Low intensity, trans-spinal focused ultrasound (tsFUS) is a noninvasive neuromodulation approach that has been shown to modulate spinal circuit excitability in healthy rats. Here, we evaluated the potential of tsFUS for alleviating neuropathic pain by testing it in a chronic constriction injury (CCI) model. Male rats underwent CCI of the left sciatic nerve and then received tsFUS (2 kHz pulse repetition frequency; 40% duty cycle) or sham stimulation, targeted at spinal segment level L5 for 3 min daily over three days. As expected, CCI causes significant reduction of von Frey Threshold (vFT), a measure of mechanical sensitivity. We found that tsFUS treatment is associated with increased vFT compared to sham; this increase persists beyond the duration of treatment, through days 4 to 23 post-CCI. In spinal cords of tsFUS-treated animals, counts of spinal microglia (Iba1 + cells) and of activated, pro-inflammatory microglia (Iba1 + /CD86 + cells), are reduced compared to sham-treated animals. This reduction in microglia counts is limited to the insonified side of the spinal cord, ipsilateral to CCI. These findings suggest that tsFUS may be a promising approach for treatment of neuropathic pain at early stages, possibly by attenuating the development of microglial-driven inflammation.
© 2025. The Author(s).

Abstract Trans-spinal focused ultrasound (tsFUS) is a relatively new noninvasive neuromodulation approach that modulates spinal reflexes in healthy rats. Here, we tested the analgesic efficacy of tsFUS in rats with chronic constriction injury (CCI). Male rats were subjected to CCI of the left sciatic nerve, and a day later were treated with either sham stimulation or tsFUS (2KHz pulse repetition frequency, targeting spinal level L5, 3 minutes per day) for 3 days. We found that CCI increases sensitivity to mechanical stimuli, indicated by a reduced von Frey Threshold (vFT). Compared to sham stimulation, tsFUS resulted increased vFT at 4 to 23 days after CCI, compared to sham stimulation, indicating reduced sensitivity to mechanical stimuli in a sustained manner. In animals that received tsFUS, we found reduced counts of spinal microglia and reduced counts of microglia expressing CD86, a marker for pro-inflammatory microglial activation, at the side ipsilateral to injury. Our study provides evidence that tsFUS may be effective in mitigating early development of pain after neural injury, in part by suppressing the activation of pro-inflammatory phenotypes of spinal microglia.

Cerebral ischemia/reperfusion (CI/R) injury is a clinical conundrum during the treatment of ischemic stroke. Cell-derived exosomes (CDE) were proved to be therapeutically effective for CI/R injury. However, production of CDE is time and effort consuming. Increasing studies reported that plants can also generate exosome-like nanoparticles (ELN) which are therapeutically effective and have higher yield compared with CDE. In this study, a commonly used Chinese herb Panax notoginseng (PN), whose active ingredients were well-documented in the treatment of CI/R injury, was chosen as a source of ELNs. It was found that Panax notoginseng derived exosome like nanoparticles (PDN) could enter the brain without modification and ameliorate cerebral infarct volume, improve behavior outcome and maintained the integrity of BBB. PDNs attenuated CI/R injury by altering the phenotype of microglia from "pro-inflammation" M1 type to "anti-inflammation" M2 type. Also, we found that lipids from PDNs were the major therapeutic effective component. As a mechanism of action, PDN was proved to exert therapeutic effect via activating pI3k/Akt pathway.
© 2023. The Author(s).

Perianal fistulas (PAFs) represent a severe complication of Crohn's disease (CD). Despite the advent of biologic and small-molecule therapeutics for luminal disease, PAFs in CD (CD-PAF) are relatively resistant to treatment, with less than 50% responding to any therapy. We report an injectable, biodegradable, mechanically fragmented nanofiber-hydrogel composite (mfNHC) loaded with adipose-derived stem cells (ADSCs) for the treatment of fistulas in a rat model of CD-PAF. The ADSC-loaded mfNHC results in a higher degree of healing when compared to surgical treatment of fistulas, which is a standard treatment. The volume of fistulas treated with mfNHC is decreased sixfold compared to the surgical treatment control. Molecular studies reveal that utilization of mfNHC reduced local inflammation and improved tissue regeneration. This study demonstrates that ADSC-loaded mfNHC is a promising therapy for CD-PAF, and warrants further studies to advance mfNHC toward clinical translation.

Colorectal cancer (CRC) is one of the prevalent malignant tumors. This study is aimed at evaluating the mechanism of anlotinib (anlo) on tumor microenvironment (TME) in CRC, and its effects in combination with immune checkpoint inhibitors (ICIs) therapy. Firstly, MC38 and CT26 cells were both exposed to different gradient concentrations of anlo for 72 h, to investigate the cell viability and synergetic therapy efficacy with ICIs by CCK8. The results showed that anlo could obviously inhibit cell growth and showed no synergistic efficacy therapy in combination with αPDL1 in vitro. Then, we found the upregulation of programmed cell death ligand 1(PDL1) expression both in vitro and in vivo after anlo treatment. In vivo, anlo could enhance the percentage of natural killer (NK) cells and M1 macrophage cells and decrease the percentage of M2 macrophage cells in TME. Moreover, we explored the mechanism and we proved that anlo could activate reactive oxygen species (ROS)/c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) signaling pathway to increase the expression levels of PDL1, IFN-α/β/γ, and CXCL2 in two cell lines in vitro. We also proved that anlo had synergistic effects with ICIs in vivo. Finally, it could also increase the mRNA and protein PDL1 expression levels in human cell lines, which was consistent with mouse CRC cell lines. However, there are still a few limitations. On one hand, the ROS/JNK/AP-1 pathway needs to be proved whether it can be activated in human cell lines. On the other hand, the mechanism behind ROS promoting phosphorylation of JNK needs to be explored.
Copyright © 2022 Bixian Luo et al.