Inhibition of TTX-S Na+ currents by a novel blocker QLS-278 for antinociception.

Genetic loss-of-function mutations of Nav1.7 channel, abundantly expressed in peripheral nociceptive neurons, cause congenital insensitivity to pain (CIP) in humans, indicating that selective inhibition of the channel may lead to potential therapy of pain disorders. In this study, we investigated a novel compound, 5-chloro-N-(cyclopropylsulfonyl)-2-fluoro-4-(2-(8-(furan-2-ylmethyl)-8-azaspiro [4.5] decan-2-yl) ethoxy) benzamide (QLS-278) that inhibits Nav1.7 channel and exhibits anti-nociceptive activity. Compound QLS-278 exhibits inactivation- and concentration-dependent inhibition of macroscopic currents of Nav1.7 channels stably expressed in HEK293 cells with an IC50 of 1.2 {plus minus} 0.2 µM. QLS-278 causes a hyperpolarization shift of the channel inactivation and delays recovery from inactivation, without an obvious effect on voltage-dependent activation. In mouse DRG neurons, QLS-278 suppresses native TTX-sensitive Nav currents and also reduces neuronal firing. Moreover, QLS-278 dose-dependently relieves neuropathic pain induced by spared nerve injury and inflammatory pain induced by formalin without significant alteration of spontaneous locomotor activity in mice. Altogether, our identification of the novel compound QLS-278 may hold developmental potential for the treatment of chronic pain. Significance Statement QLS-278, a novel voltage-gated sodium Nav1.7 channel blocker, inhibits native TTX-S Na+ current and reduces action potential firings in DRG sensory neurons. QLS-278 also exhibits antinociceptive activity in mouse models of pain, thus demonstrating potential for the development of a treatment for chronic pain.

Discovery of an Ortho-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaine Derivative as a Selective and Potent Kappa Opioid Receptor Agonist with Subsided Sedative Effect.

Research into kappa opioid receptor (KOR) agonists with attenuated central-nervous-system side effects is a critical focus for developing productive and safe analgesics. Herein, a series of ortho-substituted N-cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaines were designed, synthesized, and subjected to bioassays. Compound 7a exhibited high subtype selectivity and potent agonistic activity toward KOR (KOR, Ki = 3.9 nM, MOR/KOR = 270, DOR/KOR = 1075; [35S]GTPγS binding, EC50 = 3.4 nM). Additionally, this compound exhibited robust and persistent antinociceptive effects in rodent models with different animal strains (hot plate test, ED50 = 0.20-0.30 mg/kg, i.p.; abdominal constriction test, ED50 = 0.20-0.60 mg/kg, i.p.), with its KOR-mediated mechanism for antinociception firmly established. Notably, compound 7a, unlike conventional KOR agonists, displayed minimal sedation and aversion at the antinociceptive ED50 dose. This feature addresses a crucial limitation in existing KOR agonists, positioning compound 7a as a promising novel therapeutic agent.

Synthesis of easily-modified and useful dibenzo-[b,d]azepines by palladium(II)-catalyzed cyclization/addition with a green solvent.

A novel strategy in which palladium(II)-catalyzed tandem cyclization is used to obtain N-heterocyclic architectures containing a seven-membered ring has been developed and used to synthesize a series of derivatives. The reaction uses an eco-friendly mixed solvent (water : EtOH = 2 : 1) instead of DMSO and maintains a high yield (91%). Its potential application value and reaction mechanism have also been explored.

Machine learning-derived multi-omics prognostic signature of pyroptosis-related lncRNA with regard to ZKSCAN2-DT and tumor immune infiltration in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) has become the most prevalent gastrointestinal malignant tumor, ranking third (10.2%) in incidence and second (9.2%) in death among all malignancies globally. The most common histological subtype of CRC is colon adenocarcinoma (COAD), although the cause of CRC remains unknown, as there are no valid biomarkers. METHODS: A thorough investigation was used to build a credible biomolecular risk model based on the pyroptosis-associated lncRNAs discovered for COAD prediction. Furthermore, Cibersort and Tumor Immune Dysfunction and Exclusion (TIDE), the methods of exploring tumor immune infiltration, were adopted in our paper to detect the effects of differential lncRNAs on the tumor microenvironment. Finally, quantitative real-time polymerase chain reaction (qPCR), as the approach of exploring expressions, was utilized on four different cell lines. RESULTS: Seven pyroptosis-related lncRNAs have been identified as COAD predictive risk factors. Cox analysis, both univariate and multivariate, revealed that the established signature might serve as a novel independent factor with prognostic meaning in COAD patients. ZKSCAN2-DT was shown to be considerably overexpressed in the COAD cell line when compared to normal human colonic epithelial cells. Furthermore, ssGSEA analysis results revealed that the immune infiltration percentage of most immune cells dropped considerably as ZKSCAN2-DT expression increased, implying that ZKSCAN2-DT may play an important role in COAD immunotherapy. CONCLUSION: Our research is the first to identify pyroptosis-related lncRNAs connected with COAD patient prognosis and to construct a predictive prognosis signature, directing COAD patient prognosis in therapeutic interventions.

Reversal of subtype-selectivity and function by the introduction of a para-benzamidyl substituent to N-cyclopropylmethyl nornepenthone.

The discovery and development of novel µ-opioid receptor (MOR) antagonists is a significant area to combat Opioid Use Disorder (OUD). In this work, a series of para-substituted N-cyclopropylmethyl-nornepenthone derivatives were designed and synthesized and pharmacologically assayed. Compound 6a was identified as a selective MOR antagonist both in vitro and in vivo. Its molecular basis was elucidated using molecular docking and MD simulations. A subpocket on the extracellular side of the TM2 domain of MOR, in particular the residue Y2.64, was proposed to be responsible for the reversal of subtype selectivity and functional reversal of this compound.

Design, synthesis, and biological evaluation of acyl sulfonamide derivatives with spiro cycles as NaV1.7 inhibitors for antinociception.

Chronic pain, as an unmet medical need, severely impacts the quality of life. The voltage-gated sodium channel NaV1.7 preferentially expressed in sensory neurons of dorsal root ganglia (DRG) serves a promising target for pain therapy. Here, we report the design, synthesis, and evaluation of a series of acyl sulfonamide derivatives targeting Nav1.7 for their antinociceptive activities. Among the derivatives tested, the compound 36c was identified as a selective and potent NaV1.7 inhibitor in vitro and exhibited antinociceptive effects in vivo. The identification of 36c not only provides a new insight into the discovery of selective NaV1.7 inhibitors, but also may hold premise for pain therapy.

A critical review on odor measurement and prediction.

Odor pollution has become a global environmental issue of increasing concern in recent years. Odor measurements are the basis of assessing and solving odor problems. Olfactory and chemical analysis can be used for odor and odorant measurements. Olfactory analysis reflects the subjective perception of human, and chemical analysis reveals the chemical composition of odors. As an alternative to olfactory analysis, odor prediction methods have been developed based on chemical and olfactory analysis results. The combination of olfactory and chemical analysis is the best way to control odor pollution, evaluate the performances of the technologies, and predict odor. However, there are still some limitations and obstacles for each method, their combination, and the prediction. Here, we present an overview of odor measurement and prediction. Different olfactory analysis methods (namely, the dynamic olfactometry method and the triangle odor bag method) are compared in detail, the latest revisions of the standard olfactometry methods are summarized, and the uncertainties of olfactory measurement results (i.e., the odor thresholds) are analyzed. The researches, applications, and limitations of chemical analysis and odor prediction are introduced and discussed. Finally, the development and application of odor databases and algorithms for optimizing odor measurement and prediction methods are prospected, and a preliminary framework for an odor database is proposed. This review is expected to provide insights into odor measurement and prediction.

Rapid progress in neuroimaging technologies fuels central nervous system translational medicine.

Central nervous system (CNS) drug discovery suffers from high attrition rates; translational neuroscience approaches aiming to reduce these high rates include the use of brain imaging technologies. However, there is a need to better understand what methods are being used and for what diseases and purposes. Our analysis of the literature found that magnetic resonance imaging (MRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT) were the neuroimaging techniques used most often in clinical trials for the most prevalent CNS diseases: Alzheimer's disease (AD), Parkinson's disease (PD), depression, and schizophrenia. Moreover, the number of initiated clinical trials using MRI, PET, and SPECT increased over the period 1981-2021. Such insights indicate that the significant increase in the use of neuroimaging studies could decrease the attrition of novel drug candidates in late clinical development.

Odor emission rate of a municipal solid waste sanitary landfill during different operation stages before final closure.

This study investigated the odor emission rate from different areas of a municipal solid waste landfill. The surface odor emission rate (SOER) of eight odorous compound groups were determined by flux chamber method. The SOER of working face, seams of daily cover, membrane surface of daily cover, seams of temporary cover, membrane surface of temporary cover, seams of intermediate cover, membrane surface of intermediate cover were 138.34, 49.83, 13.56, 90.35, 14.48, 4.05, and 8.14 µg/(m2·s), respectively. Therefore, odor emission hotspots were at seams of daily and temporary cover areas. Converting the odor emissions at emission hotspots to the entire membrane cover surface, the average SOER of working face, daily cover area, temporary cover area and intermediate cover area were 138.34, 17.95, 22.43, and 6.24 µg/(m2·s), respectively. Combined with the size of each landfill area, the total odor emissions of the four above areas of a landfill zone were 830, 108, 1346, and 5175 mg/s, respectively, suggesting the necessity to control the odor emission of membrane cover stages especially for large-scale landfills. In terms of odor components, alcohols (38.7 %), sulfur compounds (22.9 %) and aldehydes (15.7 %) were major odorous groups.

Design, development and evaluation of a prodrug-type TrkA-selective inhibitor with antinociceptive effects in vivo.

Tropomyosin receptor kinase A (TrkA) is considered a therapeutic target in pain treatment, and several TrkA inhibitors have been designed and developed as potential analgesics. The subselectivity toward TrkA is closely associated with safety and efficacy and was achieved by developing an allosteric inhibitor to occupy the less conserved non-ATP binding site. Druggable modifications of potent TrkA inhibitors could be challenging due to the unique requirement of functional groups that supply potency but are accompanied by poor druggability. We developed carboxyl acid 5 as a potent (IC50 = 22.4 nM) and subselective TrkA inhibitor (>8000-fold toward TrkB and TrkC). We also converted 5 to corresponding prodrug 39 as a useful tool compound in future analgesic development with promising antinociceptive effects in both hot plate testing and formalin-induced pain models with a suitable ED50 value (7.8 mg/kg).

ALKBH1-mediated m1 A demethylation of METTL3 mRNA promotes the metastasis of colorectal cancer by downregulating SMAD7 expression.

Colorectal cancer (CRC) is one of the most common malignancies, and the main cause of death from CRC is tumor metastasis. m1 A RNA modification plays critical role in many biological processes. However, the role of m1 A modification in CRC remains unclear. Here, we find that the m1 A demethylase alkB homolog 1, histone H2A dioxygenase (ALKBH1) is overexpressed in CRC and is associated with metastasis and poor prognosis. Upregulation of ALKBH1 expression promotes CRC metastasis in vitro and in vivo. Mechanistically, knockdown of ALKBH1 results in a decrease in methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit (METTL3) expression, probably due to m1 A modification of METTL3 mRNA, followed by m6 A demethylation of SMAD family member 7 (SMAD7) mRNA. In addition, downregulation of SMAD7 establishes an aggressive phenotype. More importantly, the cell migration and invasion defects caused by ALKBH1 depletion or METTL3 depletion are significantly reversed by SMAD7 silencing. Considering these results collectively, we propose that ALKBH1 promotes CRC metastasis by destabilizing SMAD7 through METTL3.

Molecular behavior and interactions with microbes during anaerobic degradation of bio-derived DOM in waste leachate.

It is the key to control bio-derived dissolved organic matters (DOM) in order to reduce the effluent concentration of wastewater treatment, especially for waste leachate with high organic contaminants. In the present study, the anaerobic degradation of aerobically stabilized DOM was investigated with DOM substrate isolated through electrodialysis. The degradation of bio-derived DOM was confirmed by reduction of 15% of total organic carbon in 100 days. We characterized the molecular behavior of bio-derived DOM by coupling molecular and biological information analysis. Venn based Sankey diagram of mass features showed the transformation of bio-derived DOM mass features. Occurrence frequency analysis divided mass features into six categories so as to distinguish the fates of intermediate metabolites and persistent compounds. Reactivity continuum model and machine learning technologies realized the semi-quantitative determination on the kinetics of DOM mass features in the form of pseudo-first order, and confirmed the reduction of inert mass features. Furthermore, network analysis statistically establish relationship between DOM mass features and microbes to identify the active microbes that are able to utilize bio-derived DOM. This work confirmed the biological technology is still effective in controlling recalcitrant bio-derived DOM during wastewater treatment.

Primary balloon angioplasty for chronic occlusion of intracranial internal carotid artery: A case report.

Chronic occlusion of large intracranial arteries is the main cause of ischemic stroke in China. Patients with symptomatic intracranial artery occlusion and hemodynamic impairment are at high risk of recurrent stroke. Chronic occlusion of the intracranial segment of the internal carotid artery is a common type of intracranial artery occlusion. Medical management is regarded as the standard treatment for this disease. With the development of endovascular treatment, some patients with chronic cerebral artery occlusion have achieved satisfactory results with endovascular therapy. We reported a patient with symptomatic chronic occlusion of the ophthalmic segment of the internal carotid artery. Simple balloon angioplasty was performed, and the occluded ophthalmic segment of the internal carotid artery was successfully recanalized without perioperative complications. At 4 months follow-up, the internal carotid artery remained patent and perfusion of the right cerebral hemisphere improved dramatically. In addition, we briefly reviewed the relevant literature.

Occurrence of macroplastics and microplastics in biogenic waste digestate: Effects of depackaging at source and dewatering process.

Plastic debris, including macroplastics (>5 mm) and microplastics (0.1-5 mm), has proven to be an emerging contaminant. Anaerobic digestion, coupled with energy recovery, can be an effective valorization technology for biogenic waste. But the use of the resulting digestate as a soil conditioner is a source for plastic debris release into the environment. The preprocess and postprocess used could influence the quantity of plastic debris found in the digestate, but the specifics of these effects are relatively unknown. Therefore, we measured the quantity of plastic debris in raw digestate under a variety of preprocessing scenarios. We also investigated the occurrence of plastic debris in solid and liquid digestates resulting from the dewatering of raw digestate. The quantity of plastic debris ranged from 41 to 3298 particles/kg (WW) for raw digestate, 319-3604 particles/kg (WW) for solid digestate and 7-38 particles/kg (WW) for liquid digestate. We observed that depackaging at source by citizens themselves (removing the package of biogenic waste when dropping it into bins), significantly reduced the quantities of plastic debris in raw digestate by an order of magnitude. Furthermore, the number of polymer types in raw digestate, where depackaging occurred at source, were lower than that where this rule was not in place. The average size of plastic debris in solid digestate was significantly smaller than that in raw digestate, which indicated that the process of mechanical dewatering could generate MPs. It is recommended to depackage for biogenic waste at source to reduce the quantities of MPs in digestate.

[Temporal and Spatial Variation in Odor Pollution and Membrane Barrier Effect in Municipal Solid Waste Landfill].

In order to explore the source characteristics as well as the temporal and spatial variations in odor pollution in municipal waste landfills, gas samples were collected from a landfill in an eastern coastal area of China throughout winter and summer. The total concentration of malodorous substances reached 60000 µg·m-3. There were more types of odor pollutants detected in summer than in winter, the average concentration was 30-300 times higher than that in winter, and the concentration of sulfur compounds increased by 4.7-136.7 times in summer. Oxygenated compounds had the highest concentration, and the total concentration of sulfur compounds accounted for less than 10% of malodorous substances. However, sulfur compounds contributed more than 90% to the theoretical odor concentration. Sulfur compounds such as methyl mercaptan and propane mercaptan were the key odorants in the landfill. After the landfill unit was covered, the concentration of odorous substances and the theoretical odor concentration on the surface of the landfill showed an increasing trend with time, indicating that the covering had a certain odor barrier effect; however, the landfill unit still had a large odor release potential. The similarity analysis showed that the odorous gas accumulated in the unit with temporary cover and without an exhaust system could be released to the environment through the overlapping gap of the membrane and the location of membrane rupture, resulting in more serious odor pollution around the landfill at night than that during the day.

Identification of a Partial and Selective TRPV1 Agonist CPIPC for Alleviation of Inflammatory Pain.

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel, predominantly expressed in a subset of peripheral sensory neurons for pain signaling. Topical application of agonist capsaicin for desensitizing TRPV1 currents has been approved for relief of chronic pain. However, the potent TRPV1 capsaicin is not ingestible and even topical capsaicin causes common side effects such as skin irritation, swelling, erythema and pruritus, suggesting that a mild TRPV1 agonist might be helpful for reducing side effects while reliving pain. In this study, we reported on a partial and selective TRPV1 agonist 4-(5-chloropyridin-2-yl)-N-(1H-indazol-6-yl)piperazine-1-carboxamide named CPIPC that was modified based on targeting the residue Arg557, important for conversion between the channel antagonism and agonism. Whole-cell patch clamp recordings indicated a concentration-dependent activation of TRPV1 currents by CPIPC with an EC50 of 1.56 ± 0.13 µM. The maximum efficacy of CPIPC (30 µM) was about 60% of saturated capsaicin (10 µM). Repetitive additions of CPIPC caused TRPV1 current desensitization in both TRPV1-expressing HEK293 cells and dorsal root ganglion (DRG) sensory neurons. Oral administration of CPIPC dose-dependently alleviated inflammatory pain in mice. Further site-directed mutagenesis combined with molecular docking revealed that residue Arg557 is critical for TRPV1 activation by CPIPC. Taken together, we identified a novel partial and selective TRPV1 agonist CPIPC that exhibits antinociceptive activity in mice.