Ocular transient receptor potential channel function in health and disease

Transient receptor potential (TRP) channels sense and transduce environmental stimuli into Ca2+ transients that in turn induce responses essential for cell function and adaptation. These non-selective channels with variable Ca2+ selectivity are grouped into seven different subfamilies containing 28 subtypes based on differences in amino acid sequence homology. Many of these subtypes are expressed in the eye on both neuronal and non-neuronal cells where they affect a host of stress-induced regulatory responses essential for normal vision maintenance. This article reviews our current knowledge about the expression, function and regulation of TRPs in different eye tissues. We also describe how under certain conditions TRP activation can induce responses that are maladaptive to ocular function. Furthermore, the possibility of an association between TRP mutations and disease is considered. These findings contribute to evidence suggesting that drug targeting TRP channels may be of therapeutic benefit in a clinical setting. We point out issues that must be more extensively addressed before it will be possible to decide with certainty that this is a realistic endeavor. Another possible upshot of future studies is that disease process progression can be better evaluated by profiling changes in tissue specific functional TRP subtype activity as well as their gene and protein expression

L-Carnitine Reduces in Human Conjunctival Epithelial Cells Hypertonic- Induced Shrinkage through Interacting with TRPV1 Channels

Background/Aims: Ocular surface health depends on conjunctival epithelial (HCjE) layer integrity since it protects against pathogenic infiltration and contributes to tissue hydration maintenance. As the same increases in tear film hyperosmolarity described in dry eye disease can increase corneal epithelial transient receptor potential vanilloid type-1 (TRPV1) channel activity, we evaluated its involvement in mediating an osmoprotective effect by L-carnitine against such stress. Methods: Using siRNA gene silencing, Ca2+imaging, planar patch- clamping and relative cell volume measurements, we determined if the protective effects of this osmolyte stem from its interaction with TRPV1. Results: TRPV1 activation by capsaicin (CAP) and an increase in osmolarity to≈450 mOsM both induced increases in Ca2+levels. In contrast, blocking TRPV1 activation with capsazepine (CPZ) fully reversed this response. Similarly, L-carnitine (1 mM) also reduced underlying whole-cell currents. In calcein-AM loaded cells, hypertonic-induced relative cell volume shrinkage was fully blocked during exposure to L-carnitine. On the other hand, in TRPV1 gene-silenced cells, this protective effect by L-carnitine was obviated. Conclusion: The described L-carnitine osmoprotective effect is elicited through suppression of hypertonic-induced TRPV1 activation leading to increases in L-carnitine uptake through a described Na+-dependent L-carnitine transporter

Anti-inflammatory and combined antiinflammatory/ analgesic medication in the early management of iliotibial band friction syndrome A clinical trial

Forty-three athletes presenting with unilateral iliotibial band friction syndrome (ITBFS) were randomly divided into three groups for the first 7 days of treatment (placebo-controlled, double-blind): 1 - placebo (N = 13); 2 - anti-inflammatory medication (N = 14) (Voharen; Geigy); and 3 - analgesicl anti-inflammatory combined medication (N =. 16) (Myprodol; Rio Ethicals). All subjects rested from day 0 to day 7 and all groups received the same physiotherapy outpatient treatment programme from day 3 to day 7. On days 0, 3 and 7 the subjects performed a functional treadmill running test (maximum 30 minutes) during which they reported pain (scale 0-10; 0 = no pain, 10 = unbearable pain) each minute. Total running distance, total running time and the area under the pain v. time curve was calculated. Daily 24-hour recall pain scores were also recorded. The 24-hour recall pain scores decreased significantly for all the groups over the treatment period. This method of assessing efficacy of treatment therefore failed to show differences between groups. In contrast, during the running test only group 3 improved their total running time and distance from day 0 to day 7, whereas in all the groups the area under the pain v. time curve decreased from day 0 to day 7. All the other groups improved total running time and running distance from day 3 to day 7. All three treatment modalities are effective in the early. treatment of ITBFS but physiotherapy in combination with analgesicl anti-inflammatory medication is superior. A functional running test, which is more sensitive than conventional pain-recall· methods in assessing efficacy of treatment in this type of clinical trial, is described

Temperature-Sensitive Transient Receptor Potential Channels in Corneal Tissue Layers and Cells

We here provide a brief summary of the characteristics of transient receptor potential channels (TRPs) identified in corneal tissue layers and cells. In general, TRPs are nonselective cation channels which are Ca ²⁺ permeable. Most TRPs serve as thermosensitive molecular sensors (thermo-TRPs). Based on their functional importance, the possibilities are described for drug-targeting TRP activity in a clinical setting. TRPs are expressed in various tissues of the eye including both human corneal epithelial and endothelial layers as well as stromal fibroblasts and stromal nerve fibers. TRP vanilloid type 1 (TRPV1) heat receptor, also known as capsaicin receptor, along with TRP melastatin type 8 (TRPM8) cold receptor, which is also known as menthol receptor, are prototypes of the thermo-TRP family. The TRPV1 functional channel is the most investigated TRP channel in these tissues, owing to its contribution to maintaining tissue homeostasis as well as eliciting wound healing responses to injury. Other thermo-TRP family members identified in these tissues are TRPV2, 3 and 4. Finally, there is the TRP ankyrin type 1 (TRPA1) cold receptor. All of these thermo-TRPs can be activated within specific temperature ranges and transduce such inputs into chemical and electrical signals. Although several recent studies have begun to unravel complex roles for thermo-TRPs such as TRPV1 in corneal layers and resident cells, additional studies are needed to further elucidate their roles in health and disease

L-Carnitine Suppresses Transient Receptor Potential Vanilloid Type 1 Activation in Human Corneal Epithelial Cells

Tear film hyperosmolarity induces dry eye syndrome (DES) through transient receptor potential vanilloid type 1 (TRPV1) activation. L-carnitine is a viable therapeutic agent since it protects against this hypertonicity-induced response. Here, we investigated whether L-carnitine inhibits TRPV1 activation by blocking heat- or capsaicin-induced increases in Ca2+ influx or hyperosmotic stress-induced cell volume shrinkage in a human corneal epithelial cell line (HCE-T). Single-cell fluorescence imaging of calcein/AM-loaded cells or fura-2/AM-labeled cells was used to evaluate cell volume changes and intracellular calcium levels, respectively. Planar patch-clamp technique was used to measure whole-cell currents. TRPV1 activation via either capsaicin (20 & mu;mol/L), hyperosmolarity (& AP;450 mosmol/L) or an increase in ambient bath temperature to 43 & DEG;C induced intracellular calcium transients and augmented whole-cell currents, whereas hypertonicity induced cell volume shrinkage. In contrast, either capsazepine (10 & mu;mol/L) or L-carnitine (1-3 mmol/L) reduced all these responses. Taken together, L-carnitine and capsazepine suppress hypertonicity-induced TRPV1 activation by blocking cell volume shrinkage

L-carnitine suppresses transient receptor potential vanilloid type 1 activity and myofibroblast transdifferentiation in human corneal keratocytes

Corneal stromal wound healing is a well-balanced process promoted by overlapping phases including keratocyte proliferation, inflammatory-related events, and tissue remodeling. L-carnitine as a natural antioxidant has shown potential to reduce stromal fibrosis, yet the underlying pathway is still unknown. Since transient receptor potential vanilloid 1 (TRPV1) is a potential drug target for improving the outcome of inflammatory/fibrogenic wound healing, we investigated if L-carnitine can mediate inhibition of the fibrotic response through suppression of TRPV1 activation in human corneal keratocytes (HCK). We determined TRPV1-induced intracellular calcium transients using fluorescence calcium imaging, channel currents by planar patch-clamping, and cell migration by scratch assay for wound healing. The potential L-carnitine effect on TRPV1-induced myofibroblast transdifferentiation was evaluated by immunocytochemical detection of alpha smooth muscle actin. RT-PCR analysis confirmed TRPV1 mRNA expression in HCK. L-carnitine (1 mmol/l) inhibited either capsaicin (CAP) (10 µmol/l), hypertonic stress (450 mOsmol/l), or thermal increase (>43 °C) induced Ca2+ transients and corresponding increases in TRPV1-induced inward and outward whole-cell currents. This was accompanied by suppression of injury-induced increases in myofibroblast transdifferentiation and cell migration. In conclusion, L-carnitine contributes to inhibit stromal scarring through suppressing an injury-induced intrinsic TRPV1 activity that is linked with induction of myofibroblast transdifferentiation in HCK cells

On “The Analysis of Ranked Data Derived from Completely Randomized Factorial Designs”

Extensions of the Kruskal-Wallis procedure for a factorial design are reviewed and researched under various degrees and kinds of nonnullity. It was found that the distributions of these test statistics are a Function of effects other than those being tested except under the completely null situation and their use is discouraged.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline