Spinal Neuronal miR-124 Inhibits Microglial Activation and Contributes to Preventive Effect of Electroacupuncture on Chemotherapy-Induced Peripheral Neuropathy in Mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is a persistent and irreversible side effect of antineoplastic agents. Patients with CIPN usually show chronic pain and sensory deficits with glove-and-stocking distribution. However, whether spinal neuronal microRNA (miR)-124 is involved in cisplatin-induced peripheral neuropathy remains to be studied. In this study, miR-124 was significantly reduced in the spinal dorsal horn in CIPN mice. Overexpression of neuronal miR-124 induced by injecting adeno-associated virus with neuron-specific promoter into the spinal cord of mice prevented the development of mechanical allodynia, sensory deficits, and the loss of intraepidermal nerve fibers induced by cisplatin. Meanwhile, cisplatin-induced M1 microglia activation and the release of proinflammatory cytokines were significantly inhibited by overexpression of neuronal miR-124. Furthermore, electroacupuncture (EA) treatment upregulated miR-124 expression in the spinal dorsal horn of CIPN mice. Interestingly, downregulation of spinal neuronal miR-124 significantly inhibited the regulatory effect of EA on CIPN and microglia activity as well as spinal neuroinflammation induced by cisplatin. These results demonstrate that spinal neuronal miR-124 is involved in the prevention and treatment of EA on cisplatin-induced peripheral neuropathy in mice. Our findings suggest that spinal neuronal miR-124 might be a potential target for EA effect, and we provide, to our knowledge, a new experimental basis for EA prevention of CIPN.

Hydrogen alleviated cognitive impairment and blood‒brain barrier damage in sepsis-associated encephalopathy by regulating ABC efflux transporters in a PPARα-dependent manner.

Hydrogen (H2) can protect against blood‒brain barrier (BBB) damage in sepsis-associated encephalopathy (SAE), but the mechanism is still unclear. We examined whether it is related to PPARα and its regulatory targets, ABC efflux transporters. After injection with DMSO/GW6471 (a PPARα inhibitor), the mice subjected to sham/caecal ligation and puncture (CLP) surgery were treated with H2 for 60 min postoperation. Additionally, bEnd.3 cells were grown in DMSO/GW6471-containing or saline medium with LPS. In addition to the survival rates, cognitive function was assessed using the Y-maze and fear conditioning tests. Brain tissues were stained with TUNEL and Nissl staining. Additionally, inflammatory mediators (TNF-α, IL-6, HMGB1, and IL-1ß) were evaluated with ELISA, and PPARα, ZO-1, occludin, VE-cadherin, P-gp, BCRP and MRP2 were detected using Western blotting. BBB destruction was assessed by brain water content and Evans blue (EB) extravasation. Finally, we found that H2 improved survival rates and brain dysfunction and decreased inflammatory cytokines. Furthermore, H2 decreased water content in the brain and EB extravasation and increased ZO-1, occludin, VE-cadherin and ABC efflux transporters regulated by PPARα. Thus, we concluded that H2 decreases BBB permeability to protect against brain dysfunction in sepsis; this effect is mediated by PPARα and its regulation of ABC efflux transporters.

MicroRNA-122-5p promotes renal fibrosis and injury in spontaneously hypertensive rats by targeting FOXO3.

Hypertensive renal injury is accompanied by tubular interstitial fibrosis leading to increased risk for renal failure. This study aimed to explore the influences of miR-122-5p in hypertension-mediated renal fibrosis and damage. 14-week-old male SHR and WKY rats were randomly assigned to treat with rAAV-miR-122-5p or rAAV-GFP for 8 weeks. There were marked increases in miR-122-5p and Kim-1 levels and decreases in FOXO3 and SIRT6 levels in hypertensive rats. Transfection with rAAV-miR-122-5p triggered exacerbation of renal fibrosis, apoptosis and inflammatory injury in SHR, associated with downregulated levels of FOXO3, SIRT6, ATG5 and BNIP3 as well as upregulated expression of Kim-1, NOX4, CTGF, and TGF-ß1. In cultured primary mouse renal tubular interstitial fibroblasts, exposure to angiotensin II resulted in obvious downregulation of FOXO3, SIRT6, ATG5, BNIP3 and nitric oxide levels as well as augmented cellular migration, oxidative stress, and inflammation, which were exacerbated by miR-122-5p mimic while rescued by miR-122-5p inhibitor and rhFOXO3, respectively. Notably, knockdown of FOXO3 strikingly blunted cellular protective effects of miR-122-5p inhibitor. In summary, miR-122-5p augments renal fibrosis, inflammatory and oxidant injury in hypertensive rats by suppressing the expression of FOXO3. Pharmacological inhibition of miR-122-5p has potential therapeutic significance for hypertensive renal injury and fibrosis-related kidney diseases.

Spinal Neuronal GRK2 Contributes to Preventive Effect by Electroacupuncture on Cisplatin-Induced Peripheral Neuropathy in Mice.

BACKGROUND: The main symptoms of chemotherapy-induced peripheral neuropathy (CIPN) include pain and numbness. Neuronal G protein-coupled receptor kinase 2 (GRK2) plays an important role in various pain models. Cisplatin treatment can induce the activation of proinflammatory microglia in spinal cord. The purpose of this study was to investigate the role of spinal neuronal GRK2 in cisplatin-induced CIPN and in the prevention of CIPN by electroacupuncture (EA). METHODS: The pain and sensory deficit behaviors of mice were examined by von Frey test and adhesive removal test. The expression of neuronal GRK2 in the spinal cord is regulated by intraspinal injection of adeno-associated virus (AAV) containing neuron-specific promoters. The protein levels of GRK2, triggering receptor expressed on myeloid cells 2 (TREM2), and DNAX-activating protein of 12 kDa (DAP12) in spinal dorsal horn were detected by Western blot, the density of intraepidermal nerve fibers (IENFs) was detected by immunofluorescence, and microglia activation were evaluated by real-time polymerase chain reaction (PCR). RESULTS: In this study, cisplatin treatment led to the decrease of GRK2 expression in the dorsal horn of spinal cord. Overexpression of neuronal GRK2 in spinal cord by intraspinal injection of an AAV vector expressing GRK2 with human synapsin (hSyn) promotor significantly inhibited the loss of IENFs and alleviated the mechanical pain and sensory deficits induced by cisplatin. Real-time PCR analysis showed that the overexpression of neuronal GRK2 significantly inhibited the messenger RNA (mRNA) upregulation of proinflammatory cytokine interleukin (IL)-1ß, IL-6, inducible nitric oxide synthase (iNOS), and M1 microglia marker cluster of differentiation (CD)16 induced by cisplatin. Furthermore, the TREM2 and DAP12, which has been demonstrated to play a role in microglia activation and in the development of CIPN, were also downregulated by overexpression of neuronal GRK2 in this study. Interestingly, preventive treatment with EA completely mimics the effect of overexpression of neuronal GRK2 in the spinal cord in this mouse model of cisplatin-induced CIPN. EA increased GRK2 level in spinal dorsal horn after cisplatin treatment. Intraspinal injection of AAV vector specifically downregulated neuronal GRK2, completely reversed the regulatory effect of EA on CIPN and microglia activation. All these indicated that the neuronal GRK2 mediated microglial activation contributed to the process of CIPN. CONCLUSIONS: Neuronal GRK2 in the spinal cord contributed to the preventive effect of EA on CIPN. The neuronal GRK2 may be a potential target for CIPN intervention.

Neuronal GRK2 regulates microglial activation and contributes to electroacupuncture analgesia on inflammatory pain in mice.

BACKGROUND: G protein coupled receptor kinase 2 (GRK2) has been demonstrated to play a crucial role in the development of chronic pain. Acupuncture is an alternative therapy widely used for pain management. In this study, we investigated the role of spinal neuronal GRK2 in electroacupuncture (EA) analgesia. METHODS: The mice model of inflammatory pain was built by subcutaneous injection of Complete Freund's Adjuvant (CFA) into the plantar surface of the hind paws. The mechanical allodynia of mice was examined by von Frey test. The mice were subjected to EA treatment (BL60 and ST36 acupuncture points) for 1 week. Overexpression and downregulation of spinal neuronal GRK2 were achieved by intraspinal injection of adeno associated virus (AAV) containing neuron-specific promoters, and microglial activation and neuroinflammation were evaluated by real-time PCR. RESULTS: Intraplantar injection with CFA in mice induced the decrease of GRK2 and microglial activation along with neuroinflammation in spinal cord. EA treatment increased the spinal GRK2, reduced neuroinflammation, and significantly decreased CFA-induced mechanical allodynia. The effects of EA were markedly weakened by non-cell-specific downregulation of spinal GRK2. Further, intraspinal injection of AAV containing neuron-specific promoters specifically downregulated neuronal GRK2, and weakened the regulatory effect of EA on CFA-induced mechanical allodynia and microglial activation. Meanwhile, overexpression of spinal neuronal GRK2 decreased mechanical allodynia. All these indicated that the neuronal GRK2 mediated microglial activation and neuroinflammation, and subsequently contributed to CFA-induced inflammatory pain. CONCLUSION: The restoration of the spinal GRK2 and subsequent suppression of microglial activation and neuroinflammation might be an important mechanism for EA analgesia. Our findings further suggested that the spinal GRK2, especially neuronal GRK2, might be the potential target for EA analgesia and pain management, and we provided a new experimental basis for the EA treatment of pain.

[Comparison between macroscopic identification and DNA barcoding identification of Amomi Fructus].

This study aims to explore the consistency between macroscopic identification and DNA barcoding identification of Amomi Fructus. With the DNA barcoding identification results, we evaluated the reliability of identifying Amomi Fructus quality by combining macroscopic traits with main volatile chemical components. Thirteen batches of Amomi Fructus samples were collected for identification. Firstly, the morphological and sensory characteristics of each sample were observed and recorded according to the standard in Chinese Pharmacopoeia(2020 edition). The 100-fruit weight, longitudinal diameter, transverse diameter, and longitudinal diameter-to-transverse diameter ratio were measured, which correspond to large, solid, and full kernel representing good quality in the sensory evaluation. The odor value detected by electronic nose and major volatile components(borneol, camphor, limonene, and borneol acetate) correspond to the sensory evaluation of strong odor representing good quality. Secondly, DNA barcoding was employed to identify the 13 batches of samples. Finally, clustering analysis was performed for the main volatile components and macroscopic traits, and the identification results were compared with those of DNA barcoding. Except two batches of samples(No.6 and No.10), the macroscopic identification showed the results consistent with those of DNA barcoding, with an identification rate of 84.62%. The clustering results of the content of four volatile chemical components and macroscopic traits were also consistent with the DNA barcoding identification results. DNA barcoding can verify the results of macroscopic identification and provide a scientific basis for the inheritance and development of macroscopic identification. Moreover, the combination of macroscopic traits and chemical components demonstrates higher accuracy in the quality evaluation of Chinese medicinal materials.

Vascular Endothelial Growth Factor A Signaling Promotes Spinal Central Sensitization and Pain-related Behaviors in Female Rats with Bone Cancer.

BACKGROUND: Cancer pain is a pervasive clinical symptom impairing life quality. Vascular endothelial growth factor A has been well studied in tumor angiogenesis and is recognized as a therapeutic target for anti-cancer treatment. This study tested the hypothesis that vascular endothelial growth factor A and vascular endothelial growth factor receptor 2 contribute to bone cancer pain regulation associated with spinal central sensitization. METHODS: This study was performed on female rats using a metastatic breast cancer bone pain model. Nociceptive behaviors were evaluated by mechanical allodynia, thermal hyperalgesia, spontaneous pain, and CatWalk gait analysis. Expression levels were measured by real-time quantitative polymerase chain reaction, western blot, and immunofluorescence analysis. Excitatory synaptic transmission was detected by whole-cell patch-clamp recordings. The primary outcome was the effect of pharmacologic intervention of spinal vascular endothelial growth factor A/vascular endothelial growth factor receptor 2-signaling on bone cancer pain behaviors. RESULTS: The mRNA and protein expression of vascular endothelial growth factor A and vascular endothelial growth factor receptor 2 were upregulated in tumor-bearing rats. Spinal blocking vascular endothelial growth factor A or vascular endothelial growth factor receptor 2 significantly attenuated tumor-induced mechanical allodynia (mean ± SD: vascular endothelial growth factor A, 7.6 ± 2.6 g vs. 5.3 ± 3.3 g; vascular endothelial growth factor receptor 2, 7.8 ± 3.0 g vs. 5.2 ± 3.4 g; n = 6; P < 0.0001) and thermal hyperalgesia (mean ± SD: vascular endothelial growth factor A, 9.0 ± 2.4 s vs. 7.4 ± 2.7 s; vascular endothelial growth factor receptor 2, 9.3 ± 2.5 s vs. 7.5 ± 3.1 s; n = 6; P < 0.0001), as well as spontaneous pain and abnormal gaits. Exogenous vascular endothelial growth factor A enhanced excitatory synaptic transmission in a vascular endothelial growth factor receptor 2-dependent manner, and spinal injection of exogenous vascular endothelial growth factor A was sufficient to cause pain hypersensitivity via vascular endothelial growth factor receptor 2-mediated activation of protein kinase C and Src family kinase in naïve rats. Moreover, spinal blocking vascular endothelial growth factor A/vascular endothelial growth factor receptor 2 pathways suppressed protein kinase C-mediated N-methyl-D-aspartate receptor activation and Src family kinase-mediated proinflammatory cytokine production. CONCLUSIONS: Vascular endothelial growth factor A/vascular endothelial growth factor receptor 2 contributes to central sensitization and bone cancer pain via activation of neuronal protein kinase C and microglial Src family kinase pathways in the spinal cord.

Triggering receptor expressed on myeloid cells 2 (TREM2) dependent microglial activation promotes cisplatin-induced peripheral neuropathy in mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse side effect of many antineoplastic agents. Patients treated with chemotherapy often report pain and paresthesias in a "glove-and-stocking" distribution. Diverse mechanisms contribute to the development and maintenance of CIPN. However, the role of spinal microglia in CIPN is not completely understood. In this study, cisplatin-treated mice displayed persistent mechanical allodynia, sensory deficits and decreased density of intraepidermal nerve fibers (IENFs). In the spinal cord, activation of microglia, but not astrocyte, was persistently observed until week five after the first cisplatin injection. Additionally, mRNA levels of inflammation related molecules including IL-1ß, IL-6, tumor necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS) and CD16, were increased after cisplatin treatment. Intraperitoneal (i.p.) or intrathecal (i.t.) injection with minocycline both alleviated cisplatin-induced mechanical allodynia and sensory deficits, and prevented IENFs loss. Furthermore, cisplatin enhanced triggering receptor expressed on myeloid cells 2 (TREM2) /DNAX-activating protein of 12 kDa (DAP12) signaling in the spinal cord microglia. The blockage of TREM2 by i.t. injecting anti-TREM2 neutralizing antibody significantly attenuated cisplatin-induced mechanical allodynia, sensory deficits and IENFs loss. Meanwhile, anti-TREM2 neutralizing antibody prominently suppressed the spinal IL-6, TNF-α, iNOS and CD16 mRNA level, but it dramatically up-regulated the anti-inflammatory cytokines IL-4 and IL-10. The data demonstrated that cisplatin triggered persistent activation of spinal cord microglia through strengthening TREM2/DAP12 signaling, which further resulted in CIPN. Functional blockage of TREM2 or inhibition of microglia both benefited for cisplatin-induced peripheral neuropathy. Microglial TREM2/DAP12 may serve as a potential target for CIPN intervention.

In vitro and in vivo effect of paclitaxel and cepharanthine co-loaded polymeric nanoparticles in gastric cancer.

PURPOSE: Response surface methodology (RSM) using the central composite rotatable design (CCRD) model was used to optimize the formulation of paclitaxel (PTX)-cepharanthine (CEP) nanoparticles for gastric cancer. METHODS: Nanoparticles were prepared using nanoprecipitation technique and optimized using central composite rotatable design response surface methodology (CCRD-RSM). Further the optimized nanoparticles were characterised for particle size (PS), zeta potential, entrapment efficiency (EE), drug loading efficiency (DL), anticancer potential against MKN45 (human gastric cancer) cells, in vivo tumor inhibition and survival analysis. RESULTS: Significant findings were the optimal formulation of polymer concentration of 48 mg, surfactant concentration of 45% and EE of 98.12%, DL of 15.61% and mean diameter of 198±4.7 nm. The encapsulation of PTX/CEP into nanoparticles retained the synergistic anticancer efficiency against MKN45 cells. In the in vivo evaluation, PTXsCEP nanoparticles delivered into mice by intravenous injection significantly improved the antitumor efficacy of PTX/CEP. Moreover, PTX/CEP co-loaded nanoparticles substantially increased the overall survival in an established MKN45-transplanted mouse model. CONCLUSION: These data are the first to demonstrate that PTX/CEP co-loaded nanoparticles increased the anticancer efficacy in cell lines and xenograft mouse model. Our results suggest that PTX/CEP coloaded nanoparticles could be a potential useful chemotherapeutic formulation for gastric cancer.

[Rancidness of Armeniacae Semen Amarum involving Bianzhuang Lunzhi].

This article aims to compare the qualities of Armeniacae Semen Amarum before and after rancidness, in order to study the rancidness of Armeniacae Semen Amarum. In the experiment, content of fatty oil, acid value and peroxide value were determined before and after rancidness,respectively. Meanwhile, HPLC, GC-MS were utilized to analyze laetrile and fatty acid components. Besides, colorimeter and e-nose were introduced to quantify and compare "color and odor". A correlation analysis was conducted on the above results. The results showed that color of post-rancidness Armeniacae Semen Amarum changed from yellow to brown, with sour and lower content of laetrile. On the contrary, acid and peroxide values increased significantly, with changes in fatty acid component. There was a considerable correlation between appearance characteristics and changes in internal quality. The "sensory analysis-quality identification system" can provide a certain scientific basis for prediction of the content of chemical components in traditional Chinese medicine, preliminary judgment of quality of traditional Chinese medicine and real-time quality monitoring, which offers us novel ideas and reference for storage principles of traditional Chinese medicines of "pre-event prediction, during-event intervention and post-event identification".

Early single Aspirin-triggered Lipoxin blocked morphine anti-nociception tolerance through inhibiting NALP1 inflammasome: Involvement of PI3k/Akt signaling pathway.

Clinical usage of opioids in pain relief is dampened by analgesic tolerance after chronic exposure, which is related to opioid-associated neuroinflammation. In the current study, which is based on a chronic morphine tolerance rat model and sustained morphine treatment on primary neuron culture, it was observed that Akt phosphorylation, cleaved-Caspase-1-dependent NALP1 inflammasome activation and IL-1ß maturation in spinal cord neurons were significantly enhanced by morphine. Moreover, treatment with LY294002, a specific inhibitor of PI3k/Akt signaling, significantly reduced Caspase-1 cleavage, NALP1 inflammasome activation and attenuated morphine tolerance. Tail-flick tests demonstrated that pharmacological inhibition on Caspase-1 activation or antagonizing IL-1ß dramatically blocked the development of morphine tolerance. The administration of an exogenous analogue of lipoxin, Aspirin-triggered Lipoxin (ATL), caused a decline in Caspase-1 cleavage, inflammasome activation and mature IL-1ß production and thus attenuated the development of morphine tolerance by inhibiting upstream Akt phosphorylation. Additionally, treatment with DAMGO, a selective µ-opioid receptor peptide, significantly induced Akt phosphorylation, Caspase-1 cleavage and anti-nociception tolerance, all of which were attenuated by ATL treatment. Taken together, the present study revealed the involvement of spinal NALP1 inflammasome activation in the development of morphine tolerance and the role of the µ-receptor/PI3k-Akt signaling/NALP1 inflammasome cascade in this process. By inhibiting this signaling cascade, ATL blocked the development of morphine tolerance.

Spinal IL-33/ST2 Signaling Contributes to Neuropathic Pain via Neuronal CaMKII-CREB and Astroglial JAK2-STAT3 Cascades in Mice.

BACKGROUND: Emerging evidence indicates that nerve damage-initiated neuroinflammation and immune responses, which are evidenced by the up-regulation of proinflammatory cytokines, contribute to the development of neuropathic pain. This study investigated the role of spinal interleukin (IL)-33 and its receptor ST2 in spared nerve injury (SNI)-induced neuropathic pain. METHODS: The von Frey test and acetone test were performed to evaluate neuropathic pain behaviors (n = 8 to 12), and Western blot (n = 4 to 6), immunohistochemistry, real-time polymerase chain reaction (n = 5), and Bio-Plex (n = 5) assays were performed to understand the molecular mechanisms. RESULTS: Intrathecal administration of ST2-neutralizing antibody or ST2 gene knockout (ST2) significantly attenuated the SNI-induced mechanical and cold allodynia. On the 7th day after SNI, the expression of spinal IL-33 and ST2 was increased by 255.8 ± 27.3% and 266.4 ± 83.5% (mean ± SD), respectively. Mechanistic studies showed that the increased expression of the spinal N-methyl-D-aspartate (NMDA) receptor subunit 1 after SNI was reduced by ST2 antibody administration or ST2. The induction of nociceptive behaviors in naive mice due to recombinant IL-33 was reversed by the noncompetitive NMDA antagonist MK-801. ST2 antibody administration or ST2 markedly inhibited the increased activation of the astroglial janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) cascade and the neuronal calcium-calmodulin-dependent kinase II (CaMKII)-cyclic adenosine monophosphate response element-binding protein (CREB) cascade after SNI. Moreover, intrathecal pretreatment with the CaMKII inhibitor KN-93 or the JAK2-STAT3 cascade inhibitor AG490 attenuated recombinant IL-33-induced nociceptive behaviors and NMDA subunit 1 up-regulation in naive mice. CONCLUSION: Spinal IL-33/ST2 signaling contributes to neuropathic pain by activating the astroglial JAK2-STAT3 cascade and the neuronal CaMKII-CREB cascade.

A Spectroscopic Method for Distinguishing Two Novel Sandwich-Type Tungsten Oxide Cluster Compounds.

This study introduces two novel sandwich-type tungsten-oxygen cluster compounds synthesized by hydrothermal methods, H4(C6H12N2H2)3{Na(H2O)2[Mn2(H2O)(GeW9O34)]}2 (Compound 1) and H2(C6H12N2H2)3.5{Na3(H2O)4[Co2(H2O)(GeW9O34)]2}·17H2O (Compound 2). The two compounds comprise cluster anions [GeW9O34]10- coordinated with transition metal atoms, either Mn or Co, and are stabilized by organic ligands. These compounds are crystallized in the hexagonal crystal system and P63/m space group. The two compounds were characterized through various techniques. Fourier transform infrared (IR) spectroscopy showed absorption peaks of anionic backbone vibrations of the Keggin cluster at 500-1000 cm-1, IR spectral peaks of δ(N-H) and νas(C-N) of the ligand triethylenediamine at 1000-2000 cm-1, and IR spectral peaks of the ligand νas(N-H) and νas(O-H) of water at 3000-3500 cm-1. Despite similar one-dimensional (1D) IR spectra due to the same cluster anions and similar molecular structures, the two compounds exhibited distinct responses in two-dimensional correlation spectroscopy with IR under magnetic and thermal perturbations. Under magnetic perturbation, Compound 1 showed a strong response peak for νas(W-Ob-W), while Compound 2 exhibited a strong response peak for νas(W=Od), possibly linked to differing magnetic particles. Similarly, Compound 1 displayed a strong response peak under thermal perturbation for νas(W-Oc-W). In contrast, Compound 2 showed a strong response peak for νas(W=Od); these results may be attributed to the different hydrogen bonding connections between the two compounds, which affect the groups in distinct ways through vibration and transmit these vibrations to the W-O bonds. The research presented in this paper expands the theoretical and experimental data of 2D correlation IR spectroscopy.

Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer.

Availability of the essential amino acid methionine affects cellular metabolism and growth, and dietary methionine restriction has been implicated as a cancer therapeutic strategy. Nevertheless, how liver cancer cells respond to methionine deprivation and underlying mechanisms remain unclear. Here we find that human liver cancer cells undergo irreversible cell cycle arrest upon methionine deprivation in vitro. Blocking methionine adenosyl transferase 2A (MAT2A)-dependent methionine catabolism induces cell cycle arrest and DNA damage in liver cancer cells, resulting in cellular senescence. A pharmacological screen further identified GSK3 inhibitors as senolytics that selectively kill MAT2A-inhibited senescent liver cancer cells. Importantly, combined treatment with MAT2A and GSK3 inhibitors therapeutically blunts liver tumor growth in vitro and in vivo across multiple models. Together, methionine catabolism is essential for liver tumor growth, and its inhibition can be exploited as an improved pro-senescence strategy for combination with senolytic agents to treat liver cancer.

Comparative study on CdSe QDs synthesized from water and ethanol: Hydrogen bond induced particle agglomeration and enhancement on photoluminescence.

In this paper a comparative study is carried out on the CdSe QDs synthesized from water and ethanol. Our purpose is to present an insight understanding on how hydrogen bonds affect particle agglomeration and consequently photoluminescence (PL) behavior of the QDs. In comparison with those from water, the CdSe QDs from ethanol show super PL with high brightness. Detailed characterization gives the only difference of large agglomerates presented in the QDs from ethanol. The TEM and HRTEM observations reveal a tri-level microstructure for the QDs from ethanol while in the case of those from water it is bi-level. With these direct evidences weak hydrogen bond of TGA with ethanol is proposed to be responsible for these large agglomerates and consequently super PL behavior. Additional investigations on some other alcohols of methanol, n-propanol, and i-butanol yield positive results and confirm the truth of our proposal.

IL-33/ST2 Signaling in the Pathogenesis of Chronic Pain and Itch.

Interleukin-33 (IL-33) is an inflammatory factor with an extensive range of biological effects and pleiotropic roles in diseases. Evidence suggests that IL-33 and its receptor ST2 play a pivotal role in chronic pain and itch at the level of primary sensory neurons, the spinal cord, and the brain. In this review, we outline an evolving understanding of the roles and mechanisms of IL-33 in chronic pathological pain, including inflammatory, neuropathic, and cancer, and chronic pruritus, such as allergic contact dermatitis, atopic dermatitis, and dry skin. Understanding the key roles of IL-33/ST2 signaling may provide exciting insights into the mechanisms of chronic pain and itch and lead to new clues for therapeutic approaches to the resolution of chronic pain and itch.

Sex-specific gene expression patterns in head and neck squamous cell carcinomas.

Objective: The head and neck squamous cell carcinomas (HNSCCs) have higher incidence rates in men, but the reasons are still obscure. This study aimed to investigate the sex-specific gene expression patterns and predict the regulatory mechanisms. Design: Data including clinical, survival, RNA-seq, miRNA, and methylation information were derived from The Cancer Genome Atlas (TCGA). A total of 131 paired male and female cases were included based on propensity score matching. We concentrated on the prognostic values of the sex-specific pathways enriched by differentially expressed genes (DEGs) and predicted the potential regulatory mechanisms from immune cell infiltration, ceRNA regulatory network, methylation, and differential coexpression analysis. Results: Compared with females, males exhibited a lower activity of immune-related functions and higher activities of mitochondrial and ubiquitination functions. The pathway activities were associated with the prognosis of males but less relevant to females. We extracted eight pathways with sex-biased survival patterns, of which five were about down-regulated immune functions, and three were up-regulated pathways (GTP biosynthetic, DNA polymerase, and spliceosomal complex assembly). The five immune pathways were moderately or strongly correlated with the proportion of macrophages. We identified six over-expressed lncRNAs that might be involved in the regulation of the three up-regulated pathways. These lncRNAs exhibited a lower methylation density in males, which might account for their over-expression. Conclusions: For HNSCCs, males were characterized by immunosuppression. It was a sign of unfavorable prognosis and might be associated the proportion of macrophages. LncRNAs and methylation might be involved in the regulation of these pathways.

Palmoplantar pustulosis with psoriatic arthritis ineffective to interleukin-17 inhibitors: two patients successfully treated with upadacitinib.

Palmoplantar pustulosis (PPP) is a rare chronic pustular disease. Psoriatic arthritis (PsA) is one of the common manifestations of arthritis in PPP associated with a high burden of disease. The treatment of PPP is difficult and still in the exploratory stage. Only a few cases show that PPP complicated with arthritis have been successfully treated with janus kinase inhibition, interleukin (IL)-6 inhibitors, IL-12/23 inhibitors and tumor necrosis factor inhibitors. Here we reported that two patients were diagnosed as PPP with PsA and initially treated with IL-17 inhibitors. One case was only partially relieved, and the other case had severe paradoxical reaction in the trunk. The joint and skin condition of two patients had been significantly improved without reported adverse reactions after 18 weeks treatment with upadacitinib, which support upadacitinib may be a potential option for patients with PPP combined PsA.

Tachykinin receptor 3 in the lateral habenula alleviates pain and anxiety comorbidity in mice.

The coexistence of chronic pain and anxiety is a common clinical phenomenon. Here, the role of tachykinin receptor 3 (NK3R) in the lateral habenula (LHb) in trigeminal neuralgia and in pain-associated anxiety was systematically investigated. First, electrophysiological recording showed that bilateral LHb neurons are hyperactive in a mouse model of trigeminal neuralgia made by partial transection of the infraorbital nerve (pT-ION). Chemicogenetic activation of bilateral LHb glutamatergic neurons in naive mice induced orofacial allodynia and anxiety-like behaviors, and pharmacological activation of NK3R in the LHb attenuated allodynia and anxiety-like behaviors induced by pT-ION. Electrophysiological recording showed that pharmacological activation of NK3R suppressed the abnormal excitation of LHb neurons. In parallel, pharmacological inhibition of NK3R induced orofacial allodynia and anxiety-like behavior in naive mice. The electrophysiological recording showed that pharmacological inhibition of NK3R activates LHb neurons. Neurokinin B (NKB) is an endogenous high-affinity ligand of NK3R, which binds NK3R and activates it to perform physiological functions, and further neuron projection tracing showed that the front section of the periaqueductal gray (fPAG) projects NKB-positive nerve fibers to the LHb. Optogenetics combined with electrophysiology recordings characterize the functional connections in this fPAG NKB → LHb pathway. In addition, electrophysiological recording showed that NKB-positive neurons in the fPAG were more active than NKB-negative neurons in pT-ION mice. Finally, inhibition of NKB release from the fPAG reversed the analgesic and anxiolytic effects of LHb Tacr3 overexpression in pT-ION mice, indicating that fPAG NKB → LHb regulates orofacial allodynia and pain-induced anxious behaviors. These findings for NK3R suggest the cellular mechanism behind pT-ION in the LHb and suggest that the fPAG NKB → LHb circuit is involved in pain and anxiety comorbidity. This previously unrecognized pathway might provide a potential approach for relieving the pain and anxiety associated with trigeminal neuralgia by targeting NK3R.

Antipruritic effects of geraniol on acute and chronic itch via modulating spinal GABA/GRPR signaling.

BACKGROUND AND PURPOSE: Itch (pruritus) is a common unpleasant feeling, often accompanied by the urge of scratching the skin. It is the main symptom of many systemic and skin diseases, which can seriously affect the patient's quality of life. Geraniol (GE; trans-3,7-dimethyl-2,6-octadien-1-ol) is a natural monoterpene with diverse effects, including anti-inflammatory, antioxidant, neuroprotective, anti-nociceptive, and anticancer properties. The study aims to examine the effects of GE on acute and chronic itch, and explore the underlying mechanisms. METHODS: Acute itch was investigated by using Chloroquine and compound 48/80 induced model, followed by manifestation of diphenylcyclopropenone (DCP)-induced allergic contact dermatitis and the acetone-ether-water (AEW)-induced dry skin model in mice. The scratching behavior, skin thickness, c-Fos expression, and GRPR protein expression in the spinal cord were subsequently monitored and evaluated by behavioral tests as well as pharmacological and pharmacogenetic technologies. RESULTS: Dose-dependent intraperitoneal injection of GE alleviated the acute itch, induced by chloroquine and compound 48/80, as well as increased the spinal c-Fos expression. Intrathecal administration of GE suppressed the GABAA receptor inhibitor bicuculline-induced itch, GRP-induced itch, and the GABAergic neuron inhibition-induced itch. Furthermore, the subeffective dose of bicuculline blocked the anti-pruritic effect of GE on the chloroquine and compound 48/80 induced acute itch. GE also attenuated DCP and AEW-induced chronic itch, as well as the increase of spinal GRPR expression in DCP mice. CONCLUSION AND IMPLICATIONS: GE alleviates both acute and chronic itch via modulating the spinal GABA/GRPR signaling in mice. Findings of this study reveal that GE may provide promising therapeutic options for itch management. Also, considering the pivotal role of essential oils in aromatherapy, GE has great application potential in aromatherapy for treating skin diseases, and especially the skin with severe pruritus.