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Alzheimer's disease (AD) is a progressive age-related neurodegenerative disease characterized by memory loss and cognitive impairment. The major characteristics of AD are amyloid β plaques, apoptosis, autophagy dysfunction, neuroinflammation, oxidative stress, and mitochondrial dysfunction. These are mostly used as the significant indicators for selecting the effects of potential drugs. It is imperative to explain AD pathogenesis and realize productive treatments. Although the currently used chemical drugs for clinical applications of AD are effective in managing the symptoms, they are inadequate to achieve anticipated preventive or therapeutic outcomes. There are new strategies for treating AD. Traditional Chinese Medicine (TCM) has accumulated thousands of years of experience in treating dementia. Nowadays, numerous modern pharmacological studies have verified the efficacy of many bioactive ingredients isolated from TCM for AD treatment. In this review, representative TCM for the treatment of AD are discussed, and among these herbal medicines, the Lamiaceae family accounts for the highest proportion. It is concluded that monomers and extracts from TCM have potential therapeutic effect for AD treatment.

PurposeThis research examines the dynamic interrelationship between economic policy uncertainty (EPU) and the inflows of foreign direct investment (IFDI) in China.Design/methodology/approachThis research used the Granger causality and sub-sample time-varying rolling window causality method.FindingsThe empirical results reveal that EPU tends to have a negative impact on the IFDI in most periods that have been taken into consideration. However, there has been a positive relationship observed between the periods of the US subprime crisis. That is to say that the uncertainty of the Chinese economic policy does not always impede the IFDI. These results are supported by the general equilibrium model, which states that there are certain influences that come into play when moving from EPU to IFDI. On the other hand, the IFDI exert a positive influence on EPU during times of economic crisis and trade war, which indicates that the uncertainty in the economy may increase due to the sudden soar of foreign investment.Originality/valueDuring tense global trade situations and complicated economic scenarios, the results suggest the Chinese government should dedicate itself to expanding its initiatives to open up and improve the domestic business environment in order to increase the foreign investors' confidence and prevent the decline in the IFDI. In addition to this, it also suggests that multinational companies pay attention to the policy environment of the host country, especially when they decide to invest there.

Tiebangchui (TBC, Tibetan name: བང་ང་ནག་པ།), the dried tuberous root of Busch. and Hand.-Mazz., is a prevalent used Tibetan medicine, recognized for its significant therapeutic effects despite its high toxicity. It is commonly employed in treating the diseases categorized as \"Long\" (རླུང་ནད།), cold, \"Huang-shui\" (སེར་ཆུ་ནད།), leprosy, and mania in Tibetan medicine. Notably, it is utilized in the treatment of rheumatoid arthritis, which is classified under the \"Huang-shui\" disease category according to Tibetan medical theory. Given its considerable toxicity, various processing techniques aimed at reducing the harmful effects of TBC are essential for its safe application in clinical settings. Hezi-decoction-processed method is a distinctive and effective traditional processing method of Tibetan medicine, but the overall variability of chemical constituents in the Hezi-decoction-processed TBC is still unclear. This investigation sought to examine a variety of diterpenoid alkaloids and tanning constituents, identify potential metabolic markers for differentiating the unprocessed TBC and Hezi-decoction-processed TBC at varying processing times, and determine the optimal processing time for reducing toxicity and maintaining efficacy. A combination of metabolomic techniques was developed, integrating ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) with desorption electrospray ionisation mass spectrometry imaging (DESI-MSI) coupled with quantitative analytical techniques. This was done with the objective of monitoring the dynamic alterations in chemical constituents in TBC during the processing time. Metabolic markers were observed via DESI-MSI, and three alkaloids and five tannin acids were quantified through the use of UPLC and HPLC. Fifty-one compounds were identified in unprocessed TBC and processed samples, of which 31 were discernible from unprocessed TBC. A total of 22 metabolic markers, such as aconine, aconitine, benzoylaconine, chebulic acid, gallic acid, and corilagin, can proficiently distinguish between raw and processed TBC with different processing times. And the results of content determination of three alkaloids and five tannins showed that they were stabilized at 72 h. The monoester-diterpenoid alkaloids (MDAs) and diester-diterpenoid alkaloids (DDAs) levels were 0.0149% and 0.0852% in 72 h, respectively. The contents of gallic acid, corilagin, 1,2,3,4,6- -pentagalloylglucose, chebulinic acid, and ellagic acid were 8.9706, 9.3444, 1.2438, 5.7582, and 3.1160 mg/g, respectively. The distribution and accumulation of metabolic markers during processing were investigated by DESI-MS. The results of DESI-MSI were consistent with those of content determination experiments. Combined with the multivariate statistical analysis, content determination of three alkaloids and five tannin acids and DESI-MSI, 72 h is demonstrated to be the appropriate time for toxicity attenuation and efficacy reservation of TBC. The implementation of this technique could contribute to the identification of markers in Hezi decoction-processed TBC and the establishment of effective quality control and evaluation procedures to ensure the safety of TBC. The proposed method has the potential to elucidate the processing mechanism of medicines and other toxic traditional Chinese medicines, given its wide applicability.

Programmed death ligand-1 (PD-L1)/PD-1 checkpoint extensively serves as a central mediator of immunosuppression. A tumor-promoting role for abundant PD-L1 in several cancers is revealed. However, the importance of PD-L1 and how the PD-L1 expression is controlled in breast cancer remains obscure. Here, the mechanisms of controlling PD-L1 at the transcription and protein acetylation levels in promoting breast cancer growth are presented. Overexpressed PD-L1 accelerates breast cancer growth in vitro and in vivo. RNA-seq uncovers that PD-L1 can induce some target genes affecting many cellular processes, especially cancer development. In clinical breast cancer tissues and cells, PD-L1 and HBXIP are both increased, and their expressions are positively correlated. Mechanistic exploration identifies that HBXIP stimulates the transcription of PD-L1 through co-activating ETS2. Specifically, HBXIP induces PD-L1 acetylation at K270 site through interacting with acetyltransferase p300, leading to the stability of PD-L1 protein. Functionally, depletion of HBXIP attenuates PD-L1-accelerated breast tumor growth. Aspirin alleviates breast cancer via targeting PD-L1 and HBXIP. Collectively, the findings display new light into the mechanisms of controlling tumor PD-L1 and broaden the utility for PD-L1 as a target in breast cancer therapy.

Aconitine, a common and main toxic component of Aconitum, is toxic to the central nervous system. However, the mechanism of aconitine neurotoxicity is not yet clear. In this work, we had the hypothesis that excitatory amino acids can trigger excitotoxicity as a pointcut to explore the mechanism of neurotoxicity induced by aconitine. HT22 cells were simulated by aconitine and the changes of target cell metabolites were real-time online investigated based on a microfluidic chip-mass spectrometry system. Meanwhile, to confirm the metabolic mechanism of aconitine toxicity on HT22 cells, the levels of lactate dehydrogenase, intracellular Ca2+, reactive oxygen species, glutathione and superoxide dismutase, and ratio of Bax/Bcl-2 protein were detected by molecular biotechnology. Integration of the detected results revealed that neurotoxicity induced by aconitine was associated with the process of excitotoxicity caused by glutamic acid and aspartic acid, which was followed by the accumulation of lactic acid and reduction of glucose. The surge of extracellular glutamic acid could further lead to a series of cascade reactions including intracellular Ca2+ overload and oxidative stress, and eventually result in cell apoptosis. In general, we illustrated a new mechanism of aconitine neurotoxicity and presented a novel analysis strategy that real-time online monitoring of cell metabolites can provide a new approach to mechanism analysis. [Display omitted] •Aconitine could induce neurotoxicity through excitatory toxicity caused by EAAs.•There exists a cross-talk among excitatory neurotoxicity, intracellular Ca2+ overload and oxidative stress.•Benzoylaconine and aconine were identified as two metabolites after aconitine stimulating HT22 cells.•The change of cell metabolites was real-time online investigated based on microfluidic chip-mass spectrometry.

[Display omitted] •Microfluidic co-culture of BV2 microglia and HT22 neurons in a 3D scaffold are for AHM.•Microtissues resembling mNVU exhibit responsiveness to hypoxia.•Sal's anti-hypoxic mechanisms and influence on the TCA cycle was evaluated.•A cell replacement method suitable for various models is especially beneficial for drug screening.

According to Traditional Chinese Medicine (TCM), Aconiti Radix Cocta (AC) is clinically employed to expel wind, remove dampness, and relieve pain. We evaluated the antirheumatoid arthritis (RA) activities and underlying mechanisms of AC. The chemical constituents of AC were analyzed by high-performance liquid chromatography (HPLC) using three reference compounds (benzoylaconitine, benzoylmesaconine, and benzoylhypacoitine). The anti-RA effects of AC were evaluated in adjuvant-induced arthritis (AIA) rats by hind paw volume and histopathological analysis. The effects of AC on inflammatory cytokines (IL-1β and IL-17A) were determined by enzyme-linked immunosorbent assay. The regulation of cyclooxygenases (COX-1 and/or COX-2) was determined by Western blot and real-time quantitative reverse transcription polymerase chain reaction analyses. AC significantly reduced paw swelling, attenuated the inflammation and bone destruction in joint tissues, and reduced IL-1β and IL-17A in the serum. Moreover, AC downregulated the expression of COX-1 and COX-2 in the synovial tissues. We also identified that AC possesses significant anti-RA activities on AIA, which may be ascribed to the regulation of inflammatory cytokines IL-1β and IL-17, as well as to the inhibition of arachidonic acid signaling pathways. Our findings provide theoretical support for AC as an effective nature-derived therapeutic agent for RA treatment.

Sorafenib, which inhibits multiple kinases, is an effective frontline therapy for hepatocellular carcinoma (HCC). Ferroptosis is a form of iron-dependent programmed cell death regulated by lipid peroxidation, which can be induced by sorafenib treatment. Oncoprotein hepatitis B X-interacting protein (HBXIP) participates in multiple biological pro-tumor processes, including growth, metastasis, drug resistance, and metabolic reprogramming. However, the role of HBXIP in sorafenib-induced ferroptotic cell death remains unclear. In this study, we demonstrated that HBXIP prevents sorafenib-induced ferroptosis in HCC cells. Sorafenib decreased HBXIP expression, and overexpression of HBXIP blocked sorafenib-induced HCC cell death. Interestingly, suppression of HBXIP increased malondialdehyde (MDA) production and glutathione (GSH) depletion to promote sorafenib-mediated ferroptosis and cell death. Ferrostatin-1, a ferroptosis inhibitor, reversed the enhanced anticancer effect of sorafenib caused by HBXIP silencing in HCC cells. Regarding the molecular mechanism, HBXIP transcriptionally induced the expression of stearoyl-CoA desaturase (SCD) via coactivating the transcriptional factor ZNF263, resulting in the accumulation of free fatty acids and suppression of ferroptosis. Functionally, activation of the HBXIP/SCD axis reduced the anticancer activity of sorafenib and suppressed ferroptotic cell death in vivo and in vitro. HBXIP/SCD axis-mediated ferroptosis can serve as a novel downstream effector of sorafenib. Our results provide new evidence for clinical decisions in HCC therapy.

Monitoring of the inhibition of TNF-α, IL-6, iNOS, and NO is used to effectively evaluate anti-inflammatory drugs. Baicalein was found to have good anti-inflammatory activities, but its detailed cellular pharmacodynamic events have not been expatiated by any other study. The inflammatory mediators, including TNF-α, IL-6, iNOS, and NO production in RAW264.7 macrophage induced by LPS, were measured. It was found that these data showed a sequential pattern on time and based on these points a cellular pharmacodynamic model was developed and tested. TNF-α and IL-6 were quantified by ELISA, NO was detected by Griess and iNOS expression was measured by Western blot. The pharmacodynamic model was developed using a NLME modeling program Monolix® 2016R1.The results showed that baicalein quickly suppressed release of TNF-α in a concentration-dependent manner, and consequently causing the diminution of IL-6 and iNOS/NO. The pharmacodynamic model simulation successfully described the experimental data, supporting the hypothesis that IL-6 and iNOS /NO release after LPS stimulation is mediated by TNF-α rather than LPS directly. The pharmacodynamic model allowed a well understanding of the cellular pharmacodynamic mechanism of baicalein in the treatment of inflammatory diseases.

Context:Pterocephalus hookeri (C. B. Clarke) Hock., a traditional Tibetan herbal medicine rich in glycosides, has been used to treat several diseases including rheumatoid arthritis.Objective: To evaluate the anti-arthritic activity of total glycosides from P. hookeri, and its possible mechanisms of action.Materials and methods: Anti-arthritic activity of total glycosides from P. hookeri (oral administration for 30 days at 14–56 mg/kg) was evaluated using paw swelling, arthritis scores and histopathological measurement in adjuvant-induced arthritis (AA) Sprague-Dawley rats. The NF-κB p65 expression in synovial tissues, and serum superoxide dismutase (SOD) activity, malondialdehyde (MDA) and nitric oxide (NO) levels was measured in AA rats, respectively. Further assessment of anti-inflammatory and analgesic activities of these glycosides were carried out using inflammation and hyperalgesia models induced by xylene, carrageenan, agar and acetic acid, respectively.Results: Total glycosides (56 mg/kg) decreased the paw swelling (38.0%, p < 0.01), arthritis scores (25.3%, p < 0.01) and synovial inflammation in AA rats. The glycosides significantly (p < 0.05–0.01) attenuated the inflammation induced by xylene, carrageenan, acetic acid and agar, increased the pain threshold in acetic acid-induced writhing in mice and mechanical stimuli-induced hyperalgia in AA rats. The glycosides (14, 28, 56 mg/kg) also suppressed the NF-κB p65 expression (33.1–78.2%, p < 0.05–0.01), reduced MDA (21.3–35.9%, p < 0.01) and NO (20.3–32.4%, p < 0.05–0.01) levels, respectively, enhanced the SOD activity (7.8%, p < 0.05) at 56 mg/kg in AA rats.Discussion and conclusion: Our findings confirmed the anti-arthritic property of the total glycosides from P. hookeri, which may be attributed to its inhibition on NF-κB signalling and oxidative stress.