Glucocorticoid receptors involved in ginsenoside compound K ameliorate adjuvant arthritis by inhibiting the glycolysis of fibroblast-like synoviocytes via the NF-κB/HIF-1α pathway.

CONTEXT: Ginsenoside metabolite compound K (CK) is an active metabolite produced by ginsenosides in vivo that has an anti-arthritic effect related to the glucocorticoid receptor (GR). However, the potential mechanisms of CK remain unclear. OBJECTIVE: This study explores the role and potential mechanisms of CK in vivo and in vitro. MATERIALS AND METHODS: Adjuvant arthritis (AA) model was induced in Sprague-Dawley (SD) rats; the rats were randomly divided into four groups (n = 10): normal, AA, CK (80 mg/kg), and dexamethasone (Dex) group (1 mg/kg). From day 15, rats were treated with CK (once a day, i.g.) and Dex (once every 3 days, i.p.) for 18 days. To further verify the mechanism of CK, fibroblast-like synoviocytes (FLS) were stimulated by tumour necrosis factor α (TNF-α) to establish an inflammatory model in vitro. RESULTS: CK (80 mg/kg) reduced paw swelling (52%) and arthritis global assessment (31%) compared to that in AA rats. In addition, CK (80 mg/kg) suppressed GLUT1 (38%), HK2 (50%), and PKM2 (56%) levels compared with those in AA FLS. However, the effects of CK (30 µM) on these events were weakened or enhanced after GR knockdown or overexpression in FLS stimulated by TNF-α (30 ng/mL). CK (80 mg/kg) also downregulated the expression of P65 (61%), p-IκB (92%), and HIF-1α (59%). DISCUSSION AND CONCLUSIONS: The inhibition of CK on glycolysis and the NF-κB/HIF-1α pathway is potentially mediated through activating GR. These findings provide experimental evidence for elucidating the molecular mechanism of CK in treating rheumatoid arthritis (RA).

Hexokinase inhibitor 2-deoxyglucose coordinates citrullination of vimentin and apoptosis of fibroblast-like synoviocytes by inhibiting HK2 /mTORC1-induced autophagy.

High hexokinase 2 (HK2) expression is associated with aberrant activation of fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA). However, the mechanism by which this occurs has not been fully elucidated. To investigate the role of HK2 and its underlying mechanism, adjuvant arthritis (AA) rats were treated with the HK2 inhibitor, 2-deoxyglucose (2-DG). In conjunction with HK2 knockdown experiments in FLSs, we evaluated the effect of HK2 on the citrullination of vimentin (cVIM), autophagy and apoptosis-associated protein expression, including that of cVIM, LC3, p62, Beclin1, Bax, Bcl2, and caspase 3. We further investigated the interaction of HK2 with downstream mTORC1 signaling effectors. Correlation analysis revealed that 2-DG treatment and HK2 knockdown upregulated the expression levels of caspase3, Bax, and p62 and downregulated the expression levels of LC3, Bcl2, and Beclin1, as well as decreasing vimentin citrullination. Furthermore, interactions between HK2 and mTOR decreased, coinciding with mTORC1 pathway activation. These findings suggest that the regulation of apoptosis and cVIM by HK2/mTORC1-dependent autophagy involves the inhibition of aberrant FLSs activation in the rat model of arthritis.

A Multiple-Input Multiple-Output Reservoir Computing System Subject to Optoelectronic Feedbacks and Mutual Coupling.

In this paper, a multiple-input multiple-output reservoir computing (RC) system is proposed, which is composed of multiple nonlinear nodes (Mach-Zehnder modulators) and multiple mutual-coupling loops of optoelectronic delay lines. Each input signal is added into every mutual-coupling loop to implement the simultaneous recognition of multiple route signals, which results in the signal processing speed improving and the number of routes increasing. As an example, the four-route input and four-route output RC is simultaneously realized by numerical simulations. The results show that this type of RC system can successfully recognize the four-route optical packet headers with 3-bit, 8-bit, 16-bit, and 32-bit, and four-route independent digital speeches. When the white noise is added to the signals such that the signal-to-noise ratio (SNR) of the optical packet headers and the digital speeches are 35 dB and 20 dB respectively, the normalized root mean square errors (NRMSEs) of the signal recognition are all close to 0.1. The word error rates (WERs) of the optical packet header recognition are 0%. The WER of the digital speech recognition is 1.6%. The eight-route input and eight-route output RC is also numerically simulated. The recognition of the eight-route 3-bit optical packet headers is implemented. The parallel processing of multiple-route signals and the high recognition accuracy are implemented by this proposed system.

Efficient optoelectronic reservoir computing with three-route input based on optical delay lines.

In the reservoir computing (RC) system based on delay line structure, the dynamical reservoir has short-term memory capability and can map instantaneous time signals to a high-dimensional space, so that it can effectively classify and recognize complicated time signals. A new RC system is proposed in this paper, where three-way signals are simultaneously input into the dynamical reservoir, and simultaneously processed and classified. Therefore, the information processing speed of the RC system is promoted manyfold. The reservoir is composed of a semiconductor laser and two optical feedback loops, in which two input signals are injected into two optical feedback loops, and another input signal is added to the driving current of the semiconductor laser. The computation efficiency of the RC system is validated by two tasks of the optical packet header recognition and digital speech recognition. By optimizing the parameters, the multi-input RC system can simultaneously recognize three-way 3-bit, 8-bit, 16-bit, and 32-bit optical packet headers with the optimal word error rate (WER) of 0%, and recognize three-way digital speech signals with the optimal WER of 0.2%. It is proven that this multi-input system outperforms the single-inputting RC system based on delay line structure.

Efficient synthesis and antimicrobial activity of some novel S-ß-d-glucosides of 5-aryl-1,2,4-triazole-3-thiones derivatives.

A series of 3-S-ß-d-glucosides-4-arylideneamino-5-aryl-1,2,4-triazoles were rationally designed and synthesized according to the principle of superposition of bioactive substructures by the combination of 1,2,4-triazole, Schiff base and glucosides. The structures of the target compounds have been characterized by (1)H NMR, (13)C NMR, IR, MS and HRMS. All the newly synthesized compounds have been evaluated for their antimicrobial activities in vitro against Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 8099) as well as Monilia albican (ATCC 10231). The bioactive assay showed that most of the tested compounds displayed variable inhibitory effects on the growth of the Gram-positive bacterial strain (Staphylococcus aureus), Gram-negative bacterial strains (Escherichia coli) and fungal strains (Monilia albican). All the target compounds exhibited better antifungal activity than antibacterial activity. Especially, compounds 6b, 6c, 6f, 6j, 6k and 6l showed excellent activity against fungus Monilia albican with MIC values of 16 µg/mL.