CC Chemokine Family Members' Modulation as a Novel Approach for Treating Central Nervous System and Peripheral Nervous System Injury-A Review of Clinical and Experimental Findings.

Despite significant progress in modern medicine and pharmacology, damage to the nervous system with various etiologies still poses a challenge to doctors and scientists. Injuries lead to neuroimmunological changes in the central nervous system (CNS), which may result in both secondary damage and the development of tactile and thermal hypersensitivity. In our review, based on the analysis of many experimental and clinical studies, we indicate that the mechanisms occurring both at the level of the brain after direct damage and at the level of the spinal cord after peripheral nerve damage have a common immunological basis. This suggests that there are opportunities for similar pharmacological therapeutic interventions in the damage of various etiologies. Experimental data indicate that after CNS/PNS damage, the levels of 16 among the 28 CC-family chemokines, i.e., CCL1, CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL11, CCL12, CCL17, CCL19, CCL20, CCL21, and CCL22, increase in the brain and/or spinal cord and have strong proinflammatory and/or pronociceptive effects. According to the available literature data, further investigation is still needed for understanding the role of the remaining chemokines, especially six of them which were found in humans but not in mice/rats, i.e., CCL13, CCL14, CCL15, CCL16, CCL18, and CCL23. Over the past several years, the results of studies in which available pharmacological tools were used indicated that blocking individual receptors, e.g., CCR1 (J113863 and BX513), CCR2 (RS504393, CCX872, INCB3344, and AZ889), CCR3 (SB328437), CCR4 (C021 and AZD-2098), and CCR5 (maraviroc, AZD-5672, and TAK-220), has beneficial effects after damage to both the CNS and PNS. Recently, experimental data have proved that blockades exerted by double antagonists CCR1/3 (UCB 35625) and CCR2/5 (cenicriviroc) have very good anti-inflammatory and antinociceptive effects. In addition, both single (J113863, RS504393, SB328437, C021, and maraviroc) and dual (cenicriviroc) chemokine receptor antagonists enhanced the analgesic effect of opioid drugs. This review will display the evidence that a multidirectional strategy based on the modulation of neuronal-glial-immune interactions can significantly improve the health of patients after CNS and PNS damage by changing the activity of chemokines belonging to the CC family. Moreover, in the case of pain, the combined administration of such antagonists with opioid drugs could reduce therapeutic doses and minimize the risk of complications.

Design, Synthesis and Biological Evaluation of Novel Phenyl-Substituted Naphthoic Acid Ethyl Ester Derivatives as Strigolactone Receptor Inhibitor.

Strigolactones (SLs) are plant hormones that regulate several key agronomic traits, including shoot branching, leaf senescence, and stress tolerance. The artificial regulation of SL biosynthesis and signaling has been considered as a potent strategy in regulating plant architecture and combatting the infection of parasitic weeds to help improve crop yield. DL1b is a previously reported SL receptor inhibitor molecule that significantly promotes shoot branching. Here, we synthesized 18 novel compounds based on the structure of DL1b. We performed rice tillering activity assay and selected a novel small molecule, C6, as a candidate SL receptor inhibitor. In vitro bioassays demonstrated that C6 possesses various regulatory functions as an SL inhibitor, including inhibiting germination of the root parasitic seeds Phelipanche aegyptiaca, delaying leaf senescence and promoting hypocotyl elongation of Arabidopsis. ITC analysis and molecular docking experiments further confirmed that C6 can interact with SL receptor proteins, thereby interfering with the binding of SL to its receptor. Therefore, C6 is considered a novel SL receptor inhibitor with potential applications in plant architecture control and prevention of root parasitic weed infestation.

Supermolecular Confined Silicon Phosphorescence Nanoprobes for Time-Resolved Hypoxic Imaging Analysis.

Room temperature phosphorescence (RTP) nanoprobes play crucial roles in hypoxia imaging due to their high signal-to-background ratio (SBR) in the time domain. However, synthesizing RTP probes in aqueous media with a small size and high quantum yield remains challenging for intracellular hypoxic imaging up to present. Herein, aqueous RTP nanoprobes consisting of naphthalene anhydride derivatives, cucurbit[7]uril (CB[7]), and organosilicon are reported via supermolecular confined methods. Benefiting from the noncovalent confinement of CB[7] and hydrolysis reactions of organosilicon, such small-sized RTP nanoprobes (5-10 nm) exhibit inherent tunable phosphorescence (from 400 to 680 nm) with microsecond second lifetimes (up to ∼158.7 µs) and high quantum yield (up to ∼30%). The as-prepared RTP nanoprobes illustrate excellent intracellular hypoxia responsibility in a broad range from ∼0.1 to 21% oxygen concentrations. Compared to traditional fluorescence mode, the SBR value (∼108.69) of microsecond-range time-resolved in vitro imaging is up to 2.26 times greater in severe hypoxia (<0.1% O2), offering opportunities for precision imaging analysis in a hypoxic environment.

Metahemoglobinemia y hemólisis intravascular aguda después de una intoxicación por naftaleno en un paciente pediátrico / Methemoglobinemia and acute intravascular hemolysis after naphthalene poisoning in a pediatric patient

La intoxicación por naftaleno es poco frecuente en los niños. Es causada por la ingesta, la inhalación o el contacto con la piel de sustancias que contienen naftaleno. Los pacientes suelen tener orina de color marrón oscuro, diarrea acuosa y vómito bilioso. Los signos incluyen fiebre, taquicardia, hipotensión y valores bajos en la oximetría de pulso, incluso con oxigenoterapia. Los análisis de sangre detectan anemia hemolítica, metahemoglobinemia, insuficiencia renal e hiperbilirrubinemia. Además del tratamiento sintomático, se hacen transfusiones de eritrocitos y se les administran ácido ascórbico, azul de metileno y N-acetilcisteína. En este artículo, presentamos el caso de un paciente masculino de 23 meses de edad con metahemoglobinemia y hemólisis intravascular aguda que recibió atención en la unidad de cuidados intensivos durante cinco días por intoxicación por naftaleno. Si bien la intoxicación por naftaleno es muy poco frecuente, tiene consecuencias mortales y se debe ejercer precaución con su uso y venta.

Poisoning by naphthalene is uncommon in children. It is a type of poisoning brought on by ingesting, inhaling, or coming into touch with naphthalene-containing substances on the skin. Patients typically present with an initial onset of dark brown urine, watery diarrhea, and bile vomit. The signs include fever, tachycardia, hypotension, and low pulse oximetry readings even with oxygen support. Hemolytic anemia, methemoglobinemia, renal failure, and hyperbilirubinemia are all detected in blood tests. Erythrocyte transfusion, ascorbic acid, methylene blue, and N-acetylcysteine (NAC) therapies are provided to inpatients in addition to symptomatic treatment. We present a 23-month-old male patient who developed methemoglobinemia and acute intravascular hemolysis, who was followed up in the intensive care unit for five days due to naphthalene intoxication. Although naphthalene poisoning is very rare, it should be known that it has fatal consequences, and more care should be taken in its use and sale.

Interference of two typical polycyclic aromatic hydrocarbons on the induced anti-grazing defense of Tetradesmus obliquus.

Anthropogenic emissions of polycyclic aromatic hydrocarbons (PAHs) cause severe ecological impacts by contaminating natural water bodies, affecting various biological groups, and altering interspecies relationships and ecological functions. This study examined the effects of two typical PAHs, phenanthrene (Phe) and naphthalene (Nap), on the anti-grazing defense mechanisms of Tetradesmus obliquus, a primary producer in freshwater food chains. Four non-lethal concentrations (0.01, 0.1, 1, and 10 mg L-1) of Phe and Nap were tested and the population growth, photosynthetic capacity, pigment content, and morphological defense of T. obliquus were analyzed. The results indicated that Phe and Nap inhibited both the growth rate and formation of defensive colonies of T. obliquus induced by Daphnia grazing cues, and the inhibition ratio increased with concentration. Phe and Nap significantly shortened the defense colony formation time of T. obliquus. Phe and Nap significantly suppressed photosynthesis in the early stages; however, the photosynthetic efficiency recovered over time. These findings highlight the high sensitivity of grazing-induced colony formation in T. obliquus to Phe and Nap at non-lethal concentrations, which could affect the interactions between phytoplankton and zooplankton in aquatic ecosystems. Our study underscores the influence of Phe and Nap on the defense mechanisms of phytoplankton and the consequential effects on ecological interactions within freshwater ecosystems, providing insight into the complex impacts of pollutants on phytoplankton-zooplankton relationships. Therefore, it is necessary to consider interspecific interactions when assessing the potential negative effects of environmental pollutants on aquatic ecosystems.

Remediation of polycyclic aromatic hydrocarbons polluted soil by biochar loaded humic acid activating persulfate: performance, process and mechanisms.

The remediation for polycyclic aromatic hydrocarbons contaminated soil with cost-effective method has received significant public concern, a composite material, therefore, been fabricated by loading humic acid into biochar in this study to activate persulfate for naphthalene, pyrene and benzo(a)pyrene remediation. Experimental results proved the hypothesis that biochar loaded humic acid combined both advantages of individual materials in polycyclic aromatic hydrocarbons adsorption and persulfate activation, achieved synergistic performance in naphthalene, pyrene and benzo(a)pyrene removal from aqueous solution with efficiency reached at 98.2%, 99.3% and 90.1%, respectively. In addition, degradation played a crucial role in polycyclic aromatic hydrocarbons remediation, converting polycyclic aromatic hydrocarbons into less toxic intermediates through radicals of ·SO4-, ·OH, ·O2-, and 1O2 generated from persulfate activation process. Despite pH fluctuation and interfering ions inhibited remediation efficiency in some extent, the excellent performances of composite material in two field soil samples (76.7% and 91.9%) highlighted its potential in large-scale remediation.

5-HT2A receptors are involved in the pharmaco-toxicological effects of the synthetic cannabinoids JWH-018 and 5F-PB22: In vivo studies in mice.

Over the last years, Synthetic Cannabinoids (SCs) have been among the largest and most frequently seized groups of Novel Psychoactive Substances (NPS). These substances have been frequently detected in biological samples from patients involved in several intoxication and death cases. Their serious adverse effects have been related to their action as potent agonist of cannabinoid CB1 receptors. However, evidence concerning the potential interaction between SCs and serotoninergic mechanisms has emerged. Therefore, this study aims to evaluate the involvement of 5-HT2A receptors in the effects induced by acute systemic administration of 1-pentyl-3-(1-naphthoyl)indole (JWH-018; 1 mg/kg) and quinolin-8-yl 1-pentyfluoro-1H-indole-3-8-carboxylate (5F-PB22; 1 mg/kg). Sensorimotor (visual, acoustic, and tactile) responses, pain threshold (acute mechanical and thermal nociception), core temperature, breath rate and motor performance (stepping activity) have been assessed in CD-1 male mice. The present results pointed out that both substances deeply alter sensorimotor responses, nociceptive threshold, core temperature, breath rate and motor activity in mice. Noteworthy, pretreatment with the selective 5-HT2A receptors antagonist MDL100907 (0.1 mg/kg) at least partially prevented sensorimotor disruption, antinociception and hypothermic effects. Conversely, the respiratory and motor impairment was not prevented. Thus, it states the relevance of serotoninergic 5-HT2A mechanisms on pharmaco-toxicological effects induced by SCs.

The unique biodegradation pathway of benzo[a]pyrene in moderately halophilic Pontibacillus chungwhensis HN14.

Benzo[a]pyrene (BaP), as the typical representative of polycyclic aromatic hydrocarbons (PAHs), is a serious hazard to human health and natural environments. Though the study of microbial degradation of PAHs has persisted for decades, the degradation pathway of BaP is still unclear. Previously, Pontibacillus chungwhensis HN14 was isolated from high salinity environment exhibiting a high BaP degradation ability. Here, based on the intermediates identified, BaP was found to be transformed to 4,5-epoxide-BaP, BaP-trans-4,5-dihydrodiol, 1,2-dihydroxy-phenanthrene, 2-carboxy-1-naphthol, and 4,5-dimethoxybenzo[a]pyrene by the strain HN14. Furthermore, functional genes involved in degradation of BaP were identified using genome and transcriptome data. Heterogeneous co-expression of monooxygenase CYP102(HN14) and epoxide hydrolase EH(HN14) suggested that CYP102(HN14) could transform BaP to 4,5-epoxide-BaP, which was further transformed to BaP-trans-4,5-dihydrodiol by EH(HN14). Moreover, gene cyp102(HN14) knockout was performed using CRISPR/Cas9 gene-editing system which confirmed that CYP102(HN14) play a key role in the initial conversion of BaP. Finally, a novel BaP degradation pathway was constructed in bacteria, which showed BaP could be converted into chrysene, phenanthrene, naphthalene pathways for the first time. These findings enhanced our understanding of microbial degradation process for BaP and suggested the potential of using P. chungwhensis HN14 for bioremediation in PAH-contaminated environments.

Immune and glial cell alterations in the rat brain after repeated exposure to the synthetic cannabinoid JWH-018.

The use of synthetic cannabinoid receptor agonists (SCRAs) poses major psychiatric risks. We previously showed that repeated exposure to the prototypical SCRA JWH-018 induces alterations in dopamine (DA) transmission, abnormalities in the emotional state, and glial cell activation in the mesocorticolimbic DA circuits of rats. Despite growing evidence suggesting the relationship between substance use disorders (SUD) and neuroinflammation, little is known about the impact of SCRAs on the neuroimmune system. Here, we investigated whether repeated JWH-018 exposure altered neuroimmune signaling, which could be linked with previously reported central effects. Adult male Sprague-Dawley (SD) rats were exposed to JWH-018 (0.25 mg/kg, i.p.) for fourteen consecutive days, and the expression of cytokines, chemokines, and growth factors was measured seven days after treatment discontinuation in the striatum, cortex, and hippocampus. Moreover, microglial (ionized calcium-binding adaptor molecule 1, IBA-1) and astrocyte (glial fibrillary acidic protein, GFAP) activation markers were evaluated in the caudate-putamen (CPu). Repeated JWH-018 exposure induces a perturbation of neuroimmune signaling specifically in the striatum, as shown by increased levels of cytokines [interleukins (IL) -2, -4, -12p70, -13, interferon (IFN) γ], chemokines [macrophage inflammatory protein (MIP) -1α, -3α], and growth factors [macrophage colony-stimulating factor (M-CSF), vascular endothelial growth factor (VEGF)], together with increased IBA-1 and GFAP expression in the CPu. JWH-018 exposure induces persistant brain region-specific immune alterations up to seven days after drug discontinuation, which may contribute to the behavioral and neurochemical dysregulations in striatal areas that play a role in the reward-related processes that are frequently impaired in SUD.

Proliferation and migration of PC-3 prostate cancer cells is counteracted by PPARγ-cladosporol binding-mediated apoptosis and a decreased lipid biosynthesis and accumulation.

OBJECTIVES: Chemoprevention, consisting of the administration of natural and/or synthetic compounds, appears to be an alternative way to common therapeutical approaches to preventing the occurrence of various cancers. Cladosporols, secondary metabolites from Cladosporium tenuissimum, showed a powerful ability in controlling human colon cancer cell proliferation through a peroxisome proliferator-activated receptor gamma (PPARγ)-mediated modulation of gene expression. Hence, we carried out experiments to verify the anticancer properties of cladosporols in human prostate cancer cells. Prostate cancer represents one of the most widespread tumors in which several risk factors play a role in determining its high mortality rate in men. MATERIALS AND METHODS: We assessed, by viability assays, PPARγ silencing and overexpression experiments and western blotting analysis, the anticancer properties of cladosporols in cancer prostate cell lines. RESULTS: Cladosporols A and B selectively inhibited the proliferation of human prostate PNT-1A, LNCaP and PC-3 cells and their most impactful antiproliferative ability towards PC-3 prostate cancer cells, was mediated by PPARγ modulation. Moreover, the anticancer ability of cladosporols implied a sustained apoptosis. Finally, cladosporols negatively regulated the expression of enzymes involved in the biosynthesis of fatty acids and cholesterol, thus enforcing the relationship between prostate cancer development and lipid metabolism dysregulation. CONCLUSION: This is the first work, to our knowledge, in which the role of cladosporols A and B was disclosed in prostate cancer cells. Importantly, the present study highlighted the potential of cladosporols as new therapeutical tools, which, interfering with cell proliferation and lipid pathway dysregulation, may control prostate cancer initiation and progression.

NPS-2143 inhibit glioma progression by suppressing autophagy through mediating AKT-mTOR pathway.

Gliomas are the most common tumours in the central nervous system. In the present study, we aimed to find a promising anti-glioma compound and investigate the underlying molecular mechanism. Glioma cells were subjected to the 50 candidate compounds at a final concentration of 10 µM for 72 h, and CCK-8 was used to evaluate their cytotoxicity. NPS-2143, an antagonist of calcium-sensing receptor (CASR), was selected for further study due to its potent cytotoxicity to glioma cells. Our results showed that NPS-2143 could inhibit the proliferation of glioma cells and induce G1 phase cell cycle arrest. Meanwhile, NPS-2143 could induce glioma cell apoptosis by increasing the caspase-3/6/9 activity. NPS-2143 impaired the immigration and invasion ability of glioma cells by regulating the epithelial-mesenchymal transition process. Mechanically, NPS-2143 could inhibit autophagy by mediating the AKT-mTOR pathway. Bioinformatic analysis showed that the prognosis of glioma patients with low expression of CASR mRNA was better than those with high expression of CASR mRNA. Gene set enrichment analysis showed that CASR was associated with cell adhesion molecules and lysosomes in glioma. The nude mice xenograft model showed NPS-2143 could suppress glioma growth in vivo. In conclusion, NPS-2143 can suppress the glioma progression by inhibiting autophagy.

Thermo-chemical behaviour of Dunaliella salina biomass and valorising their biochar for naphthalene removal from aqueous rural environment.

Thermo-chemical behavior of a microalgal biomass; Dunaliella salina was investigated through thermo-gravimetric analyses. Fully-grown D. salina biomass were subjected for biochar conversion using pyrolytic treatment at three distinct heating rates such as 2.5, 5, and 15 °C min-1. The kinetic appraisals were explained by using model-free kinetics viz., Kissinger-Akahira-Sanose, Flynn-Waal-Ozawa and Starink iso-conversional correlations with concomitant evaluation of activation energies (Ea). The Ea value is 194.2 kJ mol-1 at 90% conversion in FWO model, which is higher as compared to other two models. Moisture, volatile substances, and other biochemical components of the biomass were volatilized between 400 and 1000 K in two separate thermo-chemical breakdown regimes. Microscopic and surface characterization analyses were carried out to elucidate the elemental and morphological characteristics of the biomass and biochar. Further, the proficiency of the prepared biochar was tested for removing naphthalene from the watery media. The novelty of the present study lies in extending the applicability of biochar prepared from D. salina for the removal of a model polyaromatic hydrocarbon, naphthalene.

Viscosities and Densities of Binary and Ternary Mixtures of Aliphatic and Polyaromatic Hydrocarbons: Pyrene +1-Methylnaphthalene + Dodecane at T = (293.15 to 343.15) K. Experiment and Modeling.

This work presents new experimental viscosity and density data for aromatic and polyaromatic compounds in binary and ternary pyrene, 1-methylnaphthalene, and dodecane mixtures. The lack of experimental viscosity data for these mixtures requires the development of a new database, which is vital for understanding the behavior of mixtures in more complex systems, such as asphaltenes and fuels. The mixtures proposed in this work have been measured over a temperature range of (293.15 to 343.15) K at atmospheric pressure. Several mixture compositions have been studied at these conditions: 1.0, 2.5, 5.0, 7.5, 10.0, 12.5, and 15.0% pyrene mass fraction. The concentration of pyrene correlates with an increase in the viscosity and density values. At the lowest temperature in binary mixtures, the corresponding values reach 4.4217 mPa·s for viscosity and 1.0447 × 103 kg·m-3 for density, respectively. In ternary mixtures, the introduction of dodecane leads to the lowest maximum values of 3.5555 mPa·s for viscosity and 1.0112 × 103 kg·m-3 for density at the same temperature. The experimental data have been employed for the specific modification of viscosity models. These modifications could facilitate the prediction of the viscosity of mixtures that are more complex than those presented in this work. Various viscosity models have been employed, such as Linear, Ratcliff and Khan, modified UNIFAC-Visco, and Krieger-Dougherty. The settings in the models used reliably reproduce the experiment reliably. However, the Ratcliff model agrees excellently with the experiment, having a low standard deviation (2.0%) compared to other models. Furthermore, a model based on the equation of state of Guo is proposed to predict the viscosity values by modifying the specific parameters and adjusting them to the mixtures proposed in this work. The results from this study are compared to previous work, where pyrene, toluene, and heptane mixtures were analyzed. In this case, we find that the decrease of aggregation grade in the present systems is predicted by the model fixed in this work.

Discovery of novel dihydronaphthalene-imidazole ligands as potential inhibitors of Staphylococcus aureus multidrug resistant NorA efflux pump: A combination of experimental and in silico molecular docking studies.

Overexpression of the efflux pump is a predominant mechanism by which bacteria show antimicrobial resistance (AMR) and leads to the global emergence of multidrug resistance (MDR). In this work, the inhibitory potential of library of dihydronapthyl scaffold-based imidazole derivatives having structural resemblances with some known efflux pump inhibitors (EPI) were designed, synthesized and evaluated against efflux pump inhibitor against overexpressing bacterial strains to study the synergistic effect of compounds and antibiotics. Out of 15 compounds, four compounds (Dz-1, Dz-3, Dz-7, and Dz-8) were found to be highly active. DZ-3 modulated the MIC of ciprofloxacin, erythromycin, and tetracycline by 128-fold each against 1199B, XU212 and RN4220 strains of S. aureus respectively. DZ-3 also potentiated tetracycline by 64-fold in E. coli AG100 strain. DZ-7 modulated the MIC of both tetracycline and erythromycin 128-fold each in S. aureus XU212 and S. aureus RN4220 strains. DZ-1 and DZ-8 showed the moderate reduction in MIC of tetracycline in E. coli AG100 only by 16-fold and 8-fold, respectively. DZ-3 was found to be the potential inhibitor of NorA as determined by ethidium bromide efflux inhibition and accumulation studies employing NorA overexpressing strain SA-1199B. DZ-3 displayed EPI activity at non-cytotoxic concentration to human cells and did not possess any antibacterial activity. Furthermore, molecular docking studies of DZ-3 was carried out in order to understand the possible binding sites of DZ-3 with the active site of the protein. These studies indicate that dihydronaphthalene scaffolds could serve as valuable cores for the development of promising EPIs.

Repurposed drug agomelatine is therapeutic against collagen-induced arthritis via iNOS targeting.

BACKGROUND: The most promising biologics tumor necrosis factor α (TNFα) inhibitors are effective in treating rheumatoid arthritis (RA) in only 50-70 % of the cases; thus, new drugs targeting TNFα-mediated inflammation are required. METHODS: Firstly, the drugs that could inhibit FLS proliferation and TNFα induced inflammatory cytokine production were screened. Secondly, treatment effects of the identified drugs were screened in collagen-induced arthritis (CIA) mouse model. Thirdly, the inhibitory effect of the identified drug, agomelatine (AOM), on TNFα induced inflammatory cytokine production and NF-κB activity were confirmed. Fourthly, bioinformatics was applied to predict the binding target of AOM and the binding was confirmed, and the already known inhibitor of target was used to test the treatment effect for CIA mouse model. Finally, the effect of AOM on signaling pathway was tested and on TNFα induced inflammatory cytokine production was observed after inhibiting the target. RESULTS: AOM effectively inhibited TNFα-induced NF-κB activation, NF-κB p65 translocation, and inflammatory cytokines production in vitro and was therapeutic against CIA. The mechanistic study indicated inducible nitric oxide synthase (iNOS) as the binding target of AOM. 1400 W, a known inhibitor of iNOS, could effectively treat CIA by decreasing iNOS activity and the levels of inflammatory cytokines. The inhibitory effect of AOM on TNFα-induced inflammation was further elucidated by 1400 W, or NF-κB p65 inhibitor JSH-23, indicating that AOM is therapeutic against CIA via iNOS/ERK/p65 signaling pathway after binding with iNOS. CONCLUSIONS: AOM is therapeutic against CIA via inhibition of the iNOS/ERK/p65 signaling pathway after binding with iNOS.

Designing a Mitochondria-Targeted Theranostic Cyclometalated Iridium(III) Complex: Overcoming Cisplatin Resistance and Inhibiting Tumor Metastasis through Necroptosis and Immune Response.

To develop a potential theranostic metal agent to reverse the resistance of cancer cells to cisplatin and effectively inhibit tumor growth and metastasis, we proposed to design a cyclometalated iridium (Ir) complex based on the properties of the tumor environment (TME). To the end, we designed and synthesized a series of Ir(III) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes by modifying the hydrogen atom(s) of the N-3 position of 2-hydroxy-1-naphthaldehyde thiosemicarbazone compounds and the structure of cyclometalated Ir(III) dimers and then investigated their structure-activity and structure-fluorescence relationships to obtain an Ir(III) complex (Ir5) with remarkable fluorescence and cytotoxicity to cancer cells. Ir5 not only possesses mitochondria-targeted properties but also overcomes cisplatin resistance and effectively inhibits tumor growth and metastasis in vivo. Besides, we confirmed the anticancer mechanisms of Ir5 acting on different components in the TME: directly killing liver cancer cells by inducing necroptosis and activating the necroptosis-related immune response.

Pharmacokinetics, Pharmacodynamics, and Safety of Evocalcet (KHK7580), a Novel Calcimimetic Agent: An Open-Label, Single- and Multiple-Dose, Phase I Trial in Healthy Chinese Subjects.

Purpose: This study explored the pharmacokinetics (PK), pharmacodynamics (PD), and safety of evocalcet (KHK7580), a new calcimimetic agent, in healthy Chinese subjects following single and multiple doses. Methods: This was a single-center, open-label phase I trial conducted in China. The study started from the single-dose cohorts (1, 3, 6, 12 mg evocalcet, step-by-step administration) and proceeded to the multiple-dose cohort (6 mg evocalcet once daily for eight days). Blood and urine samples were collected at the designated time points for pharmacokinetic and pharmacodynamic analysis. Safety was evaluated by treatment-emergent adverse events (TEAEs), clinical laboratory tests, vital signs, electrocardiograms (ECGs), and ophthalmological examination. Results: Among 42 enrolled subjects, eight in each single-dose cohort and 10 in multiple-dose cohort, 40 subjects completed the study. In single-dose cohorts, tmax was 1.00-2.00 h and declined biphasically. The mean t1/2 was 15.99-20.84 h. Evocalcet exposure in AUC0-inf, AUC0-t, and Cmax showed a dose-proportional increase. In the multiple-dose cohort, tmax was 2.00 h and declined biphasically after multiple administrations. The accumulation was negligible. Ctrough levels were similar across days and steady from 24 hours after the first administration. The mean t1/2 was 15.59 h. PD analysis showed that evocalcet decreased intact parathyroid hormone and corrected calcium levels in a dose-dependent manner. Seventeen (40.5%) subjects reported TEAEs. No serious or severe TEAE occurred. Conclusion: In healthy Chinese subjects, evocalcet demonstrated dose-dependent PK and PD properties and was well-tolerated.

Effect of Serum Vitamin B12 Levels on Premature Ejaculation.

OBJECTIVE: To assess the impact of vitamin B12 levels in the failure of the dapoxetine used in premature ejaculation (PE) treatment. STUDY DESIGN: Experimental study. Place and Duration of the Study: Andrology Clinic, between May and December 2020. METHODOLOGY: Patients with premature ejaculation complaints completed the Premature Ejaculation Diagnostic Tool (PEDT) questionnaire. Patients were also asked to fill in the Premature Ejaculation Profile (PEP) surveys. Intravaginal ejaculation latency time (IELT) were recorded based on the estimates of patients. Serum vitamin B12 levels were evaluated based on blood samples. All patients were advised to use dapoxetine 30 mg, 1-3 hours prior to intercourse. After four weeks, patients were asked to complete the PEP questionnaire again. IELT times were recorded. RESULTS: A total of 62 patients were included in the study. A total of 39 patients (62.90%) were satisfied with the treatment of the dapoxetine. In comparison to patients who benefited from dapoxetine treatment and those who did not, vitamin B12 levels of patients who did not benefit from dapoxetine were found to be significantly lower (p=0.005). CONCLUSION: Vitamin B12 deficiency can reduce the effectiveness of dapoxetine treatment in patients with PE. It is important to evaluate serum vitamin B12 levels for the evaluation of patients with PE. KEY WORDS: Premature ejaculation, Dapoxetine, Vitamin B12, Serotonin, Treatment.

Petrol Note in Riesling - 1,1,6-Trimethyl-1,2-dihydronaphthalene (TDN) Selectively Activates Human Odorant Receptor OR8H1.

Grapevine (Vitis vinifera) is one of the most important perennial fruit plants. The variety Riesling stands out by developing a characteristic petrol-like odor note during aging, elicited by the aroma compound 1,1,6-trimethyl-1,2-dihydronaphthalene (TDN). The UV-dependent TDN contents differ largely among Rieslings grown in the northern versus the southern hemisphere. Highest TDN concentrations were found in Australian Rieslings, where TDN is a scoring ingredient. In contrast, in Rieslings from Europe, for example, TDN may be a tending cause of rejection. A human receptor for TDN has been unknown. Here, we report on the identification of OR8H1 as a TDN-selective odorant receptor, out of a library of 766 odorant receptor variants. OR8H1 is selectively tuned to six carbon ring structures, identified by screening a collection of 180 key food odorants, using a HEK-293 cell-based cAMP luminescence assay equipped with the GloSensor technology.

WAY-262611 ameliorates the inflammatory bowel disease by activating Wnt/ß-catenin pathway.

Inflammatory bowel disease (IBD) is a non-specific and relapsing intestinal inflammation. The injury and repair of intestinal epithelial together determine the occurrence and development of IBD. Wnt/ß-catenin pathway is considered as the key role in the proliferation and differentiation of intestinal stem cells which is negative regulated by Dickkiop (DKKs). WAY-262611 is a novel inhibitor of DKK-1, and has demonstrated therapeutic effect on some disease including osteoporosis. Thus, we investigated the effect of WAY-262611 on IBD. Firstly, a mice model of IBD was established by DSS induction, by which the expression of Wnt3a and DKK-1 were detected by immumohistochemical staining to display their correlation. Next, using WAY-262611 the ameliorative effect on IBD was validated by histopathological staining. Using Mode-k cells the experiments in vitro were also conducted, in which the viability and apoptosis were determined. By detecting expression of Wnt3a and DKK-1 and observing nuclear translocation of ß-catenin, the activation of Wnt/ß-catenin pathway was validated. Finally, the incidence of the orthotopic colorectal cancer was calculated under continuous administration by DSS. Results demonstrated that the expression of Wnt3a is negative correlated with DKK-1. WAY-262611 ameliorated the IBD and reduced apoptosis of Mode-k cells induced by DSS. The protective effect of WAY-262611 on Mode-k cells is mediated by Wnt/ß-catenin pathway activation. In addition, WAY-262611 lowered the incidence rate of orthotopic colorectal cancer. All these results concluded that WAY-262611 could mitigate the IBD by activating Wnt/ß-catenin pathway in mice.