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Postoperative pain occurs in as many as 70% of the over 230 million surgeries performed annually worldwide. Postoperative pain management still relies on opioids despite their negative consequences, resulting in a public health crisis. Therefore, it is of utmost importance to develop alternative therapies to treat chronic pain. Natural products derived from medicinal plants are potential sources of novel and biologically active compounds for development of safe analgesics. Hence, in this study, we screened a library of natural products to identify small molecules that target the activity of voltage-gated sodium and calcium channels which have important roles in nociceptive sensory processing.Fractions derived from the Native American medicinal plant, Parthenium incanum, were assessed using depolarization-evoked calcium influx in rat dorsal root ganglion (DRG) neurons. Further separation of these fractions yielded a cycloartane-type triterpene identified as argentatin C, which was additionally evaluated using whole-cell voltage and current clamp electrophysiology, and behavioral analysis in a mouse model of postsurgical pain.We found that argentatin C blocked the activity of both voltage-gated sodium and LVA calcium channels in calcium imaging assays. Docking analysis predicted that argentatin C may bind to NaV1.7-1.9 and CaV3.1-3.3 channels. Furthermore, argentatin C decreased NaThese results suggest that the dual effect of argentatin C on voltage-gated sodium and calcium channels supports its potential as a novel treatment for painful conditions.

Expression of sterol regulatory element-binding protein 1 (SREBP1) is upregulated in thyroid cancer and associated with shorter disease-specific survival. The molecular regulatory mechanisms governing SREBP1 over-expression in thyroid cancer are still unclear.Thyroid cancer cell lines BHT-101 (with the BRAF V600E mutation) and FTC-131 (wild-type for BRAF) were treated with specific inhibitors. The expression of SREBP1 was determined at the mRNA level using quantitative real-time PCR and at the protein level using immunoblotting.Lenvatinib and a MEK inhibitor, selumetinib, suppressed SREBP1 expression in BHT-101 but not FTC-133 cells. Olitigaltin, a galectin-3 inhibitor, decreased SREBP1 expression in a time- and dose-dependent manner in both cells. MK2206, an allosteric AKT inhibitor, did not change SREBP1 expression in either cell line.The galectin-3 inhibitor attenuates SREBP1 expression in thyroid cancer cells, likely independent of AKT phosphorylation. Lenvatinib and selumetinib decreases SREBP1 expression in the BRAF-mutant cell line BHT-101.

The MELAS syndrome primarily affecting the CNS is mainly caused by the m.A3243G mutation. The heteroplasmy in different tissues affects the phenotypic spectrum, yet the impact of various levels of m.A3243G heteroplasmy on CNS remains elusive due to the lack of a proper neuronal model harboring m.A3243G mutation. We generated induced neurons (iNs) through the direct reprogramming of MELAS patients, with derived fibroblasts harboring high (>95%), intermediate (68%), and low (20%) m.A3243G mutation. iNs demonstrated neuronal morphology with neurite outgrowth, branching, and dendritic spines. The heteroplasmy and deficiency of respiratory chain complexes were retained in MELAS iNs. High heteroplasmy elicited the elevation in ROS levels and the disruption of mitochondrial membrane potential. Furthermore, high and intermediate heteroplasmy led to the impairment of mitochondrial bioenergetics and a change in mitochondrial dynamics toward the fission and fragmentation of mitochondria, with a reduction in mitochondrial networks. Moreover, iNs derived from aged individuals manifested with mitochondrial fission. These results help us in understanding the impact of various heteroplasmic levels on mitochondrial bioenergetics and mitochondrial dynamics in neurons as the underlying pathomechanism of neurological manifestations of MELAS syndrome. Furthermore, these findings provide targets for further pharmacological approaches of mitochondrial diseases and validate iNs as a reliable platform for studies in neuronal aspects of aging, neurodegenerative disorders, and mitochondrial diseases.

The use of additive manufactured (AM) titanium-based materials has increased substantially for medical implants and aerospace components. However, the inferior surface roughness of additive manufactured products affects the outward appearance and reduces performance. This study determines whether activation treatment prior to electropolishing produces a better surface. Oxalic acid (OA) is used as a pre-activator using different experimental conditions and the surface roughness is reduced by electropolishing with an electrolyte of perchloric acid and glacial acetic acid. The SEM surface morphology, mechanical properties, phase transformation and electrochemical properties are measured to determine the effect of different degrees of roughness on the surface. The results show that the surface roughness of AM titanium-based samples decreases from 8.47 µm to 1.09 µm after activation using OA as a pre-treatment for electropolishing. After electropolishing using optimal parameters, the hardness and resistance to corrosion resistance are increased.

The types of secondary metabolites of Aurantii Fructus samples from GAP base in different harvest periods were detected by UPLC-Q-TOF-MS metabolomics, and the differential metabolites were screened out by multivariate statistical analysis. The variation of the content of differential metabolites with different harvest periods was analyzed, and the correlation analysis was carried out on the differential metabolites to determine the suitable harvest period for different components. Sixteen differential metabolites were obtained. With the delay of harvest time, the content of flavonoid glycosides, including naringin, neohesperidin, poncirin, narirutin, and hesperidin, gradually decreased. It is suggested that the suitable harvest period for raw materials of Aurantii Fructus with flavonoids as active components is from July 18 to July 25(within one week before and after the Great heat). The content of nobiletin, tangeretin, natsudaidain, 7-hydroxyl-4',3,5,6,8-pentamethoxyflavone, sinensetin, isosinensetin, 5,6,7,4'-tetramethoxyflavone, and isomeranzin decreased first, then increased, and finally decreased. It is suggested that the suitable harvest time for raw materials of Aurantii Fructus with these components as the active components is July 18. The content changes of meranzin, limonin, and 3,5,6,7,8,3',4'-heptamethoxyflavone have their characteristics. According to the conditions of actual production, it is suggested that the suitable harvest time is June 27, July 11, and July 25, respectively. The results showed that there were differences in the content of chemical components of Aurantii Fructus in different harvest periods, and the suitable harvest period should be determined according to the differences in chemical component content. This study is expected to provide a scientific basis for the purchase of raw materials of Aurantii Fructus for Chinese patent medicines with different effects.

1,4-Dihydropyridines (DHPs) represent the blockbuster class of L-type calcium channel blockers that have tremendous therapeutic value against cardiovascular conditions. Due to their abilities to additionally target other subtypes of calcium channels, DHPs are also considered promising molecules for the treatment of neurological and psychiatric disorders. Having been in the market for more than forty years, DHP is one of the most modified scaffolds for the development of novel molecules acting on calcium channels. Taking the chemical structures of approved DHPs into account, it is noteworthy that C-4 position is the least modified part of the ring system. Therefore, in the present study, we focused on this location and carried out various molecular modifications to obtain twelve potential calcium channel blockers with a DHP-based hexahydroquinoline scaffold (DA1-DA12). The whole-cell patch clamp technique applied to analyze the blocking ability of the synthesized compounds on both L- (Ca

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of cortical, brain stem and spinal motor neurons that leads to muscle weakness and death. A previous study implicated CACNA1H encoding for Cav3.2 calcium channels as a susceptibility gene in ALS. In the present study, two heterozygous CACNA1H variants were identified by whole genome sequencing in a small cohort of ALS patients. These variants were functionally characterized using patch clamp electrophysiology, biochemistry assays, and molecular modeling. A previously unreported c.454GTAC > G variant produced an inframe deletion of a highly conserved isoleucine residue in Cav3.2 (p.ΔI153) and caused a complete loss-of-function of the channel, with an additional dominant-negative effect on the wild-type channel when expressed in trans. In contrast, the c.3629C > T variant caused a missense substitution of a proline with a leucine (p.P1210L) and produced a comparatively mild alteration of Cav3.2 channel activity. The newly identified ΔI153 variant is the first to be reported to cause a complete loss of Cav3.2 channel function. These findings add to the notion that loss-of-function of Cav3.2 channels associated with rare CACNA1H variants may be risk factors in the complex etiology of ALS.

T-type calcium channels are known molecular targets of certain phytocannabinoids and endocannabinoids. Here we explored the modulation of Cav3.2 T-type calcium channels by terpenes derived from cannabis plants. A screen of eight commercially available terpenes revealed that camphene and alpha-bisabolol mediated partial, but significant inhibition of Cav3.2 channels expressed in tsA-201 cells, as well as native T-type channels in mouse dorsal root ganglion neurons. Both compounds inhibited peak current amplitude with IC50s in the low micromolar range, and mediated an additional small hyperpolarizing shift in half-inactivation voltage. When delivered intrathecally, both terpenes inhibited nocifensive responses in mice that had received an intraplantar injection of formalin, with alpha-bisabolol showing greater efficacy. Both terpenes reduced thermal hyperalgesia in mice injected with Complete Freund’s adjuvant. This effect was independent of sex, and absent in Cav3.2 null mice, indicating that these compounds mediate their analgesic properties by acting on Cav3.2 channels. Both compounds also inhibited mechanical hypersensitivity in a mouse model of neuropathic pain. Hence, camphene and alpha-bisabolol have a wide spectrum of analgesic action by virtue of inhibiting Cav3.2 T-type calcium channels. Supplementary Information The online version contains supplementary material available at 10.1186/s13041-021-00876-6.

Syndiotactic poly(4-methyl-1-pentene) (sP4M1P)-based stereoregular diblock copolymers, namely sP4M1P-b-polystyrene and sP4M1P-b-polymethylmethacrylate, were prepared from an α-bromoester-capped sP4M1P macroinitiator, which was chain extended with styrene and methyl methacrylate, respectively, via the atom transfer radical polymerization reaction. The α-bromoester-capped sP4M1P was generated by the esterification of hydroxyl-capped sP4M1P with α-bromoisobutyryl bromide. The hydroxyl-capped sP4M1P was synthesized by inducing a selective chain transfer reaction to aluminum during the syndiospecific polymerization of 4-methyl-1-pentene in the presence of a syndiospecific metallocene catalyst. As stereoregular diblock copolymers are difficult to prepare using existing methods, the current study offers an effective process for the preparation of sP4M1P-based stereoregular diblock copolymers. These copolymers were found to have well-defined architectures and they can undergo molecular self-assembly into ordered nanostructures, as evidenced by small-angle X-ray scattering analyses.

BACKGROUND/AIM Ethacridine is used as a topical antiseptic as well as for second-trimester abortion. Recent studies showed that ethacridine is an inhibitor of poly(ADP-ribose) glycohydrolase (PARG) and an activator of the transcriptional coactivator with PDZ-binding motif (TAZ). This study examined the effects of ethacridine on thyroid cancer cells. MATERIALS AND METHODS Thyroid cancer cell lines (FTC133 and SW1736) and thyroid follicular epithelial cells (Nthy-ori 3-1) were treated with ethacridine. Viability, clonogenicity, cell-cycle distribution, and apoptosis were evaluated. The expression of thyroid differentiation markers (TTF-1, PAX8, and NIS) was determined by real-time PCR. RESULTS Ethacridine suppressed cell growth and clonogenic ability of thyroid cancer cells in a time- and dose-dependent manner (p

Zeolites are strongly hydrophilic materials that are widely used as water adsorbents. They are also promising candidates for antifogging coatings; however, researchers have yet to devise a suitable method for coating glass substrates with zeolite-based films. Here, we report on a direct wet deposition technique that is capable of casting zeolite films on glass substrates without exposing the glass to highly basic solutions or the vapors used in zeolite synthesis. We began by preparing cast solutions of pure silica zeolite MFI synthesized in hydrothermal reactions of various durations. The solutions were then applied to glass substrates via spin-on deposition to form zeolite films. The resulting zeolite MFI thin films were characterized in terms of transmittance to visible light, surface topography, thin film morphology, and crystallinity. Wetting and antifogging properties were also probed. We found that hydrophilicity and antifogging capability increased with the degree of thin film crystallinity. We also determined that the presence of the amorphous silica in the thin films is critical to transparency. Fabricating high-performance zeolite-based antifogging coatings requires an appropriate composition of zeolite crystals and amorphous silica.

Seeded growth is the most popular approach to the preparation of zeolite thin films and membranes. Herein, we report a simplified method of fabricating zeolite Faujasite (FAU) thin films through the direct wet deposition of zeolite FAU thin films using stabilized colloidal suspensions. Zeolite FAU suspensions are stabilized by adjusting the pH values and the suspensions are spin-coated on a silicon wafer substrate to form dense zeolite FAU thin films. Dynamic light scattering (DLS) was used to investigate the colloidal properties of the zeolite FAU suspensions. The time-dependent hydrodynamic radius Rh was derived from DLS measurements for use as a quantitative measure of colloidal stability. It was found that high pH values destabilize the colloidal suspensions. Thin film samples cast using the relatively stable zeolite FAU suspensions yielded thin films with uniform morphology. In thin films formed from suspensions with a high pH value, the zeolite FAU crystals transformed into a dense phase. We also measured the relative permittivity (er) of the thin film samples cast from various suspensions. At a low frequency (

We have previously reported that cellular prion protein (PrPC) can down-regulate NMDA receptor activity and in a copper dependent manner. Here, we employed AAV9 to introduce murine cellular prion protein into mouse hippocampal neurons in primary cultures from PrP null mice to determine the role of the six copper binding motifs located within the N-terminal domain of PrPC. The results demonstrate that viral expression of wild type PrPC lowers NMDAR activity in PrP null mouse hippocampal neurons by reducing the magnitude of non-desensitizing currents. Elimination of the last two copper binding sites alone, or in combination with the remaining four attenuates this protective effect. Thus our data suggest that copper ion interactions with specific binding sites on PrPC are critical for PrPC dependent modulation of NMDA receptor function.

T-type calcium channels are considered potential drug targets to combat cancer. Combining T-type calcium channel blockers with conventional chemotherapy drugs represents a promising strategy towards successful cancer treatment. From this perspective, we report in this study the design and synthesis of a novel series of N3-sustituted dihydropyrimidines (DHPMs) as anticancer adjuvants to cisplatin (Cis) and etoposide (Eto). Full spectral characterization of the new compounds was done using FT-IR, 1H NMR, 13C NMR, and HRMS. Structure elucidation was confirmed by 2D NMR 1H-H COSY, HSQC and NOESY experiments. Novel derivatives were tested for their Ca2+ channel blocking activity by employing the whole cell patch-clamp technique. Results demonstrated that most compounds were potential T-type calcium channel blockers with the triazole-based C12 and C13 being the most selective agents against CaV3.2 channel. Further electrophysiological studies demonstrated that C12 and C13 inhibited CaV3.2 currents with respective affinity of 2.26 and 1.27 µM, and induced 5 mV hyperpolarizing shifts in the half-inactivation potential. Subsequently, C12 and C13 were evaluated for their anticancer activities alone and in combination with Cis and Eto against A549 and MDA-MB 231 cancer cells. Interestingly, both compounds exhibited potential anticancer effects with IC50 values