancer stem cell generation, and their maintenance and expansion. They can suppress ER (oestrogen receptor)-α in breast cancer cells. Statins have been implicated in the activation of the serine/threonine protein kinase AMPK (5' adenosine monophosphate-activated protein) leading to the suppression of cell proliferation. Both statins and bisphosphonates can suppress angiogenic signalling by HIF (hypoxia- inducible factor)-1/eNOS (endothelial nitric oxide synthase) and VEGF (vascular endothelial growth factor)/VEGFR (VEGF receptor). Statins have been linked with improvements in disease prognosis. Also attributed to them is the ability of cancer prevention and reduction of risk of some forms of cancer. The wide spectrum of cancer associated events which these mevalonate inhibitors appear to influence would suggest a conceivable role for them in cancer management. However, much deliberation is warranted in the design and planning of clinical trials, their scope and definition of endpoints, modes risk assessment and the accrual of benefits.

scholarly journals Evaluation of gravimetric techniques to estimate the microvascular filtration coefficient

2011 ◽  
Vol 300 (6) ◽  
pp. R1426-R1436 ◽  
Author(s):  
R. M. Dongaonkar ◽  
G. A. Laine ◽  
R. H. Stewart ◽  
C. M. Quick
Keyword(s):  
Steady State ◽  
Interstitial Fluid ◽  
Lymphatic Vessels ◽  
Analytical Framework ◽  
Filtration Coefficient ◽  
Balance Model ◽  
Rat Intestine ◽  
Transient Technique ◽  
Gravimetric Data ◽  
Reported Data

Microvascular permeability to water is characterized by the microvascular filtration coefficient ( K f). Conventional gravimetric techniques to estimate K f rely on data obtained from either transient or steady-state increases in organ weight in response to increases in microvascular pressure. Both techniques result in considerably different estimates and neither account for interstitial fluid storage and lymphatic return. We therefore developed a theoretical framework to evaluate K f estimation techniques by 1) comparing conventional techniques to a novel technique that includes effects of interstitial fluid storage and lymphatic return, 2) evaluating the ability of conventional techniques to reproduce K f from simulated gravimetric data generated by a realistic interstitial fluid balance model, 3) analyzing new data collected from rat intestine, and 4) analyzing previously reported data. These approaches revealed that the steady-state gravimetric technique yields estimates that are not directly related to K f and are in some cases directly proportional to interstitial compliance. However, the transient gravimetric technique yields accurate estimates in some organs, because the typical experimental duration minimizes the effects of interstitial fluid storage and lymphatic return. Furthermore, our analytical framework reveals that the supposed requirement of tying off all draining lymphatic vessels for the transient technique is unnecessary. Finally, our numerical simulations indicate that our comprehensive technique accurately reproduces the value of K f in all organs, is not confounded by interstitial storage and lymphatic return, and provides corroboration of the estimate from the transient technique.

scholarly journals Heterogeneous relationships between white matter and behaviour

2020 ◽  
Author(s):  
Alberto Lazari ◽  
Piergiorgio Salvan ◽  
Michiel Cottaar ◽  
Daniel Papp ◽  
Olof Jens van der Werf ◽  
...  
Keyword(s):  
White Matter ◽  
Fractional Anisotropy ◽  
Biological Effects ◽  
Tissue Properties ◽  
Biological Substrate ◽  
Biological Aspects

Several studies have established specific relationships between White Matter (WM) and behaviour. However, these studies have typically focussed on fractional anisotropy (FA), a neuroimaging metric that is sensitive to multiple tissue properties, making it difficult to identify what biological aspects of WM may drive such relationships. Here, we carry out a pre-registered assessment of WM-behaviour relationships across multiple behavioural, anatomical and biological domains. Surprisingly, we find support for predicted relationships between FA and behaviour only in one of three pre-registered tests. We also find no evidence for consistent multimodal signatures across neuroimaging markers with different biological sensitivity, which suggests there is no common biological substrate for WM-behaviour relationships. These results demonstrate that FA-behaviour relationships from the literature may not be easily generalisable across domains. They also highlight a broad heterogeneity in WM's relationship with behaviour, indicating that variable biological effects may be shaping their interaction.

scholarly journals Minerals contributing to human health and well-being

2021 ◽  
Vol 2 (1) ◽  
pp. 58-64
Author(s):  
Ekaterina V. Kulchavenya ◽  
◽  
Keyword(s):  
Gut Microbiota ◽  
Gut Microbiome ◽  
Cell Function ◽  
Paneth Cell ◽  
Lymphatic Vessels ◽  
Selenium Deficiency ◽  
Well Being ◽  
Gastrointestinal Infections ◽  
System Functioning ◽  
Normal Human

The gut microbiome is vital for normal human body functioning. The etiological and pathogenetic significance of increased intestinal permeability in disorders of various organs and systems seems to be certain. The term “microbiota-gut-brain axis” has been defined; the crucial role of the microbiota-gut-brain axis in neurological disorders has been confirmed. Gut microbiome not only contributes to digestion, metabolism and immunity, but also mediates sleep and mental health of the host via microbiota-gut-brain axis. Such elements as zinc and selenium are essential to maintain the microbial balance in the gut. Zinc contributes to gut homeostasis and Paneth cell function. Zinc has a direct impact on gut microbiota composition (for example, on some species of Staphylococcus), modulates gut microbiota reducing the fatal entry of bacteria into the bloodstream and lymphatic vessels. Thus, zinc alters microbiome due to direct cytotoxic / cytostatic effect on certain bacteria, such as staphylococci. Zinc possesses therapeutic effect in gastrointestinal infections and diarrhea. Bacterial translocation may be also reduced with Rebamipide possessing cytoprotective and antioxidant activity. Selenium in the form of selenoproteins has a number of functions in normal health and metabolism. Selenium contributes to immune system functioning and to progression of HIV to AIDS. Selenium deficiency results in cardiovascular diseases, infertility, myodegenerative disorders, and cognitive decline.

scholarly journals FACTORS INFLUENCING THE INTERMITTENT PASSAGE OF LOCKE'S SOLUTION INTO LIVING SKIN

1941 ◽  
Vol 73 (1) ◽  
pp. 85-108 ◽  
Author(s):  
Philip D. McMaster
Keyword(s):  
Connective Tissue ◽  
Blood Vessels ◽  
Atmospheric Pressure ◽  
Interstitial Fluid ◽  
Lymphatic Vessels ◽  
Intermittent Flow ◽  
Venous Obstruction ◽  
Factors Influencing ◽  
Interstitial Connective Tissue ◽  
Living Mouse

Minute amounts of Locke's or Tyrode's solution have been brought into contact with the interstitial connective tissue of the skin of the living mouse, at atmospheric pressure, in such a manner that the blood or lymphatic vessels are not entered directly. Under such circumstances these absorbable fluids enter the tissue spontaneously. Entrance is strikingly intermittent, not continuous, and so too when very slight pressures are brought to bear on the fluids (1). Hyperemia of the tissues, with accompanying dilatation of the blood vessels, increases the entrance of fluids at atmospheric pressure but it is still intermittent. By contrast, venous obstruction leads to intermittent backflow into the apparatus, but reflex hyperemia, following release of the obstruction, is attended by an increase of flow into the tissues in spite of the great reactive dilatation of vessels. The inflow is also intermittent. If the skin is deprived of circulation, fluid does not enter it at all at atmospheric pressure, though it moves in regularly and continuously if slight pressure is put upon it. Edema-forming fluids, described in the text, also enter in a continuous manner when forced into the skin of either living or dead animals. So too do serum and sperm oil. The findings indicate that the passage of interstitial fluid into the blood vessels may be intermittent under normal circumstances and its escape from them as well. The observed occurrence of intermittent flow in the blood vessels of several tissues (9, 15–25) will go far to account for the intermittent entrance of fluid into the skin.

GHRF causes biphasic stimulation of SRIF secretion from rat hypothalamic cells

1988 ◽  
Vol 255 (6) ◽  
pp. E829-E832
Author(s):  
S. Richardson ◽  
S. Twente ◽  
T. Audhya
Keyword(s):  
Response Curve ◽  
Response Pattern ◽  
Cell Function ◽  
Physiological Regulation ◽  
Gh Secretion ◽  
Adult Rat ◽  
Complex Interactions ◽  
Hypothalamic Cells ◽  
Dose Dependent ◽  
Stimulation Of

The complex interactions of the hypothalamic releasing peptides somatostatin (SRIF) and growth hormone (GH)-releasing hormone (GHRF), which regulate GH secretion, are still incompletely understood. To further scrutinize these interactions, we have studied the effects of GHRF on SRIF secretion from dispersed adult rat hypothalamic cells. Rat GHRF caused calcium- and dose-dependent stimulation of SRIF release in static 1-h incubations. SRIF release was stimulated by GHRF in a concentration range of 1-100 nM. However, the extended dose-response curve was biphasic in nature, with a significantly lower SRIF response in the presence of 1 microM GHRF vs. 100 nM GHRF. SRIF release, stimulated by another secretagogue (10 microM veratridine), was not affected by the presence or absence of 1 microM GHRF, suggesting the lack of toxic impairment of hypothalamic cell function by GHRF at this concentration. In conclusion, a biphasic stimulatory pattern of SRIF secretion in response to GHRF was observed in experiments employing dispersed rat hypothalamic cells. The biphasic SRIF response pattern to GHRF may be relevant in the physiological regulation of GH secretion.

scholarly journals Modulation of granulosa cell function via CRISPR-Cas fuelled editing of BMPR-IB gene in goats (Capra hircus)

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sai Kumar ◽  
Meeti Punetha ◽  
Bosco Jose ◽  
Jaya Bharati ◽  
Shivani Khanna ◽  
...  
Keyword(s):  
Cell Viability ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Cell Function ◽  
Biological Effects ◽  
Capra Hircus ◽  
Gene Modulation ◽  
High Fecundity ◽  
Smad Signaling ◽  
Sheep Breeds

AbstractBMPs are multifunctional growth factors implicated in regulating the ovarian function as key intra-ovarian factors. Biological effects of BMPs are mediated through binding with membrane bound receptors like BMPR-IB and initiating downstream Smad signaling pathway. FecB mutation, regarded as a loss of function mutation in the BMPR-IB gene was identified in certain sheep breeds having high fecundity. Similar type of fecundity genes in goats have not been discovered so far. Hence, the current study was designed to investigate the effects of BMPR-IB gene modulation on granulosa cell function in goats. The BMPR-IB gene was knocked out using CRISPR-Cas technology in granulosa cells and cultured in vitro with BMP-4 stimulation for three different durations In addition, the FecB mutation was introduced in the BMPR-IB gene applying Easi-CRISPR followed by BMP-4/7 stimulation for 72 h. Steroidogenesis and cell viability were studied to explore the granulosa cell function on BMPR-IB gene modulation. BMPRs were found to be expressed stage specifically in granulosa cells of goats. Higher transcriptional abundance of R-Smads, LHR and FSHR indicating sensitisation of Smad signaling and increased gonadotropin sensitivity along with a significant reduction in the cell proliferation and viability was observed in granulosa cells upon BMPR-IB modulation. The inhibitory action of BMP-4/7 on P4 secretion was abolished in both KO and KI cells. Altogether, the study has revealed an altered Smad signaling, steroidogenesis and cell viability upon modulation of BMPR-IB gene in granulosa cells similar to that are documented in sheep breeds carrying the FecB mutation.

scholarly journals Neuropilin-1: a checkpoint target with unique implications for cancer immunology and immunotherapy

2020 ◽  
Vol 8 (2) ◽  
pp. e000967 ◽  
Author(s):  
Christopher A Chuckran ◽  
Chang Liu ◽  
Tullia C Bruno ◽  
Creg J Workman ◽  
Dario AA Vignali
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Modulation ◽  
Cell Function ◽  
Inflammatory Responses ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Standard Of Care ◽  
Peripheral Tolerance ◽  
Neuropilin 1

Checkpoint blockade immunotherapy established a new paradigm in cancer treatment: for certain patients curative treatment requires immune reinvigoration. Despite this monumental advance, only 20%–30% of patients achieve an objective response to standard of care immunotherapy, necessitating the consideration of alternative targets. Optimal strategies will not only stimulate CD8+ T cells, but concomitantly modulate immunosuppressive cells in the tumor microenvironment (TME), most notably regulatory T cells (Treg cells). In this context, the immunoregulatory receptor Neuropilin-1 (NRP1) is garnering renewed attention as it reinforces intratumoral Treg cell function amidst inflammation in the TME. Loss of NRP1 on Treg cells in mouse models restores antitumor immunity without sacrificing peripheral tolerance. Enrichment of NRP1+ Treg cells is observed in patients across multiple malignancies with cancer, both intratumorally and in peripheral sites. Thus, targeting NRP1 may safely undermine intratumoral Treg cell fitness, permitting enhanced inflammatory responses with existing immunotherapies. Furthermore, NRP1 has been recently found to modulate tumor-specific CD8+ T cell responses. Emerging data suggest that NRP1 restricts CD8+ T cell reinvigoration in response to checkpoint inhibitors, and more importantly, acts as a barrier to the long-term durability of CD8+ T cell-mediated tumor immunosurveillance. These novel and distinct regulatory mechanisms present an exciting therapeutic opportunity. This review will discuss the growing literature on NRP1-mediated immune modulation which provides a strong rationale for categorizing NRP1 as both a key checkpoint in the TME as well as an immunotherapeutic target with promise either alone or in combination with current standard of care therapeutic regimens.

scholarly journals Thioredoxin reductase

2000 ◽  
Vol 346 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Debbie MUSTACICH ◽  
Garth POWIS
Keyword(s):  
Cell Function ◽  
Biological Effects ◽  
Thioredoxin Reductase ◽  
Pyridine Nucleotide ◽  
Redox Active ◽  
Key Factor ◽  
Exogenous Compounds ◽  
New Treatments ◽  
Thioredoxin Reductases

The mammalian thioredoxin reductases (TrxRs) are a family of selenium-containing pyridine nucleotide-disulphide oxidoreductases with mechanistic and sequence identity, including a conserved -Cys-Val-Asn-Val-Gly-Cys- redox catalytic site, to glutathione reductases. TrxRs catalyse the NADPH-dependent reduction of the redox protein thioredoxin (Trx), as well as of other endogenous and exogenous compounds. The broad substrate specificity of mammalian TrxRs is due to a second redox-active site, a C-terminal -Cys-SeCys- (where SeCys is selenocysteine), that is not found in glutathione reductase or Escherichia coli TrxR. There are currently two confirmed forms of mammalian TrxRs, TrxR1 and TrxR2, and it is possible that other forms will be identified. The availability of Se is a key factor determining TrxR activity both in cell culture and in vivo, and the mechanism(s) for the incorporation of Se into TrxRs, as well as the regulation of TrxR activity, have only recently begun to be investigated. The importance of Trx to many aspects of cell function make it likely that TrxRs also play a role in protection against oxidant injury, cell growth and transformation, and the recycling of ascorbate from its oxidized form. Since TrxRs are able to reduce a number of substrates other than Trx, it is likely that additional biological effects will be discovered for TrxR. Furthermore, inhibiting TrxR with drugs may lead to new treatments for human diseases such as cancer, AIDS and autoimmune diseases.

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