Expert insights: The potential role of the gut microbiome-bile acid-brain axis in the development and progression of Alzheimer's disease and hepatic encephalopathy

Recent epidemiological and molecular studies have linked the disruption of cholesterol homeostasis to increased risk for developing Alzheimer's disease (AD). Emerging evidence also suggests that brain cholesterol accumulation contributes to the progression of hepatic encephalopathy (HE) via bile acid (BA)-mediated effects on the farnesoid X receptor. In this perspective paper, we reviewed several recently published studies that suggested a role for the gut microbiota transformation of BAs as a factor in AD and HE development/progression. We hypothesize that in addition to cholesterol elimination pathways, alteration of the gut microbiota and subsequent changes in both the serum and brain BA profiles are mechanistically involved in the development of both AD and HE, and thus, are a potential target for the prevention and treatment of the two diseases. Our understanding of the microbiome-BAs-brain axis in central nervous system disease is still evolving, and critical questions regarding the emerging links among central, peripheral, and intestinal metabolic failures contributing to brain health and disease during aging have yet to be addressed.     

Changes in Pain-Related Fear and Pain When Avoidance Behavior is no Longer Effective

Avoidance is considered key in the development of chronic pain. However, little is known about how avoidance behavior subsequently affects pain-related fear and pain. We investigated this using a robotic arm reaching avoidance task. In a between-subjects design both Experimental Group (n = 30) and Yoked Control Group (n = 30) participants perform either of 3 movement trajectories (T1–T3) to reach a target location. During acquisition, only participants of the Experimental Group could partially or fully avoid a painful electrocutaneous stimulus by choosing the intermediate trajectory (T2; 50% reinforcement) or the longest trajectory (T3; 0% reinforcement) versus the shortest trajectory (T1: 100% reinforcement). After acquisition, contingencies changed (all trajectories 50% reinforced), and the acquired avoidance behavior no longer effectively prevented pain from occurring. The Yoked Control Group received the same reinforcement schedule as the Experimental Group irrespective of their behavior. When avoidance behavior became ineffective for the Experimental Group, pain-related fear increased for the previously safe(r) trajectories (T2 and T3) and remained the same for T1, whereas pain threshold and tolerance declined. For the Yoked Group, pain-related fear increased for all trajectories. The Experimental Group persisted in emitting avoidance behavior following the contingency change, albeit at a lower frequency than during acquisition.PerspectiveResults indicate participants become more afraid of and sensitive to pain, when previously acquired avoidance is no longer effective. Also, participants continue to show avoidance behavior despite it being not adaptive anymore. These findings suggest that ineffective avoidance may play role in the maintenance and development of chronic pain.     

中药人源性毒性评判的科学基础、策略与技术关键点

中药毒性研究中因伦理原则不可能在人体进行还原论模式的临床研究,体内外结合、动物与人体临床研究的结合成为研究模式的必然选择。有毒中药药材面临着药材组成成分的定性与定量水平差异、各不同产地药材组成成分巨大变异、毒理机制的万变、体内外模型差异、种属差异、器官组织细胞组成差异、代谢与功能非均一性、评价指标与检测方法多重性等差异的众多挑战与难题。现代毒理学高度重视与强调对人源性毒理学(而非动物毒性或细胞毒性)特征及其本质的研究,但人源性毒性在体内外体系、种属差异、脏器组织特征差异、形态结构学与分子组成差异等众多影响因素的干扰下,常常迷失本质性、机制性或原理性研究方向,理清研究逻辑,选择正确的策略与技术切入点才能避免中药毒性评价与研究误入歧途。     

Junctional adhesion molecule-like protein as a novel target for kaempferol to ameliorate lung adenocarcinoma

Objective: Although there have been improvements in targeted therapy and immunotherapy, the majority of lung adenocarcinoma(LUAD) patients still lack effective therapies. Consequently, it is urgent to screen for new diagnosis biomarkers and pharmacological targets. Junctional adhesion molecule-like protein(JAML) was considered to be an oncogenic protein and may be a novel therapeutic target in LUAD.Kaempferol is a natural flavonoid that exhibits antitumor activities in LUAD. However, the effect ...     

Ferulic acid enhances insulin secretion by potentiating L-type Ca2+ channel activation

Objective: To investigate the effect of ferulic acid, a natural compound, on pancreatic beta cell viability,Ca²⁺ channels, and insulin secretion.Methods: We studied the effects of ferulic acid on rat insulinoma cell line viability using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide viability assay. The whole-cell patch-clamp technique and enzyme-linked immunosorbent assay were also used to examine the action of ferulic acid on Ca²⁺ channels and insulin se...     

Inhibition of drug-metabolizing enzymes by Jingyin granules: implications of herb–drug interactions in antiviral therapy

Jingyin granules, a marketed antiviral herbal medicine, have been recommended for treating H1N1 influenza A virus infection and Coronavirus disease 2019 (COVID-19) in China. To fight viral diseases in a more efficient way, Jingyin granules are frequently co-administered in clinical settings with a variety of therapeutic agents, including antiviral drugs, anti-inflammatory drugs, and other Western medicines. However, it is unclear whether Jingyin granules modulate the pharmacokinetics of Western drugs or trigger clinically significant herb–drug interactions. This study aims to assess the inhibitory potency of the herbal extract of Jingyin granules (HEJG) against human drug-metabolizing enzymes and to clarify whether HEJG can modulate the pharmacokinetic profiles of Western drug(s) in vivo. The results clearly demonstrated that HEJG dose-dependently inhibited human CES1A, CES2A, CYPs1A, 2A6, 2C8, 2C9, 2D6, and 2E1; this herbal medicine also time- and NADPH-dependently inhibited human CYP2C19 and CYP3A. In vivo tests showed that HEJG significantly increased the plasma exposure of lopinavir (a CYP3A-substrate drug) by 2.43-fold and strongly prolonged its half-life by 1.91-fold when HEJG (3 g/kg) was co-administered with lopinavir to rats. Further investigation revealed licochalcone A, licochalcone B, licochalcone C and echinatin in Radix Glycyrrhizae, as well as quercetin and kaempferol in Folium Llicis Purpureae, to be time-dependent CYP3A inhibitors. Collectively, our findings reveal that HEJG modulates the pharmacokinetics of CYP substrate-drug(s) by inactivating CYP3A, providing key information for both clinicians and patients to use herb–drug combinations for antiviral therapy in a scientific and reasonable way.     

Detection of tumours with nuclear magnetic resonance spectroscopy of plasma

A systematic investigation of cancer detection by water-suppressed nuclear magnetic resonance (NMR) of plasma is reported. With additional suppression of lactate, a statistically significant difference between the linewidths of the methylene group signal of patients with untreated cancer (average linewidth 26.9 ± 3.9 Hz) and normal controls (average linewidth 31.1 ± 4.9 Hz) has been found. However, overlap was found between these two groups. It is shown that recognition of malignancy could be improved by consideration of the different relations of the linewidths on the content of serum triglycerides and the observation of a shoulder at the high field side of the methylene signal. Preliminary investigations on lipid fractions separated by ultracentrifugation (UC) indicate a connection of the appearance of the high field shoulder and the HDL lipoprotein.     

红景天苷对高原红细胞增多症大鼠红细胞膜结构和功能的影响

目的研究红景天苷对高原红细胞增多症(HAPC)大鼠红细胞膜结构与功能的影响,为红景天苷防治HAPC提供科学依据。方法 40只Wistar大鼠随机分为对照组、HAPC模型组及红景天苷高、中、低剂量(200、100、50 mg/kg)组,每组8只,雌雄各半。除对照组外,其余4组制备HAPC模型。对照组、模型组大鼠ig生理盐水,红景天苷组大鼠同时ig红景天苷,给药体积为10 mL/kg,1次/d,连续给药40 d。给药结束后,股动脉取血,采用生化、酶联免疫法测定大鼠红细胞膜脂质流动性和红细胞膜总胆固醇含量、总磷脂含量,以及磷脂成分磷脂酸(PA)、磷脂酰胆碱(PC)、磷脂酰乙醇胺(PE)、磷脂酰丝氨酸(PS)的含量,Na~+,K~+-ATPase和Ca~(2+),Mg~(2+)-ATPase的活性,红细胞内Na~+和Ca~(2+)浓度。结果红景天苷可显著提高HAPC大鼠红细胞膜脂质流动性和红细胞膜总磷脂、PA、PC、PE、PS含量,提高Na~+, K~+-ATPase和Ca~(2+), Mg~(2+)-ATPase的活性;显著降低红细胞膜总胆固醇含量、红细胞内Na~+和Ca~(2+)浓度。结论红景天苷可通过调控红细胞膜脂质成分,改善红细胞膜的功能和细胞代谢活动,进而缓解HAPC的相关症状。