Purinergic P2X7 receptor involves in anti-retinal photodamage effects of berberine.

Berberine (BBR) is a Chinese herb with antioxidant and anti-inflammatory properties. In a previous study, we found that BBR had a protective effect against light-induced retinal degeneration in BALB/c mice. The purinergic P2X7 receptor (P2X7R) plays a key role in retinal degeneration via inducing oxidative stress, inflammatory changes, and cell death. The aim of this study was to investigate whether BBR can induce protective effects in light damage experiments and whether P2X7R can get involved in these effects. C57BL/6 J mice and P2X7 knockout (KO) mice on the C57BL/6 J background were used. We found that BBR preserved the outer nuclear layer (ONL) thickness and retinal ganglion cells following light stimulation. Furthermore, BBR significantly suppressed photoreceptor apoptosis, pro-apoptotic c-fos expression, pro-inflammatory responses of Mϋller cells, and inflammatory factors (TNF-α, IL-1ß). In addition, protein levels of P2X7R were downregulated in BBR-treated mice. Double immunofluorescence showed that BBR reduced overexpression of P2X7R in retinal ganglion cells and Mϋller cells. Furthermore, BBR combined with the P2X7R agonist BzATP blocked the effects of BBR on retinal morphology and photoreceptor apoptosis. However, in P2X7 KO mice, BBR had an additive effect resulting in thicker ONL and more photoreceptors. The data suggest that the P2X7 receptor is involved in retinal light damage, and BBR inhibits this process by reducing histological impairment, cell death, and inflammatory responses.

Antiplatelet and Antithrombotic Effects of Isaridin E Isolated from the Marine-Derived Fungus via Downregulating the PI3K/Akt Signaling Pathway.

Isaridin E, a cyclodepsipeptide isolated from the marine-derived fungus Amphichorda felina (syn. Beauveria felina) SYSU-MS7908, has been demonstrated to possess anti-inflammatory and insecticidal activities. Here, we first found that isaridin E concentration-dependently inhibited ADP-induced platelet aggregation, activation, and secretion in vitro, but did not affect collagen- or thrombin-induced platelet aggregation. Furthermore, isaridin E dose-dependently reduced thrombosis formation in an FeCl3-induced mouse carotid model without increasing the bleeding time. Mechanistically, isaridin E significantly decreased the ADP-mediated phosphorylation of PI3K and Akt. In conclusion, these results suggest that isaridin E exerts potent antithrombotic effects in vivo without increasing the risk of bleeding, which may be due to its important role in inhibiting ADP-induced platelet activation, secretion and aggregation via the PI3K/Akt pathways.

Inhibitory effect of gallic acid on voltage-gated Na+ channels in rat cardiomyocytes.

Gallic acid (GA) has a protective effect on the cardiovascular system. To study its cardiac electrophysiological effects, voltage-gated Na+ channel currents (INa ) were recorded in rat cardiomyocytes using whole-cell patch clamp techniques. Moreover, the effects of GA on aconitine-induced arrhythmias were assessed using electrocardiograms in vivo. We found that the current-voltage characteristic curve (I-V curve) of INa significantly shifted in the presence of 1, 3, and 10 µmol/L of GA. The peak sodium current density (INa -Peak) was reduced from -84.02 ± 5.68 pA/pF to -65.78 ± 3.96 pA/pF with 1 µmol/L, -54.45 ± 5.18 pA/pF with 3 µmol/L, and -44.20 ± 4.35 pA/pF with 10 µmol/L, respectively. GA shifted the steady-state activation curve of INa and recovery curve to the right and the steady-state inactivation curve to the left. The observed inhibitory effect was comparable to that of amiodarone. GA pre-treatment significantly prolonged the onset of fatal ventricular fibrillation. Our results indicated that GA inhibited INa in rat ventricular myocytes and aconitine-induced arrhythmias in vivo. These results suggest the potential of GA for development as a novel anti-arrhythmic therapeutic.

Discovery of Novel Coumarin-quinolinium Derivatives as Pan-KRAS Translation Inhibitors by Targeting 5'-UTR RNA G-Quadruplexes.

Hyperactivated KRAS mutations fuel tumorigenesis and represent attractive targets for cancer treatment. While covalent inhibitors have shown clinical benefits against the KRASG12C mutant, advancements for non-G12C mutants remain limited, highlighting the urgent demand for pan-KRAS inhibitors. RNA G-quadruplexes (rG4s) in the 5'-untranslated region of KRAS mRNA can regulate KRAS translation, making them promising targets for pan-KRAS inhibitor development. Herein, we designed and synthesized 50 novel coumarin-quinolinium derivatives, leveraging our previously developed rG4-specific ligand, QUMA-1. Notably, several compounds exhibited potent antiproliferative activity against cancer cells as pan-KRAS translation inhibitors. Among them, 15a displayed exceptional capability in stabilizing KRAS rG4s, suppressing KRAS translation, and consequently modulating MAPK and PI3K-AKT pathways. 15a induced cell cycle arrest, prompted apoptosis in KRAS-driven cancer cells, and effectively inhibited tumor growth in a KRAS mutant xenograft model. These findings underscore the potential of 15a as a pan-KRAS translation inhibitor, offering a novel and promising approach to target various KRAS-driven cancers.

Discovery of Clinically Used Octenidine as NRAS Repressor That Effectively Inhibits NRAS-Mutant Melanoma.

Mutations in NRAS promote tumorigenesis and drug resistance. As this protein is often considered an undruggable target, it is urgent to develop novel strategies to suppress NRAS for anticancer therapy. Recent reports indicated that a G-quadruplex (G4) structure formed in the untranslated region of NRAS mRNA can downregulate NRAS translation, suggesting a potential NRAS suppression strategy. Here, we developed a novel cell-based method for large-scale screening of NRAS G4 ligand using the G-quadruplex-triggered fluorogenic hybridization probe and successfully identified the clinically used agent Octenidine as a potent NRAS repressor. This compound suppressed NRAS translation, blocked the MAPK and PI3K-AKT signaling, and caused concomitant cell cycle arrest, apoptosis, and autophagy. It exhibited better antiproliferation effects over clinical antimelanoma agents and could inhibit the growth of NRAS-mutant melanoma in a xenograft mouse model. Our results suggest that Octenidine may be a prominent anti-NRAS-mutant melanoma agent and represent a new NRAS-mutant melanoma therapy option.

Preparation and Tribological Properties of a Multilayer Graphene-Reinforced TiO2 Composite Nanolubricant Additive.

The unique structure and physical properties of graphene and anatase TiO2 make them suitable for use as additives for engine lubricants. This study describes the use of dielectric barrier discharge plasma-assisted ball milling to synthesize a multilayer graphene-reinforced TiO2 composite nanolubricant additive (MGTC). A variety of physical and chemical tests were performed to characterize the resulting experimental materials, including X-ray diffraction (XRD), Fourier transform infrared (FT-IR), Raman, X-ray photoelectron spectroscopy (XPS), and scanning electron microscopy (SEM). Four-ball friction and wear testing machines were used to study the tribological properties and extreme pressure anti-wear properties of a base oil containing 0.1, 0.5, 1.0, and 1.5 wt % of the modified TiO2. Raman spectroscopy, XPS, SEM, and energy-dispersive spectrometry (EDS) analyses were used to examine and analyze the microstructure of the friction pairs. As a result of the plasma-assisted ball milling process, expanded graphite was successfully separated into multilayer graphene nanosheets, and spherical TiO2 was successfully bonded to the nanosheets of the multilayer graphene. The 1.0 wt % composite oil was found to provide good friction reduction and wear resistance. It had a film thickness of 27.5 nm, which was 167% thicker than base oil. Due to its excellent dispersion stability, the MGTC nanocomposite exhibited excellent lubrication performance, which was attributed to the formation of carbon protective films, titanium dioxide deposition films, transfer films, and the occurrence of nano ball effects on the surface of friction pairs.

Environmental eustress improves postinfarction cardiac repair via enhancing cardiac macrophage survival.

Macrophages play a vital role in cardiac repair following myocardial infarction (MI). An enriched environment (EE) is involved in the regulation of macrophage-related activities and disease progression; however, whether EE affects the phenotype and function of macrophages to improve postinfarction cardiac repair remains unknown. In this study, we found that EE improved cardiac function, decreased mortality, and ameliorated adverse ventricular remodeling in mice after MI, with these outcomes closely related to the increased survival of Ly6Clow macrophages and their CCR2-MHCIIlow subsets. EE increased the expression of brain-derived neurotrophic factor (BDNF) in the hypothalamus, leading to higher circulating levels of BDNF, which, in turn, regulated the cardiac macrophages. BDNF bound to tropomyosin receptor kinase B to activate downstream ERK1/2 and AKT pathways, promoting macrophage survival. These findings demonstrate that EE optimizes postinfarction cardiac repair and highlights the significance of EE as a previously unidentified strategy for impeding adverse ventricular remodeling.

Goodyschle A, a new butenolide with significant BchE inhibitory activity from Goodyera schlechtendaliana.

Goodyschle A (1), a new butenolide, was isolated from the whole grass of Goodyera schlechtendaliana, an orchidaceous edible medicinal plant. The structure of the new compound was elucidated by 1 D and 2 D NMR experiments in addition to HRESIMS analyses. Compound 1 was evaluated for its bioactivities including cytotoxic activity against human gastric cancer (SGC-7901) and human hepatocellular carcinoma (HepG2) cell lines, inhibitory activity on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and DPPH radical scavenging activity. As a result, compound 1 showed potent BChE inhibitory activity (IC50 value = 6.88 ± 1.63 µM), moderate DPPH radical scavenging activity (IC50 value = 16.25 ± 0.21 µM), and slight AChE inhibitory and cytotoxic activities. These findings suggest that compound 1 is worthy for further investigations in terms of its selective BChE inhibitory activity.

Acute suppurative thyroiditis with thyroid metastasis from oesophageal cancer.

Not required for Clinical Vignette.

Sensitized heat shock protein 27 induces retinal ganglion cells apoptosis in rat glaucoma model.

AIM: To investigate the relationships between the changes of heat shock protein 27 antibody (anti-HSP27) in serum/cerebrospinal fluid (CSF), intraocular pressure (IOP), retinal ganglion cell (RGC) apoptosis in a rat glaucoma model and disclose the underlying pathogenesis of glaucoma. METHODS: A total of 115 Wistar rats were randomly divided into 4 groups. Group 1 was the ocular hypertension group by condensing 3 episcleral & limbal veins or episcleral area of right eye (HP group, n=25) and sham operation group with conjunctiva incision without coagulation (n=25). Group 2: HSP27 or dose-matched PBS was injected into the vitreous (V-HSP27 group, n=15; V-PBS group, n=15). Group 3: HSP27 and complete Freund's adjuvant or dose-matched PBS was injected subcutaneously into the hind limb accompanied intraperitoneal injection of pertussis toxin [sensitized group (I-HSP27 group), n=15; I-PBS group, n=15)]. Group 4 was normal group without any treatment (n=5). IOPs of the rats were measured before, day 3, weeks 1, 2, 4, 6, and 8 after treatment. Paraffin-embedded sections were prepared for HE staining and RGCs apoptosis were detected by TUNEL. Anti-HSP27 level in serum and CSF were examined by ELISA. RESULTS: IOPs were elevated significantly in HP and V-HSP27, V-PBS groups (P<0.01) and positively related to anti-HSP27 levels in serum and CSFs. Anti-HSP27 levels in serum and CSF were elevated significantly in I-HSP27 group compared to other groups (P<0.05). However, the IOPs did not show any relationship with the high-level anti-HSP27 in serum and CSFs. RGC apoptosis were all elevated significantly in the HP, V-HSP27, V-PBS and I-HSP27 groups and also positively relative with anti-HSP27 level in serum and CSFs except that high-level of anti-HSP27 in the serum of I-HSP group. CONCLUSION: The increases of anti-HSP27 levels in serum and CSFs both promote IOP escalation and the increase of RGC apoptosis in retina when anti-HSP27 is at low level. The case of high-level anti-HSP27 is opposite and shows protective function in preventing IOP increase and RGC apoptosis.

[Effects of preemptive analgesia with flurbiprofen on the blood sugar and interleukin-6 of patients after radical excision of breast cancer].

OBJECTIVE: To investigate the effects of preemptive analgesia with flurbiprofen on the blood sugar and Interleukin-6 of patients after radical excision of breast cancer. METHODS: A total of 60 ASA I-II patients scheduled for radical excision of breast cancer were randomly assigned to three groups: group A, B and C (n = 20 each), patients of group A and C received intravenous flurbiprofen 100 mg before or at the end of surgery respectively. Blood samples were collected from the patients before anaesthesia induction and 1, 6, 24 h after surgery for the determination of blood sugar and serum interleukin-6 concentration. Analgesic efficacy was assessed after surgery based on visual analog scales (VAS). RESULTS: The blood sugar and serum interleukin-6 concentration of the patients in three groups at different time points after surgery were significantly higher than those before surgery, and increased gradually in group B, and there were very significant difference between the time point of 1 h and 24 h after surgery (P < 0.01), but there were no increasing trend for those of group A and C. The blood sugar and serum interleukin-6 concentration of the patient of group A were significantly lower than those of group B and C (P < 0.01 or 0.05). The highest VAS of group A and C at different time points after surgery were significantly lower than that of group B(P < 0.05). CONCLUSION: Preemptive analgesia with flurbiprofen 100 mg can effectively suppress the elevation of blood sugar and serum interleukin-6 concentration after radical excision of breast cancer, and is better than postoperation analgesia.

Resolution and evaluation of 3-chlorophenyl-3-hydroxypropionylhydroxamic acid as antivirulence agent with excellent eradication efficacy in Helicobacter pylori infected mice.

The continuing emergence of drug-resistant Helicobacter pylori (HP) drives the ongoing need for the development of new and effective anti-HP drugs. Urease inhibitor has now gained strong interest as an alternative approach for HP infections. 3-Chlorophenyl-3-hydroxypropionylhydroxamic acid (CPH), a novel urease inhibitor identified in our group, shows impressive potency, which was optically separated for a further exploration. Here, we report in vitro/in vivo pharmacological evaluation of (±)-CPHs and the enantiomers. The raceme and the individual enantiomers significantly suppress gastritis at 32 mg/kg b.i.d dose with lower toxicity to mammalian cells (with CC50s ≥ 3.16 mM) and mice (LD50s ≥ 2338 mg/kg) than the clinically used agent acetohydroxamic acid. Furthermore, a significant increase of eradication of HP is observed for the combination of (±)-CPHs or the enantiomers with an antimicrobial. These studies revealed that CPH is a promising candidate for an alternative treatment of HP-dependent conditions by targeting virulence factor urease, and CPH may be used as a raceme.

The Retinal Pigment Epithelium Is a Notch Signaling Niche in the Mouse Retina.

Notch signaling in neural progenitor cell is triggered by ligands expressed in adjacent cells. To identify the sources of active Notch ligands in the mouse retina, we negatively regulated Notch ligand activity in various neighbors of retinal progenitor cells (RPCs) by eliminating mindbomb E3 ubiquitin protein ligase 1 (Mib1). Mib1-deficient retinal cells failed to induce Notch activation in intra-lineage RPCs, which prematurely differentiated into neurons; however, Mib1 in post-mitotic retinal ganglion cells was not important. Interestingly, Mib1 in the retinal pigment epithelium (RPE) also contributed to Notch activation in adjacent RPCs by supporting the localization of active Notch ligands at RPE-RPC contacts. Combining this RPE-driven Notch signaling and intra-retinal Notch signaling, we propose a model in which one RPC daughter receives extra Notch signals from the RPE to become an RPC, whereas its sister cell receives only a subthreshold level of intra-retinal Notch signal and differentiates into a neuron.

[Study of inorganic elements in silybum marianum: distribution and extraction rate].

The contents of multiple inorganic elements in silybum marianum products in different processing stages, including dry fruit, seedcake and extracts, were simultaneously measured by inductively coupled plasma atom emission spectrometry (ICP-AES) and inductively coupled plasma mass spectrometry (ICP-MS). The results indicated that the contents of the elements are the highest in the seedcake and the lowest in the extracts. Moreover, the different decoctions of Silybum marianum fruit made for different immersion times were determined. It was demonstrated that most of the elements measured are soluble, and the total content extracted for the first four immersion times is much higher than that for the latter three times. The certificate reference tea (GBW070605) was analyzed by this method, and the analysis results of most elements in the reference tea were in agreement with the certified values.

Diversified syntheses of multifunctionalized thiazole derivatives via regioselective and programmed C-H activation.

The sequential construction of diversified multifunctionalized thiazole derivatives through Pd-catalyzed regioselective C-H alkenylation has been accomplished. This versatile approach provides the diversified thiazole derivatives featuring orthogonal substitution patterns at the C-2, C-4 and C-5 positions from mono-substituted (2- or 4-substituted) thiazole derivatives or even more challenging simple thiazole.

Determination of aluminum in environmental and biological samples by reversed-phase high-performance liquid chromatography via pre-column complexation with morin.

Morin was used as a pre-column reagent for the determination of aluminum by RP-HPLC with fluorescence detection. This method has been successfully applied to direct determination of trace Al in environmental and biological samples. The response was linear from 6 x 10(-9) to 6 x 10(-5) M with a detection limit of 2 x 10(-9) M. In addition, the different Al complexes with morin were separated by the proposed HPLC procedure and their coordination ratios were depicted by molar-ratio method. The results showed that 1:1 and 2:1 Al-morin complexes formed.

[Speciation of aluminum in natural waters by fluorimetry].

Fluorimetric method has been proposed for the speciation of Al in natural waters, based on the different competitive complexation behavior of analytical reagent and natural organic matter to Al. With eriochrome blue black R (EBBR) or morin, the monomeric inorganic Al (Al(i)) was determined, while with 8-hydroxylquinoline, the total monomeric Al (Al(a)) was obtained. The analytical results of Al speciation in natural water are close to those by Driscoll's method. The method is simple and reliable. Fractionation of Al was realized by selecting appropriate reagents under the pH of natural water determined. The merits of this novel strategy are that the disturbance to original equilibrium of Al species is minimized and the results conform to the actual situation of natural waters.

Application of Prussian blue staining in the diagnosis of ocular siderosis.

AIM: To explore the value of Prussian blue staining in the diagnosis of ocular siderosis. METHODS: Between January 2012 and January 2013, the Prussian blue stain used in anterior lens capsule and vitreous liquid after centrifugation from patients with definitive diagnosis and suspicious diagnosed of ocular siderosis. At the same time, give a negative control. RESULTS: Anterior lens capsule membrane and liquid of vitreous cavity from patients with definitive diagnosis and suspicious diagnosed of ocular siderosis revealed ferric ions that stained positively with Prussian blue. In the control group, there is no positive reaction. CONCLUSION: Prussian blue staining in the diagnosis of ocular siderosis has a very significant worth, suspected cases can be definitive diagnosed.

Reigoselective arylation of thiazole derivatives at 5-position via Pd catalysis under ligand-free conditions.

An efficient regioselective arylation of thiazole derivatives via Pd-catalyzed C-H activation is reported. The transformation was hypothesized through a Pd(0/II) catalytic cycle in the absence of special ligand sets. This method provided an efficient process to direct arylation of thiazoles at the 5-position.