Neonatal head circumference as a risk factor for obstetric anal sphincter injuries: a systematic review and meta-analysis.

OBJECTIVE: Between 53% and 79% of women will sustain some degree of perineal laceration during vaginal delivery. Third- and fourth-degree perineal lacerations are known as obstetric anal sphincter injuries. Timely diagnosis and prompt treatment of obstetric anal sphincter injuries can help to prevent the development of severe consequences like fecal incontinence, urinary incontinence, and rectovaginal fistula. Neonatal head circumference is routinely measured postpartum but is often not mentioned as a risk factor for obstetric anal sphincter injuries in clinical guidelines. Thus far, no review article on the risk factors for obstetric anal sphincter injuries has discussed the role of neonatal head circumference. This study aimed to review and analyze the relationship between head circumference and the occurrence of obstetric anal sphincter injuries among previous studies to conclude whether head circumference should be recognized as an important risk factor. DATA SOURCES: Through study screening on Google Scholar, PubMed, Scopus, and Science Direct for articles published between 2013 to 2023, followed by assessment of eligibility, this study ended up reviewing 25 studies, 17 of which were included in the meta-analysis. STUDY ELIGIBILITY CRITERIA: Only studies that reported both the neonatal head circumference and the occurrence of obstetric anal sphincter injuries were included in this review. METHODS: The included studies were appraised using the Dartmouth Library risk of bias assessment checklist. Qualitative synthesis was based on the study population, findings, adjusted confounding factors, and suggested causative links in each study. Quantitative synthesis was conducted using calculation and pooling of odds ratios and inverse variance using Review Manager 5.4.1. RESULTS: A statistically significant association between head circumference and obstetric anal sphincter injuries was reported in 21 of 25 studies; 4 studies reported that head circumference was a true independent risk factor. A meta-analysis of the studies that reported neonatal head circumference as a dichotomous categorical variable with a cutoff point of 35±1 cm yielded statistically significant pooled results (odds ratio, 1.92; 95% confidence interval, 1.80-2.04). CONCLUSION: The risk for obstetric anal sphincter injuries increased as the neonatal head circumference increased-this should be considered in decision-making during labor and postpartum management to attain the best outcome.

Multimodality Imaging of Aortic Valve Calcification and Function in a Murine Model of Calcific Aortic Valve Disease and Bicuspid Aortic Valve.

Calcific aortic valve disease (CAVD) is a prevailing disease with increasing occurrence and no known medical therapy. Dcbld2-/- mice have a high prevalence of bicuspid aortic valve (BAV), spontaneous aortic valve calcification, and aortic stenosis (AS). 18F-NaF PET/CT can detect the aortic valve calcification process in humans. However, its feasibility in preclinical models of CAVD remains to be determined. Here, we sought to validate 18F-NaF PET/CT for tracking murine aortic valve calcification and leveraged it to examine the development of calcification with aging and its interdependence with BAV and AS in Dcbld2-/- mice. Methods: Dcbld2-/- mice at 3-4 mo, 10-16 mo, and 18-24 mo underwent echocardiography, 18F-NaF PET/CT (n = 34, or autoradiography (n = 45)), and tissue analysis. A subset of mice underwent both PET/CT and autoradiography (n = 12). The aortic valve signal was quantified as SUVmax on PET/CT and as percentage injected dose per square centimeter on autoradiography. The valve tissue sections were analyzed by microscopy to identify tricuspid and bicuspid aortic valves. Results: The aortic valve 18F-NaF signal on PET/CT was significantly higher at 18-24 mo (P < 0.0001) and 10-16 mo (P < 0.05) than at 3-4 mo. Additionally, at 18-24 mo BAV had a higher 18F-NaF signal than tricuspid aortic valves (P < 0.05). These findings were confirmed by autoradiography, with BAV having significantly higher 18F-NaF uptake in each age group. A significant correlation between PET and autoradiography data (Pearson r = 0.79, P < 0.01) established the accuracy of PET quantification. The rate of calcification with aging was significantly faster for BAV (P < 0.05). Transaortic valve flow velocity was significantly higher in animals with BAV at all ages. Finally, there was a significant correlation between transaortic valve flow velocity and aortic valve calcification by both PET/CT (r = 0.55, P < 0.001) and autoradiography (r = 0.45, P < 0.01). Conclusion: 18F-NaF PET/CT links valvular calcification to BAV and aging in Dcbld2-/- mice and suggests that AS may promote calcification. In addition to addressing the pathobiology of valvular calcification, 18F-NaF PET/CT may be a valuable tool for evaluation of emerging therapeutic interventions in CAVD.

Positron Emission Tomography Imaging of Vessel Wall Matrix Metalloproteinase Activity in Abdominal Aortic Aneurysm.

BACKGROUND: Matrix metalloproteinases (MMPs) play a key role in the pathogenesis of abdominal aortic aneurysm (AAA). Imaging aortic MMP activity, especially using positron emission tomography to access high sensitivity, quantitative data, could potentially improve AAA risk stratification. Here, we describe the design, synthesis, characterization, and evaluation in murine AAA and human aortic tissue of a first-in-class MMP-targeted positron emission tomography radioligand, 64Cu-RYM2. METHODS: The broad spectrum MMP inhibitor, RYM2 was synthetized, and its potency as an MMP inhibitor was evaluated by a competitive inhibition assay. Toxicology studies were performed. Tracer biodistribution was evaluated in a murine model of AAA induced by angiotensin II infusion in Apolipoprotein E-deficient mice. 64Cu-RYM2 binding to normal and aneurysmal human aortic tissues was assessed by autoradiography. RESULTS: RYM2 functioned as an MMP inhibitor with nanomolar affinities. Toxicology studies showed no adverse reaction in mice. Upon radiolabeling with Cu-64, the resulting tracer was stable in murine and human blood in vitro. Biodistribution and metabolite analysis in mice showed rapid renal clearance and acceptable in vivo stability. In vivo positron emission tomography/computed tomography in a murine model of AAA showed a specific aortic signal, which correlated with ex vivo measured MMP activity and Cd68 gene expression. 64Cu-RYM2 specifically bound to normal and aneurysmal human aortic tissues in correlation with MMP activity. CONCLUSIONS: 64Cu-RYM2 is a first-in-class MMP-targeted positron emission tomography tracer with favorable stability, biodistribution, performance in preclinical AAA, and importantly, specific binding to human tissues. These data set the stage for 64Cu-RYM2-based translational imaging studies of vessel wall MMP activity, and indirectly, inflammation, in AAA.

Assessing the effect of multiple variables on the production of bioflocculant by Serratia marcescens: Flocculating activity, kinetics, toxicity, and flocculation mechanism.

Bioflocculants gain attention as alternatives to chemical flocculants because they are more environmentally friendly and highly biodegradable. This study aims to improve the bioflocculant production by Serratia marcescens using one-variable-at-a-time (OVAT) analysis and analyze its flocculating activity performance, toxicity, and the flocculation mechanism. The effect of multiple variables including initial inoculum size, pH, mixing speed, temperature, growth medium, and incubation period was assessed through OVAT. Flocculating activity was then determined via jar test analysis, and toxicity test was performed using Daphnia magna and Daphnia pulex. The flocculation mechanism was determined via particle size distribution and zeta potential analysis. The optimum conditions for the improved bioflocculant production were as follows: 10% v/v initial inoculum size, pH 7, mixing speed of 150 rpm, room temperature, nutrient broth medium, and 72 h of incubation period. Scanning electron microscopy showed flake-like intact structure with coarse surface. The produced bioflocculant showed flocculating activity of 48% in 5227 ± 580 NTU initial kaolin turbidity with 1 mg/L concentration and 5% v/v dosage of bioflocculant, following the second-order kinetics. Toxicity test to D. magna and D. pulex showed the 48 h LC50 values of 8.06 and 6.42 g/L, respectively; these values are greatly higher than the fabricated chemical flocculants. The flocculation process using bioflocculant produced by S. marcescens was suggested to occur via bridging mechanism because it greatly affected the particle size distribution. Results indicated that bioflocculant produced by S. marcescens is much environmentally friendly and has great potential for turbidity removal in water/wastewater.

Differential BMP Signaling Mediates the Interplay Between Genetics and Leaflet Numbers in Aortic Valve Calcification.

Expression of a neuropilin-like protein, DCBLD2, is reduced in human calcific aortic valve disease (CAVD). DCBLD2-deficient mice develop bicuspid aortic valve (BAV) and CAVD, which is more severe in BAV mice compared with tricuspid littermates. In vivo and in vitro studies link this observation to up-regulated bone morphogenic protein (BMP)2 expression in the presence of DCBLD2 down-regulation, and enhanced BMP2 signaling in BAV, indicating that a combination of genetics and BAV promotes aortic valve calcification and stenosis. This pathway may be a therapeutic target to prevent CAVD progression in BAV.

TRPC1 channels underlie stretch-modulated sarcoplasmic reticulum calcium leak in cardiomyocytes.

Transient receptor potential canonical 1 (TRPC1) channels are Ca2+-permeable ion channels expressed in cardiomyocytes. An involvement of TRPC1 channels in cardiac diseases is widely established. However, the physiological role of TRPC1 channels and the mechanisms through which they contribute to disease development are still under investigation. Our prior work suggested that TRPC1 forms Ca2+ leak channels located in the sarcoplasmic reticulum (SR) membrane. Prior studies suggested that TRPC1 channels in the cell membrane are mechanosensitive, but this was not yet investigated in cardiomyocytes or for SR localized TRPC1 channels. We applied adenoviral transfection to overexpress or suppress TRPC1 expression in neonatal rat ventricular myocytes (NRVMs). Transfections were evaluated with RT-qPCR, western blot, and fluorescent imaging. Single-molecule localization microscopy revealed high colocalization of exogenously expressed TRPC1 and the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2). To test our hypothesis that TRPC1 channels contribute to mechanosensitive Ca2+ SR leak, we directly measured SR Ca2+ concentration ([Ca2+]SR) using adenoviral transfection with a novel ratiometric genetically encoded SR-targeting Ca2+ sensor. We performed fluorescence imaging to quantitatively assess [Ca2+]SR and leak through TRPC1 channels of NRVMs cultured on stretchable silicone membranes. [Ca2+]SR was increased in cells with suppressed TRPC1 expression vs. control and Transient receptor potential canonical 1-overexpressing cells. We also detected a significant reduction in [Ca2+]SR in cells with Transient receptor potential canonical 1 overexpression when 10% uniaxial stretch was applied. These findings indicate that TRPC1 channels underlie the mechanosensitive modulation of [Ca2+]SR. Our findings are critical for understanding the physiological role of TRPC1 channels and support the development of pharmacological therapies for cardiac diseases.

What compound inside biocoagulants/bioflocculants is contributing the most to the coagulation and flocculation processes?

Biocoagulants and bioflocculants are alternative items that can be used to substitute the utilization of common-chemical coagulants and flocculants. Biocoagulants/bioflocculants can be extracted from animals, microorganisms, and plants. Moreover, biocoagulants/bioflocculants have specific characteristics that contribute to the coagulation and flocculation processes. The active compounds inside biocoagulants/bioflocculants vary and correspond to the specific working mechanisms, including charge neutralization, sweep coagulation, adsorption, bridging, and patch flocculation. This review paper summarizes the characteristics of biocoagulants/bioflocculants from different sources and its performance in treating various pollutants. Furthermore, this paper discusses the most contributing compounds and functional groups of biocoagulants/bioflocculants that can be related to their working mechanisms. Several functional groups and compounds in biocoagulants/bioflocculants are highlighted in this review article, as well as the correlation between the highlighted groups/compounds to the aforementioned coagulation-flocculation mechanisms. In addition, current knowledge gaps in the study of biocoagulants/bioflocculants and future approaches that may serve as research directions are also emphasized. This review article is expected to shed information on the characteristics of biocoagulants/bioflocculants, which may then become a focus in the optimization to obtain higher performance in future application of coagulation-flocculation processes.

Potential of local plant leaves as natural coagulant for turbidity removal.

The performance of local plants was tested using synthetic turbid water resembling real wastewater by measuring their ability to remove turbidity. The selected plants were A. indica, S. palustris, D. linearis, S. polyanthum, M. esculenta, P. sarmentosum, and M. malabathricum which can easily be found locally. The experiment was run based on coagulant dosages varied from 0 to 10 g/L for each plant with a rapid mixing speed at 180 rpm for 3 min, slow mixing speed at 10 rpm for 20 min, and settling time for 30 min. The results demonstrated that each plant has been capable of reducing turbidity by different amounts, with an increase in the coagulant dosage. The optimum coagulant dosages achieved for A. indica, S. palustris, S. polyanthum, and D. linearis were 10 g/L with turbidity removal at 26.9%, 24.9%, 24.9%, and 17.5%, respectively. P. sarmentosum and M. esculenta attained optimum coagulant dosages at 5 g/L with turbidity removal at 24.2% and 22.2%, and lastly M. malabathricum at 0.1 g/L (12.2%). P. sarmentosum was suggested to the best natural coagulant which achieved the highest removal of turbidity with a low dosage used.

Contaminants of emerging concern (CECs) in aquaculture effluent: Insight into breeding and rearing activities, alarming impacts, regulations, performance of wastewater treatment unit and future approaches.

The contamination of aquaculture products and effluents by contaminants of emerging concern (CECs) from the direct chemical use in aquaculture activities or surrounding industries is currently an issue of increasing concern as these CECs exert acute and chronic effects on living organisms. CECs have been detected in aquaculture water, sediment, and culture species, and antibiotics, antifoulants, and disinfectants are the commonly detected groups. Through accumulation, CECs can reside in the tissue of aquaculture products and eventually consumed by humans. Currently, effluents containing CECs are discharged to the surrounding environment while producing sediments that eventually contaminate rivers as receiving bodies. The rearing (grow-out) stages of aquaculture activities are issues regarding CECs-contamination in aquaculture covering water, sediment, and aquaculture products. Proper regulations should be imposed on all aquaculturists to control chemical usage and ensure compliance to guidelines for appropriate effluent treatment. Several techniques for treating aquaculture effluents contaminated by CECs have been explored, including adsorption, wetland construction, photocatalysis, filtration, sludge activation, and sedimentation. The challenges imposed by CECs on aquaculture activities are discussed for the purpose of obtaining insights into current issues and providing future approaches for resolving associated problems. Stakeholders, such as researchers focusing on environment and aquaculture, are expected to benefit from the presented results in this article. In addition, the results may be useful in establishing aquaculture-related CECs regulations, assessing toxicity to living biota, and preventing pollution.

Exploring the extraction methods for plant-based coagulants and their future approaches.

The application of plant-based coagulants in wastewater treatment has increasingly progressed in the coagulation-flocculation process toward green economy and cleaner production. Plant-based coagulants have a potential as essential substitutes for commercially used chemical coagulants because of their natural characteristics and biodegradability. Chemical coagulants leave residues in treated water and generated sludge, which cause harm to human health and the ecosystem. Thus, the exploration of plant-based coagulants in wastewater treatment could reduce and eliminate the potential damage of chemical coagulants and promote the alternative approach for sustainable environment. The general processing steps of the end-to-end plant-based coagulant production, which includes primary, secondary, and tertiary stages, are discussed. However, this review focuses more on the extraction process using different solutions and compares the performance of different coagulants in removal activities after effluent treatment. Discussion on the arising challenges is elaborated, and approaches for plant-based coagulant research in the near future are suggested.

The Involvement of l-Arginine-Nitric Oxide-cGMP-ATP-Sensitive K+ Channel Pathway in Antinociception of BBHC, a Novel Diarylpentanoid Analogue, in Mice Model.

The present study focuses on the possible involvement of l-arginine-nitric oxide-cGMP-ATP-sensitive K+ channel pathway in the antinociceptive activity of a novel diarylpentanoid analogue, 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol (BBHC) via a chemical nociceptive model in mice. The antinociceptive action of BBHC (1 mg/kg, i.p.) was attenuated by the intraperitoneal pre-treatment of l-arginine (a nitric oxide synthase precursor) and glibenclamide (an ATP-sensitive K+ channel blocker) in acetic acid-induced abdominal constriction tests. Interestingly, BBHC's antinociception was significantly enhanced by the i.p. pre-treatment of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective inhibitor of soluble guanylyl cyclase (p < 0.05). Altogether, these findings suggest that the systemic administration of BBHC is able to establish a significant antinociceptive effect in a mice model of chemically induced pain. BBHC's antinociception is shown to be mediated by the involvement of l-arginine-nitric oxide-cGMP-ATP-sensitive K+ channel pathway, without any potential sedative or muscle relaxant concerns.

Macrophytes as wastewater treatment agents: Nutrient uptake and potential of produced biomass utilization toward circular economy initiatives.

Macrophytes have been widely used as agents in wastewater treatment. The involvement of plants in wastewater treatment cannot be separated from wetland utilization. As one of the green technologies in wastewater treatment plants, wetland exhibits a great performance, especially in removing nutrients from wastewater before the final discharge. It involves the use of plants and consequently produces plant biomasses as treatment byproducts. The produced plant biomasses can be utilized or converted into several valuable compounds, but related information is still limited and scattered. This review summarizes wastewater's nutrient content (macro and micronutrient) that can support plant growth and the performance of constructed wetland (CW) in performing nutrient uptake by using macrophytes as treatment agents. This paper further discusses the potential of the utilization of the produced plant biomasses as bioenergy production materials, including bioethanol, biohydrogen, biogas, and biodiesel. This paper also highlights the conversion of plant biomasses into animal feed, biochar, adsorbent, and fertilizer, which may support clean production and circular economy efforts. The presented review aims to emphasize and explore the utilization of plant biomasses and their conversion into valuable products, which may solve problems related to plant biomass handling during the adoption of CW in wastewater treatment plants.

Patient Factors in Inappropriate Antibiotic Prescribing for Upper Respiratory Tract Infection in the Emergency Department.

BACKGROUND: Emergency departments (EDs) are frequently misused for non-emergency cases such as upper respiratory tract infections (URTIs). Flooding of these cases may contribute to inappropriate antibiotic prescribing. The aim of this study was to determine the patient factors associated with inappropriate antibiotic prescribing for URTIs in the EDs. METHODS: This cross-sectional study involved patients over age 3 years old who presented with URTI to the green zone of the ED of a tertiary hospital on the east coast of Malaysia in 2018-2019. Convenient sampling was done. The patients were categorised into two groups according to their McIsaac scores: positive (≥ 2) or negative (< 2). Antibiotics given to the negative McIsaac group were considered inappropriate. RESULTS: A total of 261 cases were included - 127 with positive and 134 with negative McIsaac scores. The most common symptoms were fever and cough. About 29% had inappropriate antibiotic prescribing with a high rate for amoxycillin. Duration of symptoms of one day or less (OR 18.5; 95% CI: 1.65, 207.10; P = 0.018), presence of chills (OR 4.36; 95% CI: 1.13, 16.88; P = 0.033) and diagnosis of acute tonsillitis (OR 5.26; 95% CI: 1.76, 15.72; P = 0.003) were significantly associated with inappropriate antibiotic prescription. CONCLUSION: Factors influencing inappropriate antibiotic prescribing should be pointed out to emergency doctors to reduce its incidence.

Aquaculture industry: Supply and demand, best practices, effluent and its current issues and treatment technology.

The aquaculture industry has become increasingly important and is rapidly growing in terms of providing a protein food source for human consumption. With the increase in the global population, demand for aquaculture is high and is estimated to reach 62% of the total global production by 2030. In 2018, it was reported that the demand for aquaculture was 46% of the total production, and with the current positive trends, it may be possible to increase tremendously in the coming years. China is still one of the main players in global aquaculture production. Due to high demand, aquaculture production generates large volumes of effluent, posing a great danger to the environment. Aquaculture effluent comprises solid waste and dissolved constituents, including nutrients and contaminants of emerging concern, thereby bringing detrimental impacts such as eutrophication, chemical toxicity, and food insecurity. Waste can be removed through culture systems, constructed wetlands, biofloc, and other treatment technologies. Some methods have the potential to be applied as zero-waste discharge treatment. Thus, this article analyses the supply and demand for aquaculture products, the best practices adopted in the aquaculture industry, effluent characteristics, current issues, and effluent treatment technology.

Modulation of Calcium Transients in Cardiomyocytes by Transient Receptor Potential Canonical 6 Channels.

Transient receptor potential canonical 6 (TRPC6) channels are non-selective cation channels that are thought to underlie mechano-modulation of calcium signaling in cardiomyocytes. TRPC6 channels are involved in development of cardiac hypertrophy and related calcineurin-nuclear factor of activated T cells (NFAT) signaling. However, the exact location and roles of TRPC6 channels remain ill-defined in cardiomyocytes. We used an expression system based on neonatal rat ventricular myocytes (NRVMs) to investigate the location of TRPC6 channels and their role in calcium signaling. NRVMs isolated from 1- to 2-day-old animals were cultured and infected with an adenoviral vector to express enhanced-green fluorescent protein (eGFP) or TRPC6-eGFP. After 3 days, NRVMs were fixed, immunolabeled, and imaged with confocal and super-resolution microscopy to determine TRPC6 localization. Cytosolic calcium transients at 0.5 and 1 Hz pacing rates were recorded in NRVMs using indo-1, a ratio-metric calcium dye. Confocal and super-resolution microscopy suggested that TRPC6-eGFP localized to the sarcolemma. NRVMs infected with TRPC6-eGFP exhibited higher diastolic and systolic cytosolic calcium concentration as well as increased sarcoplasmic reticulum (SR) calcium load compared to eGFP infected cells. We applied a computer model comprising sarcolemmal TRPC6 current to explain our experimental findings. Altogether, our studies indicate that TRPC6 channels play a role in sarcolemmal and intracellular calcium signaling in cardiomyocytes. Our findings support the hypothesis that upregulation or activation of TRPC6 channels, e.g., in disease, leads to sustained elevation of the cytosolic calcium concentration, which is thought to activate calcineurin-NFAT signaling and cardiac hypertrophic remodeling. Also, our findings support the hypothesis that mechanosensitivity of TRPC6 channels modulates cytosolic calcium transients and SR calcium load.

Location and function of transient receptor potential canonical channel 1 in ventricular myocytes.

Transient receptor potential canonical 1 (TRPC1) protein is abundantly expressed in cardiomyocytes. While TRPC1 is supposed to be critically involved in cardiac hypertrophy, its physiological role in cardiomyocytes is poorly understood. We investigated the subcellular location of TRPC1 and its contribution to Ca2+ signaling in mammalian ventricular myocytes. Immunolabeling, three-dimensional scanning confocal microscopy and quantitative colocalization analysis revealed an abundant intracellular location of TRPC1 in neonatal rat ventricular myocytes (NRVMs) and adult rabbit ventricular myocytes. TRPC1 was colocalized with intracellular proteins including sarco/endoplasmic reticulum Ca2+ ATPase 2 in the sarcoplasmic reticulum (SR). Colocalization with wheat germ agglutinin, which labels the glycocalyx and thus marks the sarcolemma including the transverse tubular system, was low. Super-resolution and immunoelectron microscopy supported the intracellular location of TRPC1. We investigated Ca2+ signaling in NRVMs after adenoviral TRPC1 overexpression or silencing. In NRVMs bathed in Na+ and Ca2+ free solution, TRPC1 overexpression and silencing was associated with a decreased and increased SR Ca2+ content, respectively. In isolated rabbit cardiomyocytes bathed in Na+ and Ca2+ free solution, we found an increased decay of the cytosolic Ca2+ concentration [Ca2+]i and increased SR Ca2+ content in the presence of the TRPC channel blocker SKF-96365. In a computational model of rabbit ventricular myocytes at physiological pacing rates, Ca2+ leak through SR TRPC channels increased the systolic and diastolic [Ca2+]i with only minor effects on the action potential and SR Ca2+ content. Our studies suggest that TRPC1 channels are localized in the SR, and not present in the sarcolemma of ventricular myocytes. The studies provide evidence for a role of TRPC1 as a contributor to SR Ca2+ leak in cardiomyocytes, which was previously explained by ryanodine receptors only. We propose that the findings will guide us to an understanding of TRPC1 channels as modulators of [Ca2+]i and contractility in cardiomyocytes.

Anti-Edematogenic and Anti-Granuloma Activity of a Synthetic Curcuminoid Analog, 5-(3,4-Dihydroxyphenyl)-3-hydroxy-1-(2-hydroxyphenyl)penta-2,4-dien-1-one, in Mouse Models of Inflammation.

Curcumin, derived from the rhizome Curcuma longa, has been scientifically proven to possess anti-inflammatory activity but is of limited clinical and veterinary use owing to its low bioavailability and poor solubility. Hence, analogs of curcuminoids with improved biological properties have been synthesized to overcome these limitations. This study aims to provide the pharmacological basis for the use of 5-(3,4-dihydroxyphenyl)-3-hydroxy-1-(2-hydroxyphenyl)penta-2,4-dien-1-one (DHHPD), a synthetic curcuminoid analog, as an anti-edematogenic and anti-granuloma agent. The carrageenan-induced paw edema and the cotton pellet-induced granuloma assays were used to assess the anti-inflammatory activity of DHHPD in mice. The effects of DHHPD on the histaminergic, serotonergic, and bradykininergic systems were determined by the histamine-, serotonin-, and bradykinin-induced paw edema tests, respectively. DHHPD (0.1, 0.3, 1, and 3 mg/kg, intraperitoneal) evoked significant reductions (p < 0.05) in carrageenan-induced paw edema at different time intervals and granuloma formation (p < 0.0001) by 22.08, 32.57, 37.20, and 49.25%, respectively. Furthermore, DHHPD significantly reduced paw edema (p < 0.05) induced by histamine, serotonin, and bradykinin. The present study suggests that DHHPD exerts anti-edematogenic activity, possibly by inhibiting the synthesis or release of autacoid mediators of inflammation through the histaminergic, serotonergic, and bradykininergic systems. The anti-granuloma effect may be attributed to the suppression of transudative, exudative, and proliferative activities associated with inflammation.

Analgesic Effect of 5-(3,4-Dihydroxyphenyl)-3-hydroxy-1-(2-hydroxyphenyl)penta-2,4-dien-1-one in Experimental Animal Models of Nociception.

Curcuminoids derived from turmeric rhizome have been reported to exhibit antinociceptive, antioxidant and anti-inflammatory activities. We evaluated the peripheral and central antinociceptive activities of 5-(3,4-dihydroxyphenyl)-3-hydroxy-1-(2-hydroxyphenyl)penta-2,4-dien-1-one (DHHPD), a novel synthetic curcuminoid analogue at 0.1, 0.3, 1 and 3 mg/kg (intraperitoneal), through chemical and thermal models of nociception. The effects of DHHPD on the vanilloid and glutamatergic systems were evaluated through the capsaicin- and glutamate-induced paw licking tests. Results showed that DHHPD significantly (p < 0.05) attenuated the writhing response produced by the 0.8% acetic acid injection. In addition, 1 and 3 mg/kg of DHHPD significantly (p < 0.05) reduced the licking time spent by each mouse in both phases of the 2.5% formalin test and increased the response latency of mice on the hot-plate. However, the effect produced in the latter was not reversed by naloxone, a non-selective opioid receptor antagonist. Despite this, DHHPD decreased the licking latency of mice in the capsaicin- and glutamate-induced paw licking tests in a dose response manner. In conclusion, DHHPD showed excellent peripheral and central antinociceptive activities possibly by attenuation of the synthesis and/or release of pro-inflammatory mediators in addition to modulation of the vanilloid and glutamatergic systems without an apparent effect on the opioidergic system.

Physiological and pathophysiological role of transient receptor potential canonical channels in cardiac myocytes.

Transient receptor potential canonical (TRPC) channels constitute a family of seven Ca2+ permeable ion channels, named TRPC1 to 7. These channels are abundantly expressed in the mammalian heart, yet mechanisms underlying activation of TRPC channels and their precise role in cardiac physiology remain poorly understood. In this review, we perused original literature regarding TRPC channels in cardiomyocytes. We first reviewed studies on TRPC channel assembly and sub-cellular localization across multiple species and cell types. Our review indicates that TRPC localization in cardiac cells is still a topic of controversy. We then examined common molecular biology tools used to infer on location and physiological roles of TRPC channels in the heart. We subsequently reviewed pharmacological tools used to modulate TRPC activity in both cardiac and non-cardiac cells. Suggested physiological roles in the heart include modulation of heart rate and sensing of mechanical strain. We examined studies on the contribution of TRPC to cardiac pathophysiology, mainly hypertrophic signaling. Several TRPC channels, particularly TRPC1, 3 and 6 were proposed to play a crucial role in hypertrophic signaling. Finally, we discussed gaps in our understanding of the location and physiological role of TRPC channels in cardiomyocytes. Closing these gaps will be crucial to gain a full understanding of the role of TRPC channels in cardiac pathophysiology and to further explore these channels as targets for treatments for cardiac diseases, in particular, hypertrophy.