A real-world evaluation of an herbal treatment for infantile colic reported by 1218 parents in Israel.

PURPOSE: Infantile colic (IC) or fussing and crying behavior of unknown cause, affects up to 20% of the infant population and is one of the major reasons for parents to seek medical advice. Therapeutic options are limited and the key component for IC management is parental support. Fennel-based herbal treatments were shown to significantly reduce crying time. The current study was designed to evaluate the parent perception of effectiveness of a fennel-based commercially-available herbal treatment for IC (BabyCalm, Hisunit Ltd., Israel) using a retrospective online survey. DESIGN AND METHODS: This was a real-world observational, case-control retrospective study. Parents of babies with IC symptoms, who either used the herbal product for their baby or did not use any product were invited to participate in an online survey during August-December 2019. The primary outcome was the perceived level of treatment success and symptom improvement. RESULTS: 1218 parents of IC babies (48% females, 90% up to 3 months of age, 58% exclusively breast-fed) responded to the survey of whom 771 used the treatment. Significantly fewer IC-related symptoms were reported by parents who used the product compared to those that did not. Parents perceived the treatment as successful in 65% of the cases, reporting meaningful improvements within 30 min for 69%-79% of the symptoms. CONCLUSIONS: The majority of parents perceived the herbal treatment as effective in rapid symptom reduction suggesting that this may provide a satisfactory solution for IC in the community.

Wastewater-derived organic contaminants in fresh produce: Dietary exposure and human health concerns.

Irrigation with reclaimed wastewater is a growing practice aimed at conserving freshwater sources, especially in arid and semiarid regions. Despite the apparent advantages to water management, the practice of irrigation with reclaimed wastewater exposes the agroenvironment to contaminants of emerging concern (CECs). In this report, we estimated the unintentional dietary exposure of the Israeli population (2808 participants) to CECs from consumption of produce irrigated with reclaimed wastewater using detailed dietary data obtained from a National Health and Nutrition Survey (Rav Mabat adults; 2014-2016). Human health risk analyses were conducted based on acceptable daily intake (ADI) and threshold of toxicological concern (TTC) approaches. The highest unintentional exposure to wastewater-borne CECs was found to occur through the consumption of leafy vegetables. All analyzed CECs exhibited hazard quotients <1 for the mean- and high-exposure scenarios, indicating no human health concerns. However, for the extreme exposure scenario, the anticonvulsant agents lamotrigine and carbamazepine, and the carbamazepine metabolite epoxide-carbamazepine exhibited the highest exposure levels of 29,100, 27,200, and 19,500 ng/person (70 kg) per day, respectively. These exposure levels exceeded the TTC of lamotrigine and the metabolite epoxide-carbamazepine, and the ADI of carbamazepine, resulting in hazard quotients of 2.8, 1.1, and 1.9, respectively. According to the extreme estimated scenario, consumption of produce irrigated with reclaimed wastewater (leafy vegetables in particular) may pose a threat to human health. Minimizing irrigation of leafy vegetables using reclaimed wastewater and/or improving the quality of the reclaimed wastewater using an advanced treatment would significantly reduce human dietary exposure to CECs.

Hair growth-promotion effects at the cellular level and antioxidant activity of the plant-based extract Phyllotex™.

Hair loss and predominantly female hair loss is a common dermatologic condition with serious psychosocial consequences. Effective treatments remain scarce mainly due to the multifactorial elements involved in the onset of this chronic condition. The approved drugs available are based on molecules designed towards a single pharmacological target and do not interact with the various biochemical mechanisms involved in alopecia. Phytochemical compounds and their derivatives represent a plethora of biologically active agents, which act in synergism and simultaneously activate different biochemical pathways. Here we present an herbal formulation composed of herbs, vitamins, and minerals acting on hair regrowth and hair micro vascularization. This study aimed at evaluating the potential of Phyllotex™ to treat multifactorial androgenetic alopecia (AGA) in males and females, as well as delving into its molecular mechanisms of action. In vitro studies showed that the herbal formula stimulates cell proliferation of both dermal papilla and HaCaT cells and increases the phosphorylated form of the extracellular signal-regulated kinase 1 and 2 (ERK1/2), a well-known marker for cell proliferation. Surprisingly, expression of TGF-ß1 was significantly suppressed without blocking DHT production. Additionally, the formula was able to rescue cells from the oxidative stress conditions generated by 2,2'-Azobis (2-amidinopropane) dihydrochloride (AAPH), a high oxidative agent. This data supports the potential use of this formulation as a hair growth-promoting agent for the treatment of both male and female AGA due to its multifactorial composition, which grants it the ability to cope with the different mechanisms involved in alopecia.

Bioaccessibility of Shore Magic® collagen, a low-molecular-weight collagen supplement, in different in vitro barrier models.

Hydrolyzed collagen consists of peptides, which exert important biological functions in different body systems. This study aimed at testing the biological effects of a low molecular weight collagen (LMWC), namely Shore Magic® Collagen (SMC), in a series of in vitro assays and three different in vitro barrier models with translational significance. We also compared SMC's biological activities with its trypsinized form (TSMC). SMC enhanced migration in both epithelial and endothelial cells; and increased the adhesion of epithelial cells, but surprisingly not of endothelial cells. It also diminished the tightness in the gut and blood-brain barriers in vitro while TSMC did not. SMC induced both neurogenesis and BJ epithelial cell proliferation of cells growing below the in vitro barriers. In conclusion, the intact form of SMC shows enhanced bioavailability and efficiency compared with TSMC.

Importance of ABC Transporters in Drug Development.

ATP-binding cassette (ABC) transporters are a huge family of ATP-dependent transmembrane proteins whose main function is exporting or importing substances or molecules through the cell membranes, plasma cell membrane, or inner membranes in organelles. They fulfill these functions by maintaining cell integrity, metabolism, and homeostasis. They are expressed in a variety of tissues as they transport numerous essential compounds including lipids and other signaling molecules. ABC transporters became widely studied since the discovery of their ability to carry a multitude of xenobiotics, including therapeutic drugs, and in light of the fact that they represent a hurdle for the treatment of resistant cancers. In contrast, the role of ABC transporters in neurological diseases like Alzheimer`s and Parkinson`s, depression, schizophrenia, and epilepsy remains controversial and their mechanism of action in these pathologies remains elusive, thus hindering the implementation of therapies aimed at modulating the functions of these transporters. To date, a number of natural and synthetic compounds are known to act as inhibitors, substrates, and even inducers of these transporters, being able to modulate their expression and/or function; however, their implication as therapeutic agents is far from reaching wide clinical utilization. This review highlights the importance of overcoming the challenges posed by ABC transporters in drug development.

Salivary levels of inflammatory cytokines and their association to periodontal disease in systemic lupus erythematosus patients. A case-control study.

Both Systemic Lupus Erythematosus (SLE) and periodontal disease (PD) present a similar immunological profile mainly characterized by altered cytokine levels. In this study we sought to investigate the salivary levels of inflammatory cytokines and their association with PD in SLE patients. 60 patients with SLE and 54 systemically healthy individuals underwent a full periodontal clinical examination. They were then grouped according to their periodontal status. Stimulated saliva was collected in order to evaluate the salivary levels of interferon (IFN-γ), Interleukin (IL)-10, IL-17, IL-1ß, and IL-4. Systemically healthy individuals with periodontitis (group P) presented higher levels of cytokines when compared to systemically healthy individuals, with no periodontal disease (group S) (p<0.05). Additionally, in the P group, patients presented similar levels of cytokines to those of the patients with SLE, regardless of the presence of PD (p>0.05), for most of the analyzed cytokines. There was a positive correlation in SLE patients, including IL-1ß and all periodontal clinical parameters (p<0.05), and between IL-4 and gingival bleeding index and the presence of biofilm (p<0.05). Thus, our results confirmed, that patients with PD showed higher salivary levels of cytokines and, in SLE patients, the increased levels of salivary cytokines were observed even in the absence of periodontitis. IL-1ß and IL-4 salivary levels were also positively correlated with periodontal status indicating their potential as markers of the amount and extent of periodontal damage in patients with SLE.

Human Exposure to Wastewater-Derived Pharmaceuticals in Fresh Produce: A Randomized Controlled Trial Focusing on Carbamazepine.

Fresh water scarcity has led to increased use of reclaimed wastewater as an alternative and reliable source for crop irrigation. Beyond microbiological safety, concerns have been raised regarding contamination of reclaimed wastewater by xenobiotics including pharmaceuticals. This study focuses on carbamazepine, an anticonvulsant drug which is ubiquitously detected in reclaimed wastewater, highly persistent in soil, and taken up by crops. In a randomized controlled trial we demonstrate that healthy individuals consuming reclaimed wastewater-irrigated produce excreted carbamazepine and its metabolites in their urine, while subjects consuming fresh water-irrigated produce excreted undetectable or significantly lower levels of carbamazepine. We also report that the carbamazepine metabolite pattern at this low exposure level differed from that observed at therapeutic doses. This "proof of concept" study demonstrates that human exposure to xenobiotics occurs through ingestion of reclaimed wastewater-irrigated produce, providing real world data which could guide risk assessments and policy designed to ensure the safe use of wastewater for crop irrigation.

Carryover Effects of Acute DEHP Exposure on Ovarian Function and Oocyte Developmental Competence in Lactating Cows.

We examined acute exposure of Holstein cows to di(2-ethylhexyl) phthalate (DEHP) and its carryover effects on ovarian function and oocyte developmental competence. Synchronized cows were tube-fed with water or 100 mg/kg DEHP per day for 3 days. Blood, urine and milk samples were collected before, during and after DEHP exposure to examine its clearance pattern. Ovarian follicular dynamics was monitored through an entire estrous cycle by ultrasonographic scanning. Follicular fluids were aspirated from the preovulatory follicles on days 0 and 29 of the experiment and analyzed for phthalate metabolites and estradiol concentration. The aspirated follicular fluid was used as maturation medium for in-vitro embryo production. Findings revealed that DEHP impairs the pattern of follicular development, with a prominent effect on dominant follicles. The diameter and growth rate of the first- and second-wave dominant follicles were lower (P < 0.05) in the DEHP-treated group. Estradiol concentration in the follicular fluid was lower in the DEHP-treated group than in controls, and associated with a higher number of follicular pathologies (follicle diameter >25 mm). The pattern of growth and regression of the corpus luteum differed between groups, with a lower volume in the DEHP-treated group (P < 0.05). The follicular fluid aspirated from the DEHP-treated group, but not the controls, contained 23 nM mono(2-ethylhexyl) phthalate. Culturing of cumulus oocyte complexes in the follicular fluid aspirated from DEHP-treated cows reduced the proportion of oocytes progressing to the MII stage, and the proportions of 2- to 4-cell-stage embryos (P < 0.04) and 7-day blastocysts (P < 0.06). The results describe the risk associated with acute exposure to DEHP and its deleterious carryover effects on ovarian function, nuclear maturation and oocyte developmental competence.

Irrigation of root vegetables with treated wastewater: evaluating uptake of pharmaceuticals and the associated human health risks.

To meet mounting water demands, treated wastewater has become an important source of irrigation. Thus, contamination of treated wastewater by pharmaceutical compounds (PCs) and the fate of these compounds in the agricultural environment are of increasing concern. This field study aimed to quantify PC uptake by treated wastewater-irrigated root crops (carrots and sweet potatoes) grown in lysimeters and to evaluate potential risks. In both crops, the nonionic PCs (carbamazepine, caffeine, and lamotrigine) were detected at significantly higher concentrations than ionic PCs (metoprolol, bezafibrate, clofibric acid, diclofenac, gemfibrozil, ibuprofen, ketoprofen, naproxen, sulfamethoxazole, and sildenafil). PCs in leaves were found at higher concentrations than in the roots. Carbamazepine metabolites were found mainly in the leaves, where the concentration of the metabolite 10,11-epoxycarbamazepine was significantly higher than the parent compound. The health risk associated with consumption of wastewater-irrigated root vegetables was estimated using the threshold of toxicological concern (TTC) approach. Our data show that the TTC value of lamotrigine can be reached for a child at a daily consumption of half a carrot (∼60 g). This study highlights that certain PCs accumulated in edible organs at concentrations above the TTC value should be categorized as contaminants of emerging concern.

Cannabidiol inhibits growth and induces programmed cell death in kaposi sarcoma-associated herpesvirus-infected endothelium.

Kaposi sarcoma is the most common neoplasm caused by Kaposi sarcoma-associated herpesvirus (KSHV). It is prevalent among the elderly in the Mediterranean, inhabitants of sub-Saharan Africa, and immunocompromised individuals such as organ transplant recipients and AIDS patients. Current treatments for Kaposi sarcoma can inhibit tumor growth but are not able to eliminate KSHV from the host. When the host's immune system weakens, KSHV begins to replicate again, and active tumor growth ensues. New therapeutic approaches are needed. Cannabidiol (CBD), a plant-derived cannabinoid, exhibits promising antitumor effects without inducing psychoactive side effects. CBD is emerging as a novel therapeutic for various disorders, including cancer. In this study, we investigated the effects of CBD both on the infection of endothelial cells (ECs) by KSHV and on the growth and apoptosis of KSHV-infected ECs, an in vitro model for the transformation of normal endothelium to Kaposi sarcoma. While CBD did not affect the efficiency with which KSHV infected ECs, it reduced proliferation and induced apoptosis in those infected by the virus. CBD inhibited the expression of KSHV viral G protein-coupled receptor (vGPCR), its agonist, the chemokine growth-regulated protein α (GRO-α), vascular endothelial growth factor receptor 3 (VEGFR-3), and the VEGFR-3 ligand, vascular endothelial growth factor C (VEGF-C). This suggests a potential mechanism by which CBD exerts its effects on KSHV-infected endothelium and supports the further examination of CBD as a novel targeted agent for the treatment of Kaposi sarcoma.

Nonpsychotropic cannabinoids, abnormal cannabidiol and canabigerol-dimethyl heptyl, act at novel cannabinoid receptors to reduce intraocular pressure.

The objective of our study was to examine the pharmacology of the intraocular pressure (IOP)-lowering actions of the behaviorally inactive cannabinoids, abnormal cannabidiol (abn-CBD), and a cannabigerol analog, cannabigerol-dimethyl heptyl (CBG-DMH), in comparison to that of the nonselective cannabinoid 1 receptor (CB(1)R) and CB(2)R agonist, WIN55,212-2, in Brown Norway rats. The IOP was measured noninvasively using a hand-held tonometer in nonanesthetized animals. The IOP measurements were taken every 15 min for a period of 2 h after drug administration. All drugs were administered via intraperitoneal (i.p.) injections, and abn-CBD and CBG-DMH were also given topically. Both abn-CBD and CBG-DMH reduced IOP when administrated i.p. at doses of ≥2.5 mg/kg or topically at concentrations of 1%-2%. The IOP-lowering effects of abn-CBD and CBG-DMH were reduced by i.p. administration of O-1918 (2.5 mg/kg), a selective antagonist of the abn-CBD-sensitive cannabinoid-related receptor (CBx), but were unaffected by the CB(1)R antagonist, AM251 (2.5 mg/kg), or the CB(2)R antagonist, AM630 (2.5 mg/kg). In contrast, the IOP-lowering action of WIN55,212-2 was completely blocked by the CB(1)R-selective antagonist, AM251, and was unaffected by the CBx receptor antagonist, O-1918. However, similar to the nonpsychotropic cannabinoids, the ocular hypotensive actions of WIN55,212-2 were also insensitive to block by the CB(2)R antagonist, AM630. Consistent with this, the selective CB(2)R agonist, HU-308 (2 mg/kg) failed to reduce IOP in Brown Norway rats. Concurrent application of a dose of WIN55,212-2 that was subthreshold to reduce IOP (0.25 mg/kg), together with a topical dose of either abn-CBD (0.5%) or CBG-DMH (0.25%), respectively, potentiated the ocular hypotensive effect of either compound applied alone. This study demonstrates that the atypical cannabinoid, abn-CBD, and the cannabigerol analog, CBG-DMH, decrease IOP in the normotensive Brown Norway rat eye independent of CB(1)R or CB(2)R activation, via activation of CBx receptors. The enhanced decrease in IOP seen after coapplication of the CB(1)R agonist, WIN55,212-2, together with either abn-CBD or CBG-DMH, respectively, further suggests that the ocular pharmacodynamics of abn-CBD and CBG-DMH are mediated by receptor targets distinct from CB(1)R. These results indicate that both CBG-DMH and abn-CBD have the potential for further investigation as novel ocular hypotensive cannabinoids devoid of CB(1)R-mediated side-effects.

N-arachidonoyl L-serine, an endocannabinoid-like brain constituent with vasodilatory properties.

The endocannabinoid N-arachidonoyl ethanolamine (anandamide), found both in the CNS and in the periphery, plays a role in numerous physiological systems. One might expect that the chemically related N-arachidonoyl-L-serine (ARA-S) could also be formed alongside anandamide. We have now isolated ARA-S from bovine brain and elucidated its structure by comparison with synthetic ARA-S. Contrary to anandamide, ARA-S binds very weakly to cannabinoid CB1 and CB2 or vanilloid TRPV1 (transient receptor potential vanilloid 1) receptors. However, it produces endothelium-dependent vasodilation of rat isolated mesenteric arteries and abdominal aorta and stimulates phosphorylation of p44/42 mitogen-activated protein (MAP) kinase and protein kinase B/Akt in cultured endothelial cells. ARA-S also suppresses LPS-induced formation of TNF-alpha in a murine macrophage cell line and in wild-type mice, as well as in mice deficient in CB1 or CB2 receptors. Many of these effects parallel those reported for abnormal cannabidiol (Abn-CBD), a synthetic agonist of a putative novel cannabinoid-type receptor. Hence, ARA-S may represent an endogenous agonist for this receptor.

Evidence that (-)-7-hydroxy-4'-dimethylheptyl-cannabidiol activates a non-CB(1), non-CB(2), non-TRPV1 target in the mouse vas deferens.

Previous experiments showed that R-(+)-WIN55212-induced inhibition of electrically-evoked contractions of mouse vasa deferentia could be antagonized by cannabidiol in a manner that appeared to be competitive but not to involve direct competition for established cannabinoid receptors. We have now discovered that (-)-7-hydroxy-4'-dimethylheptyl-cannabidiol (7-OH-DMH-CBD) inhibits electrically-evoked contractions of the vas deferens (EC(50)=13.3 nM). This it appeared to do by acting on prejunctional neurones as 100 nM 7-OH-DMH-CBD did not attenuate contractile responses to phenylephrine or beta,gamma-methylene-ATP. Although 7-OH-DMH-CBD was antagonized by SR141716A, it was less susceptible to antagonism by this CB(1) receptor antagonist than R-(+)-WIN55212. 7-OH-DMH-CBD was also antagonized by cannabidiol (1 microM; apparent K(B)=222.2 nM) but not by the CB(2) receptor antagonist, SR144528 (32 nM), or by naloxone (300 nM), ruthenium red (1 microM) or capsazepine (10 microM). Yohimbine (100 nM) enhanced the ability of 7-OH-DMH-CBD to inhibit electrically-evoked contractions. R-(+)-WIN55212 was also potentiated by 100 nM yohimbine, possibly reflecting ongoing sequestration of G(i/o) proteins from CB(1) receptors by alpha(2)-adrenoceptors. Our results suggest that 7-OH-DMH-CBD may activate a neuronal target in the vas deferens that is not a CB(1), CB(2), TRPV1, opioid or alpha(2)-adrenergic receptor but do not exclude the possibility that it also activates CB(1) receptors.