Thymoquinone Alleviates Paclitaxel-Induced Peripheral Neuropathy through Regulation of the TLR4-MyD88 Inflammatory Pathway.

Paclitaxel-induced peripheral neuropathy (PIPN) is one of the common adverse effects during the paclitaxel (PTX) treatment of cancer. In this study, we investigated the neuroprotective effects and mechanisms of thymoquinone (TQ) in the PIPN model. Through pain behavioral assays and histological assessment, we demonstrated that TQ significantly alleviated the nociceptive behavior, modulated the pathological changes in peripheral nerves, and decreased the expression of inflammatory factors TNF-α, IL-1ß, and IL-6 induced by PIPN in mice. In addition, TQ significantly reversed the reduced viability and inflammatory response of primary DRG neurons caused by PTX. Moreover, the gene expression of related pathways was detected by Western blot, qPCR, and immunofluorescence, and the results showed that TQ exerts neuroprotective effects by regulating TLR4/MyD88 and its downstream NF-κB and MAPKs inflammatory pathways in vivo and in vitro. The treatment with TLR4 antagonist TAK-242 further indicated the important role of the TLR4/MyD88 signaling pathway in PIPN. Furthermore, molecular docking and a cellular thermal shift assay were used to confirm the interaction of TQ with TLR4. In summary, our study shows that TQ can inhibit inflammatory responses against PIPN by regulating TLR4 and MyD88 and its downstream inflammatory pathways.

Schwann Cell-Derived Exosomes Ameliorate Paclitaxel-Induced Peripheral Neuropathy Through the miR-21-Mediated PTEN Signaling Pathway.

Paclitaxel-induced peripheral neuropathy (PIPN) is a neurological disorder resulting from paclitaxel (PTX) treatment for cancer patients. There are currently no drugs available that can definitively prevent or treat PIPN. Exosomes are cell-secreted nanoscale vesicles that mediate communication between neurons and glial cells. We found that Schwann cell-derived exosomes (SC-EXOs) robustly improved PIPN both in vitro and in vivo. In vivo studies showed that SC-EXOs were able to alleviate PTX-induced mechanical nociceptive sensitization in rats. Pathomorphological analysis showed that SC-EXOs ameliorated PTX-induced plantar intraepidermal nerve fiber loss and dorsal root ganglion (DRG) injury. Additionally, the results of in vitro studies showed that SC-EXOs had significant protective effects on the DRG cells damaged by PTX, and did not affect the antitumor effect of PTX against Hela cells. Further, mechanism research revealed that SC-EXOs promoted axonal regeneration and protected damaged neurons by upregulating miR-21 to repress the phosphatase and tensin homolog (PTEN) pathway, which could improve PIPN. Taken together, these findings suggest that SC-EXOs ameliorate PTX-induced peripheral neuropathy via the miR-21-mediated PTEN signaling pathway, which provides a novel strategy for the treatment of PIPN.

A single-wavelength excited NIR fluorescence probe for distinguishing GSH/H2S and Cys/Hcy in living cells and zebrafish through separated dual-channels.

Biothiols and hydrogen sulfide, as critical sulfur-containing reactive substances, serve essential functions in various human pathological processes, making it challenging to simultaneously distinguish them due to their similar reactivity and structures (-SH). Here, we rationalized the development of a single-wavelength excitation near-infrared (NIR) fluorescence probe, FC-NBD, for distinguishing GSH/H2S and Cys/Hcy by separated fluorescence dual channels. In this probe, FC-NBD, composed of coumarin-benzopyrylium derivatives linked with nitro benzoxadiazole (NBD) via ether bonds, could quantitatively and selectively distinguish GSH/H2S and Cys/Hcy with a low limit of detection (LOD) of 0.199/0.177 µM and 0.106/0.076 µM, respectively. As expected, under single-wavelength excitation (470 nm), FC-NBD demonstrated distinctly separable green and NIR fluorescence emissions towards Cys/Hcy at 550 and 660 nm, but only exhibited a noticeable NIR fluorescence emission towards GSH/H2S at 660 nm. Moreover, FC-NBD could simultaneously visualize and discriminate GSH/H2S and Cys/Hcy in living cells as well as zebrafish through green and NIR channels at a single excitation wavelength.

Silibinin Schiff Base Derivatives Counteract CCl4-Induced Acute Liver Injury by Enhancing Anti-Inflammatory and Antiapoptotic Bioactivities.

Background: Silibinin (Sil), a flavonoid lignan-like natural compound derived from milk thistle seeds, has been used to treat hepatic diseases, including early-phase hepatocirrhosis and fatty liver, for many years. However, its poor water solubility limits its gastrointestinal absorption and bioavailability. It clinical use has been limited due to its slow onset of action. Faced with this problem, research on the derivatives of silibinin has been receiving much attention. Purpose: A series of silibinin derivatives with good biosafety and higher hepatoprotective activity were obtained by a safe, efficient and green chemical synthesis method. Patients and Methods: First, the carbonyl group in the structure of silibinin was used to obtain silibinin Schiff base derivatives by dehydration condensation with the carboxyl group in the sulfur-containing amino acid. Next, relevant experiments were performed to characterize the structure, physical form and solubility of the derivatives. Then, toxicity tests of the derivatives were performed in LO-2 cells and SD rats to evaluate their biosafety. Finally, the anti-inflammatory and antiapoptotic activities were observed using a carbon tetrachloride (CCl4)-induced acute liver injury model in C57BL/6J mice using silibinin as a control. Results: The studies showed that SS and ST behaved as amorphous substances and showed a significant increase in solubility compared to silibinin. These two derivatives showed low toxicity in biosafety tests and higher bioactivity (anti-inflammatory and anti-apoptotic) than silibinin against acute liver injury induced by CCl4. Conclusion: Two silibinin derivatives (SS and ST) obtained by the Schiff base reaction improved the solubility of the silibinin parent nucleus in biological media with the help of the hydrophilic and amorphous morphology of the ligand. The low toxicity in vivo and in vitro ensures the biosafety of the derivatives. The hepatoprotective activity (anti-inflammatory and anti-apoptotic) was significantly improved compared to silibinin.

A fluorescent probe for rapid detection of low concentration mercury ions and its application in biological cells.

As a toxic substance, mercury can easily cause harm to organisms and humans. The development of methods that allow rapid detection of low concentrations of mercury ions has a positive effect on the natural environment and human health. The fluorescent probe RBSH reported in this paper has a detection limit as low as 5.9 nM, and a fast response time and allows naked eye detection. We characterized its structure by nuclear magnetic resonance and mass spectrometry, and explored the response mechanism of the probe using Job's plot, and 1H NMR and mass spectrometry. UV-vis spectrophotometry and fluorescence spectroscopy show the excellent optical properties of the probe RBSH. The low toxicity and high cell penetration capacity demonstrated by the cellular assay open up the possibility of biological experiments. By selecting hosts (natural water samples, soybean plants and zebrafish) where mercury ions are likely to be present in the biological chain for low concentration Hg2+ detection, the results all demonstrated the excellent performance of the probe RBSH.

Berberine Alleviate Cisplatin-Induced Peripheral Neuropathy by Modulating Inflammation Signal via TRPV1.

Chemotherapy induced peripheral neuropathy (CIPN) is a severe neurodegenerative disorder caused by chemotherapy drugs. Berberine is a natural monomer compound of Coptis chinensis, which has anti-tumor effect and can improve neuropathy through anti-inflammatory mechanisms. Transient receptor potential vanilloid (TRPV1) can sense noxious thermal and chemical stimuli, which is an important target for the study of pathological pain. In both vivo and in vitro CIPN models, we found that berberine alleviated peripheral neuropathy associated with dorsal root ganglia inflammation induced by cisplatin. We confirmed that berberine mediated the neuroinflammatory reaction induced by cisplatin by inhibiting the overexpression of TRPV1 and NF-κB and activating the JNK/p38 MAPK pathways in early injury, which inhibited the expression of p-JNK and mediated the expression of p38 MAPK/ERK in late injury in vivo. Moreover, genetic deletion of TRPV1 significantly reduced the protective effects of berberine on mechanical and heat hyperalgesia in mice. In TRPV1 knockout mice, the expression of NF-κB increased in late stage, and berberine inhibited the overexpression of NF-κB and p-ERK in late injury. Our results support berberine can reverse neuropathic inflammatory pain response induced by cisplatin, TRPV1 may be involved in this process.