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Imbalanced immune homeostasis in cancer microenvironment is a hallmark of cancer. Increasing evidence demonstrated that long non-coding RNAs (lncRNAs) have emerged as key regulatory molecules in directly blocking the cancer immunity cycle, apart from activating negative regulatory pathways for restraining tumor immunity. lncRNAs reshape the tumor microenvironment via the recruitment and activation of innate and adaptive lymphoid cells. In this review, we summarized the versatile mechanisms of lncRNAs implicated in cancer immunity cycle, including the inhibition of antitumor T cell activation, blockade of effector T cell recruitment, disruption of T cell homing, recruitment of immunosuppressive cells, and inducing an imbalance between antitumor effector cells (cytotoxic T lymphocytes, M1 macrophages, and T helper type 1 cells) versus immunosuppressive cells (M2 macrophages, T helper type 2 cells, myeloid derived suppressor cells, and regulatory T cells) that infiltrate in the tumor. As such, we would highlight the potential of lncRNAs as novel targets for immunotherapy.

Abstract Fatty acid oxidation (FAO) is the emerging hallmark of cancer metabolism because certain tumor cells preferentially utilize fatty acids for energy. Lymph node metastasis, the most common way of tumor metastasis, is much indispensable for grasping tumor progression, formulating therapy measure and evaluating tumor prognosis. There is a plethora of studies showing different ways how tumor cells metastasize to the lymph nodes, but the role of FAO in lymph node metastasis remains largely unknown. Here, we summarize recent findings and update the current understanding that FAO may enable lymph node metastasis formation. Afterward, it will open innovative possibilities to present a distinct therapy of targeting FAO, the metabolic rewiring of cancer to terminal cancer patients.

Abstract The perineural invasion (PNI), which refers to tumor cells encroaching on nerve, is a clinical feature frequently occurred in various malignant tumors, and responsible for postoperative recurrence, metastasis and decreased survival. The pathogenesis of PNI switches from ‘low-resistance channel’ hypothesis to ‘mutual attraction’ theory between peripheral nerves and tumor cells in perineural niche. Among various molecules in perineural niche, microRNA (miRNA) as an emerging modulator of PNI through generating RNA-induced silencing complex (RISC) to orchestrate oncogene and anti-oncogene has aroused a wide attention. This article systematically reviewed the role of microRNA in PNI, promising to identify new biomarkers and offer cancer therapeutic targets.

Podophyllotoxin (PTOX) is a biologically active compound derived from the podophyllum plant, and both it and its derivatives possess excellent antitumor activity. The PTOX derivatives etoposide (VP-16) and teniposide (VM-26) have been approved by the U.S. Food and Drug Administration (FDA) for cancer treatment, but are far from perfect. Hence, numerous PTOX derivatives have been developed to address the major limitations of PTOX, such as systemic toxicity, drug resistance, and low bioavailability. Regarding their anticancer mechanism, extensive studies have revealed that PTOX derivatives can induce cell cycle G2/M arrest and DNA/RNA breaks by targeting tubulin and topoisomerase II, respectively. However, few studies are dedicated to exploring the interactions between PTOX derivatives and downstream cancer-related signaling pathways, which is reasonably important for gaining insight into the role of PTOX. This review provides a comprehensive analysis of the role of PTOX derivatives in the biological behavior of tumors and potential molecular signaling pathways, aiming to help researchers design and develop better PTOX derivatives.

The therapeutic effects of electroacupuncture (EA) on the comorbidity of visceral pain and anxiety in patients with inflammatory bowel disease (IBD) is well known. It has been known that the ventral hippocampus (vHPC) and the cannabinoid type 1 receptors (CB1R) are involved in regulating anxiety and pain. Therefore, in this study, we determined whether EA reduces visceral pain and IBD-induced anxiety via CB1R in the vHPC. We found that EA alleviated visceral hyperalgesia and anxiety in TNBS-treated IBD mice. EA reversed over-expression of CB1R in IBD mice and decreased the percentage of CB1R-expressed GABAergic neurons in the vHPC. Ablating CB1R of GABAergic neurons in the vHPC alleviated anxiety in TNBS-treated mice and mimicked the anxiolytic effect of EA. While ablating CB1R in glutamatergic neurons in the vHPC induced severe anxiety in wild type mice and inhibited the anxiolytic effect of EA. However, ablating CB1R in either GABAergic or glutamatergic neurons in the vHPC did not alter visceral pain. In conclusion, we found CB1R in both GABAergic neurons and glutamatergic neurons are involved in the inhibitory effect of EA on anxiety but not visceral pain in IBD mice. EA may exert anxiolytic effect via downregulating CB1R in GABAergic neurons and activating CB1R in glutamatergic neurons in the vHPC, thus reducing the release of glutamate and inhibiting the anxiety circuit related to vHPC. Thus, our study provides new information about the cellular and molecular mechanisms of the therapeutic effect of EA on anxiety induced by IBD.

Abstract Background Chronic pain is a major clinical problem with limited treatment options. Previous studies have demonstrated that activation of adenosine monophosphate-activated protein kinase (AMPK) can attenuate neuropathic pain. Inflammation/immune response at the site of complete Freund’s adjuvant (CFA) injection is known to be a critical trigger of the pathological changes that produce inflammatory pain. However, whether activation of AMPK produces an analgesic effect through inhibiting the proinflammatory cytokines, including interleukin-1β (IL-1β), in inflammatory pain remains unknown. Methods Inflammatory pain was induced in mice injected with CFA. The effects of AICAR (5-aminoimidazole-4-carboxyamide ribonucleoside, an AMPK activator), Compound C (an AMPK inhibitor), and IL-1ra (an IL-1 receptor antagonist) were tested at day 4 after CFA injection. Inflammatory pain was assessed with von Frey filaments and hot plate. Immunoblotting, hematoxylin and eosin (H&E) staining, and immunofluorescence were used to assess inflammation-induced biochemical changes. Results The AMPK activator AICAR produced an analgesic effect and inhibited the level of proinflammatory cytokine IL-1β in the inflamed skin in mice. Moreover, activation of AMPK suppressed CFA-induced NF-κB p65 translocation from the cytosol to the nucleus in activated macrophages (CD68+ and CX3CR1+) of inflamed skin tissues. Subcutaneous injection of IL-1ra attenuated CFA-induced inflammatory pain. The AMPK inhibitor Compound C and AMPKα shRNA reversed the analgesic effect of AICAR and the effects of AICAR on IL-1β and NF-κB activation in inflamed skin tissues. Conclusions Our study provides new information that AMPK activation produces the analgesic effect by inhibiting NF-κB activation and reducing the expression of IL-1β in inflammatory pain.

BackgroundClinical studies have shown that electroacupuncture (EA) alleviates chronic itch. Gastrin-releasing peptide receptor (GRPR) and dynorphin (DYN) in the spinal dorsal horn positively or negatively regulate itch, respectively. However, which frequency of EA is effective on relieving chronic itch and reducing the expression of GRPR, whether DYN-A in the spinal cord is involved in the underlying mechanism of the antipruritus effect of EA remains unknown.MethodsThe mixture of acetone and diethyl ether (1:1) [designated as AEW (acetone/diethyl ether and water) treatment] was used to induce the dry skin model of chronic itch. EA was applied to Quchi (LI11) and Hegu (LI4). Western blot was used to detect the expression of GRPR and DYN-A. Immunofluorescence was used to detect the expression of DYN-A.ResultsThe AEW administration induced remarkable spontaneous scratching, enhanced the expression of GRPR, and reduced the expression of DYN-A. Compared with the sham EA, 2 Hz EA, or 15 Hz EA group, 100 Hz EA was the most effective frequency for relieving chronic itch, reducing the expression of GRPR, and increasing the expression of DYN-A in the cervical dorsal horn. Furthermore, intraperitoneal injection of kappa opioid receptors (KORs) antagonist nor-Binaltorphimine dihydrochloride (nor-BNI) significantly reversed the effect of 100 Hz EA on the inhibition of both itching behavior and GRPR expression.ConclusionEA at 100 Hz is the most effective frequency that inhibits chronic itch and GRPR expression through activation of KORs in the spinal dorsal horn, which can effectively guide the clinical treatment and improve the antipruritic effect of acupuncture.

Although electroacupuncture (EA) has become a worldwide practice, little is understood about its precise target in the central nervous system (CNS) and the cell type-specific analgesia mechanism. In the present study, we found that EA has significant antinociceptive effects both in inflammatory and neuropathic pain models. Chemogenetic inhibition of GABAergic neurons in the ventrolateral periaqueductal gray (vlPAG) replicated the effects of EA, whereas the combination of chemogenetic activation of GABAergic neurons and chemogenetic inhibition of glutamatergic neurons in the vlPAG was needed to reverse the effects of EA. Specifically knocking out CB1 receptors on GABAergic neurons in the vlPAG abolished the EA effect on pain hypersensitivity, while specifically knocking out CB1 receptors on glutamatergic neurons attenuated only a small portion of the EA effect. EA synchronously inhibits GABAergic neurons and activates glutamatergic neurons in the vlPAG through CB1 receptors to produce EA-induced analgesia. The CB1 receptors on GABAergic neurons localized in the vlPAG was the basis of the EA effect on pain hypersensitivity. This study provides new experimental evidence that EA can bidirectionally regulate GABAergic neurons and glutamatergic neurons via the CB1 receptors of the vlPAG to produce analgesia effects.

Knee osteoarthritis (KOA) is a highly prevalent, chronic joint disorder, which can lead to chronic pain. Although electroacupuncture (EA) is effective in relieving chronic pain in the clinic, the involved mechanisms remain unclear. Reduced diffuse noxius inhibitory controls (DNIC) function is associated with chronic pain and may be related to the action of endocannabinoids. In the present study, we determined whether EA may potentiate cannabinoid receptor-mediated descending inhibitory control and inhibit chronic pain in a mouse model of KOA. We found that the optimized parameters of EA inhibiting chronic pain were the low frequency and high intensity (2 Hz + 1 mA). EA reversed the reduced expression of CB1 receptors and the 2-arachidonoylglycerol (2-AG) level in the midbrain in chronic pain. Microinjection of the CB1 receptor antagonist AM251 into the ventrolateral periaqueductal gray (vlPAG) can reversed the EA effect on pain hypersensitivity and DNIC function. In addition, CB1 receptors on GABAergic but not glutamatergic neurons are involved in the EA effect on DNIC function and descending inhibitory control of 5-HT in the medulla, thus inhibiting chronic pain. Our data suggest that endocannabinoid (2-AG)-CB1R-GABA-5-HT may be a novel signaling pathway involved in the effect of EA improving DNIC function and inhibiting chronic pain.