Search Results (21)

Background and Clinical Significance: The recreational use of semisynthetic cannabinoids (SSCs) is increasing, and SSCs account for more than 40% of all new substances reported at the European level. Although designed to mimic the effects of tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, evidence suggests that certain SSCs may elicit stronger, prolonged and unintended pharmacological effects. SSCs are easily accessible, particularly via online retailers, but in some countries, SSCs are also sold in convenience stores or specialty stores selling legal low-THC or cannabidiol (CBD) products. Often, SSCs are sold as “legal highs” and are found in various forms, including herbal mixtures (spice), vape products, and edibles such as cookies and candies, specifically targeting young users, including children. The products are frequently mislabeled and sold as souvenirs or aromatic potpourri to bypass regulations. Case Presentation: We present a case of a male in his early forties who was admitted to the Emergency Department due to noticeable deficits in alertness and responsiveness after recreational ingestion of two cannabis cookies labeled to contain 40 mg “CC9” and a bite of a gummy with unknown contents. The patient experienced vomiting and visual problems, and suffered from nine days of cognitive and physical impairment. HHC-C9, a novel SSC, was detected in blood through forensic toxicological analysis. Conclusions: Recreational use of HHC-C9 can cause vomiting, visual disturbances, and drowsiness, potentially requiring hospital treatment. Potency, clinical effects, and toxicity of SSCs can vary significantly, and in combination with easy accessibility, SSCs pose a potential risk of intoxication to unaware consumers. Full article

The enhancement of stress resistance is crucial for delaying aging and extending a healthy lifespan. Traditional Chinese medicine (TCM), a cherished treasure of Chinese heritage, has shown potential in mitigating stress and promoting longevity. This study integrates network pharmacology and in vivo analysis to investigate the mechanisms and effects of Curcumae Rhizoma (C. Rhizoma), known as “E Zhu” in Chinese. Ultra-Performance Liquid Chromatography–Tandem Mass Spectrometry (UPLC-MS/MS) identified 10 active compounds in its aqueous extract, interacting with 128 stress-related targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed pathways such as stress response, FoxO signaling, and insulin resistance. In Caenorhabditis elegans, 10 mg/mL of C. Rhizoma aqueous extract improved resistance to UV, thermal, oxidative, and pathogen-induced stress, extending lifespan in a dose-dependent manner. Mechanistically, it reduced reactive oxygen species (ROS), increased superoxide dismutase (SOD) activity, and enhanced UV resistance via the insulin/IGF-1 pathway and DAF-16 translocation. Molecular docking highlighted hexahydrocurcumin (HHC) and related compounds as key bioactives. Furthermore, we also observed that C. Rhizoma aqueous extract significantly extended both the lifespan and healthspan of nematodes. These findings highlight the potential of C. Rhizoma in stress mitigation and longevity promotion, offering valuable insights into the therapeutic applications of TCM. Full article

Recently, hexahydrocannabinol (HHC) was posed under strict control in Europe due to the increasing HHC-containing material seizures. The lack of analytical methods in clinical laboratories to detect HHC and its metabolites in biological matrices may result in related intoxication underreporting. We developed and validated a comprehensive GC-MS/MS method to quantify 9(R)-HHC, 9(S)-HHC, 9αOH-HHC, 9βOH-HHC, 8(R)OH-9(R)-HHC, 8(S)OH-9(S)HHC, 11OH-9(R)HHC, 11OH-9(S)HHC, 11nor-carboxy-9(R)-HHC, and 11nor-carboxy-9(S)-HHC in whole blood, urine, and oral fluid. A novel QuEChERS extraction protocol was optimized selecting the best extraction conditions suitable for all the three matrices. Urine and blood were incubated with β-glucuronidase at 60 °C for 2 h. QuEChERS extraction was developed assessing different ratios of Na₂SO₄:NaCl (4:1, 2:1, 1:1, w/w) to be added to 200 µL of any matrix added with acetonitrile. The chromatographic separation was achieved on a 7890B GC with an HP-5ms column, (30 m, 0.25 mm × 0.25 µm) in 12.50 min. The analytes were detected with a triple-quadrupole mass spectrometer in the MRM mode. The method was fully validated following OSAC guidelines. The method showed good validation parameters in all the matrices. The method was applied to ten real samples of whole blood (n = 4), urine (n = 3), and oral fluid (n = 3). 9(R)-HHC was the prevalent epimer in all the samples (9(R)/9(S) = 2.26). As reported, hydroxylated metabolites are proposed as urinary biomarkers, while carboxylated metabolites are hematic biomarkers. Furthermore, 8(R)OH-9(R)HHC was confirmed as the most abundant metabolite in all urine samples. Full article

Yellowing leaves are ideal materials for studying the metabolic pathways of photosynthetic pigment chloroplast development, and the mechanism of photosynthetic systems. Here, we obtained a triploid material HCC (2n = 3x = 26), which was derived from hybridization between the artificial tetraploid Cucumis × hytivus (2n = 4x = 38, HHCC) and the cultivated cucumber Cucumis sativus (2n = 2x = 14, CC), and this triploid HCC showed obvious leaf yellowing characteristics. Phenotypic observation results showed that chloroplast development was impaired, the chlorophyll content decreased, and photosynthesis decreased in yellowing HCC leaves. The transcriptome results indicated that HCC-GLK is significantly downregulated in HCC and participates in the regulation of leaf yellowing. GO enrichment analysis revealed that differential genes were enriched in the heme binding and tetrapyrrole binding pathways related to leaf color. KEGG enrichment analysis revealed that differential genes were predominantly enriched in photosynthesis-related pathways. The experimental results of VIGS and yeast hybridization showed that silencing the GLK gene can induce leaf yellowing in cucumber plants, and the GLK protein can affect plant chloroplast development by interacting with the CAB3C protein (light-harvesting chlorophyll a/b binding) in the plant chlorophyll synthesis pathway. The current findings have not only enhanced our understanding of the regulatory mechanism of the GLK transcription factor in cucumber but also introduced novel insights and directions for investigating the molecular mechanism underlying polyploid leaf yellowing. Full article

Migmatites and partial melts are exposed in both the lower and upper package of the Higher Himalayan Crystallines (HHC) thrust sheet within the Sikkim Himalayas. Zircon monazite and quartz oxygen isotopic ratios from Yumthang Valley, North Sikkim, and Rathong Chuu, West Sikkim, have been used to identify their sources and equilibrium conditions. Monazites show homogeneous growth, whereas zircons show growth rings. U-Th-Pb data on monazite only indicate the latest metamorphic event. However, zircons show metamorphic rim growth between 36 and 24 Ma over their detrital core with trailing growth from 22 Ma to 15 Ma. Pervasive fluids have been interpreted in coeval development during metamorphism, as shown by monazite and zircon c. 30 Ma. The Th/U ratio of zircon is higher and variable with weak residual zoning in the samples from higher elevations. Quartz–metamorphic zircon oxygen fractionation suggests Teq > 600 °C, while quartz–monazite fractionation shows the same or lower temperatures. Multiple sources of melts in the HHC (even along a single valley) have been observed by δ¹⁸O of 7‰ to 10‰ in zircon and 5‰ to 9‰ in monazite. Zircon and monazite generated in the same rock have similar δ18O values. Monazite grown ~20 Ma in the lower elevation sample had a low δ¹⁸O, suggesting interaction with an external fluid. Full article

Our aim was to carry out a qualitative and quantitative synthesis of the influence of CCR5 genetic variants on Chagas disease (CD) through a systematic review. A total of 1197 articles were analyzed, and eleven were included in the review. A meta-analysis was conducted along with principal component analyses (PCAs). The polymorphisms found were analyzed using the SNP2TFBS tool to identify possible variants that influence the interaction with gene binding sites. Eleven studied variants were identified: rs2856758, rs2734648, rs1799987, rs1799988, rs41469351, rs1800023, rs1800024, Δ32/rs333, rs3176763, rs3087253 and rs11575815. The studies analyzed were published between 2001 and 2019, conducted in Argentina, Brazil, Spain, Colombia and Venezuela, and included Argentine, Brazilian, Colombian, Peruvian and Venezuelan patients. Eight polymorphisms were subjected to the meta-analysis, of which six were associated with the development of the cardiac form of CD: rs1799987—G/G and G/A in the dominance model and G/G in the recessiveness model; rs2856758—A/G in the codominance model; rs2734648—T/T and T/G in the dominance model; rs1799988—T/T in both the codominance and recessiveness models; rs1800023—G allele and the G/G genotype in the codominance and recessiveness models, and the G/G and G/A genotypes in the dominance model; and rs1800024—T allele. The PCA analyses were able to indicate the relationships between the alleles and the genotypes of the polymorphisms. The SNP2TFBS tool identified rs1800023 as an influencer of the Spi1 transcription factor (p < 0.05). A correlation was established between the alleles associated with the cardiac form of CD in this review, members of the C haplotype of the gene (HHC–TGTG), and the cardiac form of CD. Full article

Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare, frequently misdiagnosed, autosomal dominant disease caused by mutations in the FTL gene. It causes bilateral pediatric cataract and hyperferritinemia without iron overload. The objective of this case series, describing three Brazilian families, is to increase awareness of HHCS, as well as to discuss possible phenotypic interactions with concurrent mutations in HFE, the gene associated with autosomal recessive inheritance hereditary hemochromatosis. Whole-exome sequencing was performed in eight individuals with HHCS from three different families, as well as one unaffected member from each family for trio analysis—a total of eleven individuals. Ophthalmological and clinical genetic evaluations were conducted. The likely pathogenic variant c.-157G>A in FTL was found in all affected individuals. They presented slowly progressing bilateral cataract symptoms before the age of 14, with a phenotype of varied bilateral diffuse opacities. Hyperferritinemia was present in all affected members, varying from 971 ng/mL to 4899 ng/mL. There were two affected individuals with one concurrent pathogenic variant in HFE (c.187C>G, p.H63D), who were also the ones with the highest values of serum ferritin in our cohort. Few publications describe individuals with pathogenic mutations in both FTL and HFE genes, and further studies are needed to assess possible phenotypic interactions causing higher values of hyperferritinemia. Full article

Hexahydrocurcumin-encapsulated chitosan nanoparticles (HHC-CS-NPs) were formulated by oil-in-water emulsification and ionotropic gelation and optimized using the Box–Behnken design. The particle size, zeta potential, and encapsulation efficiency of the optimized HHC-CS-NPs were 256 ± 14 nm, 27.3 ± 0.7 mV, and 90.6 ± 1.7%, respectively. The TEM analysis showed a spherical shape and a dense structure with a narrow size distribution. The FT-IR analysis indicated no chemical interaction between the excipients and the drugs in the nanoparticles, but the existence of the drugs was molecularly dispersed in the nanoparticle matrices. The drug release profile showed a preliminary burst release followed by a sustained release under simulated gastrointestinal (GI) and physiological conditions. A stability study suggested that the HHC-CS-NPs were stable under UV light, simulated GI, and body fluids. The in vitro bioaccessibility and bioavailability of the HHC-CS-NPs were 2.2 and 6.1 times higher than those of the HHC solution, respectively. The in vitro evaluation of the antioxidant, anti-inflammatory, and cytotoxic effects of the optimized HHC-CS-NPs demonstrated that the CS-NPs significantly improved the biological activities of HHC in radical scavenging, hemolysis protection activity, anti-protein denaturation, and cytotoxicity against MDA-MB-231 breast cancer cells. Western blot analysis showed that the apoptotic protein expression of Bax, cytochrome C, caspase-3, and caspase-9, were significantly up-regulated, whereas the anti-apoptotic protein Bcl-2 expression was down-regulated in the HHC-CS-NP-treated cells. Our findings suggest that the optimized HHC-CS-NPs can be further developed as an efficient oral treatment for breast cancer. Full article

The formation and the blockage of plant equipment such as heat exchangers by heavy hydrocarbon (HHC) solids is an inherent risk in cryogenic natural gas processing. The accuracy of the gas mixture’s compositional characterization significantly impacts the reliability of solid formaiton temperature predictions. Recently, we showed that complete characterization of the mixture is necessary to obtain accurate predictions of the melting temperature, as current methods based on pseudocomponent characterizations of HHCs are inadequate. Here, we present an improved method of characterizing HHCs that represents each pseudocomponent up to C₁₄₊ by a paraffinic, isoparaffinic, naphthenic and aromatic (PINA) composition and allocates an associated defined component to represent these sub-fractions. This new, extended PINA-based characterization of HHC pseudocomponents is derived from 46 different pipeline natural gas samples, and the method is validated against three representative gas samples that were fully characterized. The melting temperatures of the three gas samples based on their full characterizations are 263.2 K (14.1 °F), 260.1 K (8.5 °F) and 248.3 K (−12.8 °F), respectively. Predictions made with the new method match these within (1 to 2) K, while previous correlation methods under-predict them by (10 to 20) K. The improved performance arises from (1) the selection of suitable discrete components to represent each PINA fraction within a pseudocomponent, (2) the more representative distribution of PINA fractions as a function of carbon number, and (3) the use of discrete components to represent the pseudocomponent’s thermodynamic properties in both the fluid and solid phases. These results show how the new characterization method can reliably predict HHC freeze-out conditions, particularly when a full compositional analysis is unavailable. Future research should aim to test the new method on natural gas samples from regions other than the US Gulf Coast. Full article

For patients with inoperable huge hepatocellular carcinoma (H-HCC, tumor size ≥10 cm), treatment options are limited. This study aimed to evaluate the characteristics and outcomes of patients with H-HCC who use Chinese herbal medicine (CHM). Multi-institutional cohort data were obtained from the Chang Gung Research Database (CGRD) between 1 January 2002 and 31 December 2018. All patients were followed up for 3 years or until the occurrence of death. Characteristics of CHM users and risk of all-cause mortality were assessed, and core CHMs with potential pharmacologic pathways were explored. Among 1618 patients, clinical features of CHM users (88) and nonusers (1530) were similar except for lower serum α-fetoprotein (AFP) and higher serum albumin levels in CHM users. CHM users had significantly higher 3 year overall survival rates (15.0% vs. 9.7%) and 3 year liver-specific survival rates (13.4% vs. 10.7%), about 3 months longer median survival time, and lower risk of all-cause mortality. Core CHMs were discovered from the prescriptions, including Hedyotis diffusa Willd combined with Scutellaria barbata D.Don, Salvia miltiorrhiza Bunge., Curcuma longa L., Rheum palmatum L., and Astragalus mongholicus Bunge. CHM use appears safe and is possibly beneficial for inoperable H-HCC patients; however, further clinical trials are still required. Full article

The prognostic value of the tumor growth rate (TGR) in huge hepatocellular carcinoma (HHCC) patients treated with transcatheter arterial chemoembolization (TACE) as an initial treatment remains unclear. This two-center retrospective study was conducted in 97 patients suffering from HHCC. Demographic characteristics, oncology characteristics, and some serological markers were collected for analysis. The TGR was significantly linear and associated with the risk of death when applied to restricted cubic splines. The optimal cut-off value of TGR was −8.6%/month, and patients were divided into two groups according to TGR. Kaplan–Meier analysis showed that the high-TGR group had a poorer prognosis. TGR (hazard ratio (HR), 2.06; 95% confidence interval (CI), 1.23–3.43; p = 0.006), presence of portal vein tumor thrombus (PVTT) (HR, 1.93; 95% CI, 1.13–3.27; p = 0.016), and subsequent combination therapy (HR, 0.59; 95% CI, 0.35–0.99; p = 0.047) were independent predictors of OS in the multivariate analysis. The model with TGR was superior to the model without TGR in the DCA analysis. Patients who underwent subsequent combination therapy showed a longer survival in the high-TGR group. This study demonstrated that higher TGR was associated with a worse prognosis in patients with HHCC. These findings will distinguish patients who demand more personalized combination therapy and rigorous surveillance. Full article

Practicing physical activity in a hot and humid climate (HHC) is becoming increasingly common due to anthropogenic climate change and the growing number of international sports events held in warm countries. The aim of this study was to understand the physiological and psychological effects of breathing two air temperatures during cycling exercise in HHC. Ten male athletes performed two sessions of exercise in HHC (T°: 32.0 ± 0.5 °C, relative humidity: 78.6 ± 0.7%) during which they breathed hot air (HA, 33.2 ± 0.06 °C) or temperate air (TA, 22.6 ± 0.1 °C). Each session was composed of 30 min of pre-fatigue cycling at constant intensity, followed by a 10 min self-regulated performance. During pre-fatigue, TA induced a better feeling score and a lower rating of perceived effort (respectively, +0.9 ± 0.2, p < 0.05; 1.13 ± 0.21; p < 0.05) with no changes in physiological parameters. During performance, oxygen consumption and mechanical workload were increased by TA (respectively, +0.23 ± 0.1 L min⁻¹, p < 0.05 and +19.2 ± 6.1 W, p < 0.01), whereas no significant differences were observed for psychological parameters. Reducing the breathed air temperature decreased the discomfort induced by HHC during exercise and increased the performance capacity during self-regulated exercise. Thus, breathed air temperature perception is linked to the hardship of training sessions and directly contributes to the performance decrease in HHC. Full article

Hepatocellular carcinoma (HCC) accounts for 75–85% of primary liver malignancies, and elderlies have the highest incidence rates. Direct-acting antiviral agents (DAAs) have shown satisfying results in terms of HCV sustained viral response (SVR). However, data regarding HCC risk post-DAA-SVR is still conflicting. This study aims to consider HCC onset in moderate underlying liver disease. We conducted a retrospective study on 227 chronically infected patients (cHCV), treated with DAAs. Patients were divided into three groups: “de novo occurrent HCC”, “recurrent HCC”, and “without HCC”. Fifty-six patients aged <65 years (yDAA) were studied separately. HCC patients aged ≥65 years (DAA-HCC) were compared to a historical group of 100 elderly HCC patients, treated with peginterferon (Peg-IFN) ± ribavirin antiviral agents, non-SVR (hHCC). The HCC prevalence in DAA patients was 32.75%: “de novo occurrent’’ 18.13% and “recurrent’’ 14.62%, despite 42.85% of them having no fibrosis to mild or moderate fibrosis (F0-F1-F2). yDAA showed 5.36% “de novo occurrent” HCC. Curative procedure rates were compared between DAA-HCC and hHCC at the first and at recurrent presentation (22 (39.29%) vs. 72 (72%); 17 (30.36%) vs. 70 (70%), respectively (p < 0.001)). No significant difference was found in 3-year OS (p = 0.6). However, in cause-specific mortality analysis, HCC-related death was higher in the DAA-treated group, whereas cirrhosis-related death was more common in the historical group (p = 0.0288), considering together the two causes of death. A more accurate patient stratification according to multifactorial and new diagnostic investigations identifying HCC risk might allow an improvement in management and access to curative therapies. Full article

Hedgehog (HH) is a highly conserved secretory signalling protein family mainly involved in embryonic development, homeostasis, and tumorigenesis. HH is generally synthesised as a precursor, which subsequently undergoes autoproteolytic cleavage to generate an amino-terminal fragment (HH-N), mediating signalling, and a carboxyl-terminal fragment (HH-C), catalysing the auto-processing reaction. The N-terminal region of HH-N is required for HH multimer formation to promote signal transduction, whilst the functions of the C-terminal region of HH-N remain ambiguous. This study focused on Indian Hedgehog (IHH), a member of the HH family, to explore the functions of the C-terminal region of the amino-terminal fragment of IHH (IHH-N) via protein truncation, cell-based assays, and 3D structure prediction. The results revealed that three amino acids, including S195, A196, and A197, were crucial for the multimer formation by inserting the mutual binding of IHH-N proteins. K191, S192, E193, and H194 had an extremely remarkable effect on IHH self-cleavage. In addition, A198, K199, and T200 evidently affected the stability of IHH-N. This work suggested that the C-terminus of IHH-N played an important role in the physiological function of IHH at multiple levels, thus deepening the understanding of HH biochemical properties. Full article

In this study at the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of quantum-mechanical theory it was explored conformational variety of the isolated quercetin molecule due to the mirror-symmetrical hindered turnings of the O3H, O5H and O7H hydroxyl groups, belonging to the A and C rings, around the exocyclic C–O bonds. These dipole active conformational transformations proceed through the 72 transition states (TSs; C₁ point symmetry) with non-orthogonal orientation of the hydroxyl groups relatively the plane of the A or C rings of the molecule (HO7C7C8/HO7C7C6 = ±(89.9–93.3), HO5C5C10 = ±(108.9–114.4) and HO3C3C4 = ±(113.6–118.8 degrees) (here and below signs ‘±’ corresponds to the enantiomers)) with Gibbs free energy barrier of activation ΔΔG_TS in the range 3.51–16.17 kcal·mol⁻¹ under the standard conditions (T = 298.1 K and pressure 1 atm): ΔΔG_TS^O7H (3.51–4.27) < ΔΔG_TS^O3H (9.04–11.26) < ΔΔG_TS^O5H (12.34–16.17 kcal mol⁻¹). Conformational dynamics of the O3H and O5H groups is partially controlled by the intramolecular specific interactions O3H…O4, C2′/C6′H…O3, O3H…C2′/C6′, O5H…O4 and O4…O5, which are flexible and cooperative. Dipole-active interconversions of the enantiomers of the non-planar conformers of the quercetin molecule (C₁ point symmetry) is realized via the 24 TSs with C₁ point symmetry (HO3C3C2C1 = ±(11.0–19.1), HC2′/C6′C1′C2 = ±(0.6–2.9) and C3C2C1′C2′/C3C2C1′C6′ = ±(1.7–9.1) degree; ΔΔG_TS = 1.65–5.59 kcal·mol⁻¹), which are stabilized by the participation of the intramolecular C2′/C6′H…O1 and O3H…HC2′/C6′ H-bonds. Investigated conformational rearrangements are rather quick processes, since the time, which is necessary to acquire thermal equilibrium does not exceed 6.5 ns. Full article