Lipid-Lowering Meroterpenoids Penihemeroterpenoids A-F from Penicillium herquei GZU-31-6 via Targeting the AMPK/ACC/SREBP-1c Signaling Pathway.

Penihemeroterpenoids A-C, the first meroterpenoids with an unprecedented 6/5/6/5/5/6/5 heptacyclic ring system, together with precursors penihemeroterpenoids D-F, were co-isolated from the fungus Penicillium herquei GZU-31-6. Among them, penihemeroterpenoids C-F exhibited lipid-lowering effects comparable to those of the positive control simvastatin by the activation of the AMPK/ACC/SREBP-1c signaling pathway, downregulated the mRNA levels of lipid synthesis genes FAS and PNPLA3, and increased the level of mRNA expression of the lipid export gene MTTP.

Novel 6/7/6 ring system diterpenoids and cytochalasins from the fungus Eutypella scoparia GZU-4-19Y and their anti-inflammatory activity.

Two new compounds eutyditerpenoid A (1) and seco-phenochalasin B (5), together with seven known compounds diaporthein A (2), aspergillon A (3), phenochalasin B (4), cytochalasins Z24 and Z25 (6 and 7), scoparasins A and B (8 and 9) were isolated from marine-derived Eutypella scoparia GZU-4-19Y. Among them, eutyditerpenoid A (1) with a rare 6/7/6 ring system possesing an anhydride moiety was the first example in the pimarane-type diterpenoids. Their structures were determined based on spectroscopic methods and the electronic circular dichroism (ECD) calculations. In the bioassays, all of the isolates were evaluated for their inhibitory activity against NO production induced by lipopolysaccharide in RAW 264.7 cells. Compounds 3 and 7 showed potent NO inhibition activity with IC50 values of 2.1 and 17.1 µM respectively, and the former also significantly suppressed the protein expression of iNOS and COX-2 at the concentration of 2.5 µM.

The Roles of Periaqueductal Gray and Dorsal Raphe Nucleus Dopaminergic Systems in the Mechanisms of Thermal Hypersensitivity and Depression in Mice.

Depression and thermal hypersensitivity share pathogenic features and symptomology, but their pathophysiologic interactions have not been fully elucidated. Dopaminergic systems in the ventrolateral periaqueductal gray (vlPAG) and dorsal raphe nucleus have been implicated in these conditions due to their antinociception and antidepression effects, although their specific roles and underlying mechanisms remain obscure. In this study, chronic unpredictable mild stress (CMS) was used to induce depression-like behaviors and thermal hypersensitivity in C57BL/6J (wild-type) or dopamine transporter promoter mice to establish a mouse model of pain and depression comorbidity. Microinjections of quinpirole, a dopamine D2 receptor agonist, up-regulated D2 receptor expression in dorsal raphe nucleus and reduced depressive behaviors and thermal hypersensitivity with CMS, while dorsal raphe nucleus injections of JNJ-37822681, an antagonist of D2 receptors, had the reciprocal effect on dopamine D2 receptor expression and behaviors. Moreover, using a chemical genetics approach to activate or inhibit dopaminergic neurons in vlPAG ameliorated or exacerbated depression-like behaviors and thermal hypersensitivity, respectively, in dopamine transporter promoter-Cre CMS mice. Collectively these results demonstrated the specific role of vlPAG and dorsal raphe nucleus dopaminergic systems in the regulation of pain and depression comorbidity in mice. PERSPECTIVE: The current study provides insights into the complex mechanisms underlying thermal hypersensitivity induced by depression, and the findings suggest that pharmacological and chemogenetic modulation of dopaminergic systems in the vlPAG and dorsal raphe nucleus may be a promising therapeutic strategy to simultaneously mitigate pain and depression.

Time trends and heterogeneity in the disease burden of trachoma, 1990-2019: a global analysis.

PURPOSE: To evaluate the epidemiological trends and associated risk factors of disease burden due to trachoma. METHODS: Data for the country-specific disability-adjusted life year (DALY) number, rate and age-standardised rate of trachoma together with related data of other common eye diseases were acquired from the Global Burden of Disease Study 2019 database. The Socio-Demographic Index (SDI), Human Development Index (HDI), inequality-adjusted HDI and other related indices were obtained from published data or publicly available databases. Regression analyses were conducted to evaluate the associations between potential risk factors and the age-standardised DALY burden of trachoma. RESULTS: The global DALY burden due to trachoma decreased by 37% from 1990 to 2019 and decreased by 69.8% after adjusting for age and population growth, and, in available 1990-2019 data, had the greatest reduction in attributable DALYs of all common eye disease, with the others analysed being cataract, glaucoma, refractive disorders and age-related macular degeneration. Women had higher age-standardised DALY burden due to trachoma than men (p<0.001). The African region (p<0.001) had the heaviest burden among global regions. The age-standardised DALY rate was higher in countries with lower income (p<0.001) and lower SDI (p<0.001). Higher disease burden due to trachoma was associated with lower HDI (ß=-48.102, 95% CI -86.888 to -9.316, p=0.016), lower SDI (ß=-48.063, 95% CI -83.702 to -12.423, p<0.001) and lower expected years of schooling (ß=-2.352, 95% CI -3.756 to -0.948, p=0.002). CONCLUSIONS: The global disease burden due to trachoma decreased from 1990 to 2019 and it had the greatest reduction compared with other common eye diseases. Lower HDI, socioeconomic status and educational level were related to a higher national disease burden of trachoma. Our findings could provide necessary information for trachoma control and prevention.

Diterpenoids with anti-inflammatory activity from the lateral root of Aconitum carmichaelii debeaux.

Five undescribed diterpenoids, including two ent-cleistanthane-type diterpenoids aconicleistanthanes A and B, a hetisine-type diterpenoid aconihetisine A, two aconitines-type diterpenoids aconicarmines A and B, and thirteen known diterpenoids alkaloids, were co-isolated from the lateral root of the Aconitum carmichaelii Debeaux (Ranunculaceae). Their structures were elucidated based on spectroscopic methods, and the absolute configurations were determined by X-ray diffraction and electronic circular dichroism (ECD) calculations. Among them, aconicleistanthanes A and B as ent-cleistanthane-type diterpenoid featuring a unique five-membered lactone D ring, is the first reported example of ent-cleistanthane-type diterpenoids in the Aconitum, which provided a new type of diterpene metabolites for Aconitum and enriched the chemical space of the plant of the Aconitum. In the bioassays, aconicleistanthane A significantly suppressed the production of pro-inflammatory mediators (IL-6, IL-1ß and COX-2) and the protein expression of the enzyme iNOS at the concentration of 6.25 µM.

PRG-1 prevents neonatal stimuli-induced persistent hyperalgesia and memory dysfunction via NSF/Glu/GluR2 signaling.

Neonatal repetitive noxious stimuli (RNS) has been shown to cause long-term harmful effects on nociceptive processing, learning, and memory which persist until adulthood. Plasticity-related gene 1 (PRG-1) regulates synaptic plasticity and functional reorganization in the brain during neuronal development. In this study, neonatal RNS rats were established by repetitive needle pricks to neonatal rats on all four feet to model repetitive pain exposure in infants. Neonatal RNS caused thermal hyperalgesia, mechanical allodynia, learning, and memory impairments which manifested in young rats and persisted until adulthood. Hippocampal PRG-1/N-ethylmaleimide sensitive fusion protein (NSF) interaction was determined to be responsible for the RNS-induced impairment via enhanced extracellular glutamate release and AMPAR GluR2 trafficking deficiency in a cell-autonomous manner. These pathways likely act synergistically to cause changes in dendritic spine density. Our findings suggest that PRG-1 prevents the RNS-induced hyperalgesia, learning, and memory impairment by regulating synaptic plasticity via NSF/Glu/GluR2 signaling.

Abdominal massage alleviates functional diarrhea in immature rats via modulation of intestinal microbiota and tight junction protein.

Functional diarrhea (FD) is a common type of chronic diarrhea in children. Recurrent diarrhea can negatively impact children's quality of life and raise healthcare costs significantly. However, conventional treatments are ineffective and limited. Moreover, children with chronic conditions have poor medication compliance. Therefore, non-pharmacological and complementary treatments are urgently needed. In China, abdominal massage is widely used to treat diarrhea in children. Numerous clinical studies have verified its usefulness in treating gastrointestinal disorders as well. Nevertheless, its intrinsic mechanisms are still unclear, and the impact of massage direction on treatment effects has received less attention. In our study, we found that FD was not associated with pathogen infection. A dysbiosis of the intestinal microbiota and disruption of the intestinal barrier are most likely to cause FD. Moreover, this study also substantiates that abdominal massage can mitigate functional diarrhea by altering the intestinal microbiota structure and decreasing the number of bacteria that damage intestinal mucosal barriers. The reduction of Ruminococcus_torques_group and Clostridium_innocuum_group at the genus level potentially mediated the beneficial effects of abdominal massage on alleviating diarrhea. Furthermore, massaging from two different directions, clockwise (CW) and counter-clockwise (CCW) massage, would not significantly influence the effect of the massage on intestinal microbiota or tight junction proteins. In summary, abdominal massage is an effective complementary therapy for children suffering from functional diarrhea.

Longitudinal Changes of Axial Length and Associated Factors in Congenital Ectopia Lentis Patients.

Purpose: To investigate the longitudinal changes and associated factors of axial length (AL) in congenital ectopia lentis (CEL) patients. Methods: In this retrospective study, medical records of CEL patients were reviewed from January 2014 to December 2019 at the Zhongshan Ophthalmic (ZOC) in China. Patients were divided into the surgery group and the nonsurgery group. Data of refractive power, best-corrected visual acuity (BCVA), and intraocular pressure (IOP) as well as ocular biometrics including AL, corneal curvature, white-to-white (WTW), and central corneal thickness (CCT) were collected at baseline and each follow-up visit. Multiple linear regression was performed to assess the potential associated factors for axial length growth in congenital ectopia lentis patients. Results: Compared with the nonsurgery group, the change rate of AL among children aged 3 to 6 years old was slower in the surgery group (0.443 ± 0.340 mm/year vs. 0.278 ± 0.227 mm/year, P < 0.05). However, no statistically significant difference for the change rate of AL was detected between the surgery group and the nonsurgery group (P > 0.05) among patients aged 7 years or older. For the surgery group, the results of the linear regression model showed that a higher change rate of AL was associated with younger age (older age: ß = -0.009, 95% CI: -0.014 to -0.003, and P=0.002) and worse baseline BCVA (logMAR) (ß = 0.256, 95% CI: 0.072 to 0.439, and P=0.007). As for the nonsurgery group, younger baseline age (older age: ß = -0.027, 95% CI: -0.048 to -0.007, and P=0.01) and longer baseline AL (ß = 0.073, 95% CI: 0.023 to 0.122, and P=0.006) were associated with a higher change rate of AL. Conclusions: The AL change rate was clearly associated with age both in the surgery group and in the nonsurgery group. Intervention strategies such as surgery should be performed earlier for CEL that meets the surgical criteria. Worse baseline BCVA and longer baseline AL are associated factors that would affect the growth rate of AL in the surgery and nonsurgery group, respectively.

Linderasesterterpenoids A and B: Two 7-Cyclohexyldecahydroazulene Carbon Skeleton Sesterterpenoids Isolated from the Root of Lindera glauca.

Two novel sesterterpenoids linderasesterterpenoids A (1) and B (2) with an unprecedented 7-cyclohexyldecahydroazulene carbon skeleton isolated from the root of Lindera glauca. Their structures were elucidated by X-ray diffraction, quantum chemical calculations, and spectroscopic methods. The biogenetic pathway for 1 and 2 is proposed. In the bioassay, linderasesterterpenoids A and B showed good inhibitory activities against LPS-induced NO production in RAW 264.7 cells compared to a positive control.

Fluorocitrate and neurotropin confer analgesic effects on neuropathic pain in diabetic rats via inhibition of astrocyte activation in the periaqueductal gray.

Currently, effective treatments for diabetic neuropathic pain (DNP) are still unmet clinical needs. Activation of astrocytes in the ventrolateral region of periaqueductal gray (vlPAG) has a regulating effect on pain responses. The present study was designed to confirm that repeated intra-vlPAG injection of fluorocitrate (FC), a selective inhibitor of astrocyte activation or intraperitoneal (IP) injection of neurotropin, a widely prescribed analgesic drug for chronic pain, inhibited the activation of astrocytes in vlPAG and thus produced an analgesic effect on DNP. An in vivo model was developed to study DNP in rats. The changes in mechanical withdrawal threshold (MWT) and activation levels of astrocytes in the vlPAG were evaluated in all experimental rats. Compared with normal rats, vlPAG-based glial fibrillary acid protein (GFAP) was clearly upregulated, whereas the MWTs of DNP rats were markedly diminished. The intra-vlPAG injections of FC or IP injections of neurotropin attenuated the alterations both in MWTs and expression levels of GFAP in vlPAG in DNP rats. Collectively, these findings suggest the antinociceptive effects of FC and neurotropin in DNP rats, which were associated with suppressing the activation of astrocytes in vlPAG.

Association between workplace bullying and nurses' professional quality of life: The mediating role of resilience.

AIM: We aim to determine workplace bullying in relation to the professional quality of life of nurses and the mediating role of resilience between workplace bullying and the professional quality of life. BACKGROUND: Workplace bullying is an increasingly serious problem worldwide and deleteriously affects the occupational health and quality of life of nurses. However, it has not attracted adequate managerial attention. METHOD: A cross-sectional study was conducted using a sample of 493 clinical nurses from two tertiary grade A hospitals in Guangzhou, China. Data were collected through an online questionnaire survey in July 2020 and analysed with structural equation modelling. RESULTS: Workplace bullying had negative and direct effects on the professional quality of life of nurses. Resilience mediated the relationship between workplace bullying and the professional quality of life. CONCLUSION: Resilience is a protective factor that helps nurses cope with workplace bullying. Managers can improve the professional quality of life of nurses by reducing workplace bullying and strengthening the resilience of nurses. IMPLICATIONS FOR NURSING MANAGEMENT: Managers must take measures to prevent the workplace bullying of nurses. In addition, nurse supervisors should pay attention to the resilience of nurses and strengthen resilience training to help nurses withstand the pressure of workplace bullying and improve their professional quality of life.

PRG-1 relieves pain and depressive-like behaviors in rats of bone cancer pain by regulation of dendritic spine in hippocampus.

Rationale: Pain and depression, which tend to occur simultaneously and share some common neural circuits and neurotransmitters, are highly prevalent complication in patients with advanced cancer. Exploring the underlying mechanisms is the cornerstone to prevent the comorbidity of chronic pain and depression in cancer patients. Plasticity-related gene 1 (PRG-1) protein regulates synaptic plasticity and brain functional reorganization during neuronal development or after cerebral lesion. Purinergic P2X7 receptor has been proposed as a therapeutic target for various pain and neurological disorders like depression in rodents. In this study, we investigated the roles of PRG-1 in the hippocampus in the comorbidity of pain and depressive-like behaviors in rats with bone cancer pain (BCP). Methods: The bone cancer pain rat model was established by intra-tibial cell inoculation of SHZ-88 mammary gland carcinoma cells. The animal pain behaviors were assessed by measuring the thermal withdrawal latency values by using radiant heat stimulation and mechanical withdrawal threshold by using electronic von Frey anesthesiometer, and depressive-like behavior was assessed by sucrose preference test and forced swim test. Alterations in the expression levels of PRG-1 and P2X7 receptor in hippocampus were separately detected by using western blot, immunofluorescence and immunohistochemistry analysis. The effects of intra-hippocampal injection of FTY720 (a PRG-1/PP2A interaction activator), PRG-1 overexpression or intra-hippocampal injection of A438079 (a selective competitive P2X7 receptor antagonist) were also observed. Results: Carcinoma intra-tibia injection caused thermal hyperalgesia, mechanical allodynia and depressive-like behaviors in rats, and also induced the deactivation of neurons and dendritic spine structural anomalies in the hippocampus. Western blot, immunofluorescence and immunohistochemistry analysis showed an increased expression of PRG-1 and P2X7 receptor in the hippocampus of BCP rats. Intra-hippocampal injection of FTY720 or A438079 attenuated both pain and depressive-like behaviors. Furthermore, overexpression of PRG-1 in hippocampus has similar analgesic efficacy to FTY720. In addition, they rescued neuron deactivation and dendritic spine anomalies. Conclusion: The results suggest that both PRG-1 and P2X7 receptor in the hippocampus play important roles in the development of pain and depressive-like behaviors in bone cancer condition in rats by dendritic spine regulation via P2X7R/PRG-1/PP2A pathway.

Short-Term High Fructose Intake Impairs Diurnal Oscillations in the Murine Cornea.

Purpose: Endogenous and exogenous stressors, including nutritional challenges, may alter circadian rhythms in the cornea. This study aimed to determine the effects of high fructose intake (HFI) on circadian homeostasis in murine cornea. Methods: Corneas of male C57BL/6J mice subjected to 10 days of HFI (15% fructose in drinking water) were collected at 3-hour intervals over a 24-hour circadian cycle. Total extracted RNA was subjected to high-throughput RNA sequencing. Rhythmic transcriptional data were analyzed to determine the phase, rhythmicity, unique signature, metabolic pathways, and cell signaling pathways of transcripts with temporally coordinated expression. Corneas of HFI mice were collected for whole-mounted techniques after immunofluorescent staining to quantify mitotic cell number in the epithelium and trafficking of neutrophils and γδ-T cells to the limbal region over a circadian cycle. Results: HFI significantly reprogrammed the circadian transcriptomic profiles of the normal cornea and reorganized unique temporal and clustering enrichment pathways, but did not affect core-clock machinery. HFI altered the distribution pattern and number of corneal epithelial mitotic cells and enhanced recruitment of neutrophils and γδ-T cell immune cells to the limbus across a circadian cycle. Cell cycle, immune function, metabolic processes, and neuronal-related transcription and associated pathways were altered in the corneas of HFI mice. Conclusions: HFI significantly reprograms diurnal oscillations in the cornea based on temporal and spatial distributions of epithelial mitosis, immune cell trafficking, and cell signaling pathways. Our findings reveal novel molecular targets for treating pathologic alterations in the cornea after HFI.

Furanaspermeroterpenes A and B, two unusual meroterpenoids with a unique 6/6/6/5/5 pentacyclic skeleton from the Marine-derived fungus Aspergillus terreus GZU-31-1.

Furanaspermeroterpenes A (1) and B (2), with a unique 6/6/6/5/5 pentacyclic skeleton, and five new congeners aspermeroterpenes D-H (3-7) were co-isolated from the marine-derived fungus Aspergillus terreus GZU-31-1. Among them, compounds 1 and 2 with rare five-membered D/E coupling rings were the first example of DMOA-derived meroterpenoids. Moreover, compound 3 was the first reported 6/6/6/6/5 pentacyclic meroterpenoid featuring an unusual cis-fused A/B ring. In the bioassays, all of the isolates were evaluated on the inhibitory activities against lipopolysaccharide-induced nitric oxide production in RAW 264.7 cells, and compounds 3-7 exhibited significant anti-inflammatory activity with IC50 values ranging from 6.74 to 29.59 µM than positive control (Indomethacin, IC50 30.98 µM).

Neurotropin alleviates rat osteocarcinoma pain via P2X3 receptor activation in the midbrain periaqueductal gray.

OBJECTIVES: Clinically effective analgesia treatment for patients afflicted with osteocarcinoma lessens the intensity of pain. The midbrain periaqueductal gray (PAG) plays a critical role in pain modulation, and activation of P2X3 receptors in this region mediates pain processing. Neurotropin is a small molecule drug used for analgesic treatment of a number of chronic pain conditions. The present study aims at determining whether P2X3 receptor activation in PAG is responsible for the analgesic effect of neurotropin in rats with osteocarcinoma pain. MATERIALS AND METHODS: The tibia of female Sprague-Dawley rats was inoculated with breast carcinoma cells to establish the osteocarcinoma pain model. The effects of intraperitoneal injection of 6, 12, and 18 neurotropin units (NU)/kg on pain threshold and receptor expression of P2X3 in the ventrolateral PAG (vlPAG) were assessed. The P2X3 receptor antagonist A-317491 (1.5 nmol/0.3 µl) was administered into vlPAG with a high-dose neurotropin (18 NU/kg) to determine the role of this receptor in the analgesic effect. RESULTS: The pain thresholds of the rats with osteocarcinoma pain continuously decreased, whereas P2X3 receptor expression in vlPAG only slightly increased after osteocarcinoma cell inoculation. Neurotropin substantially elevated the pain threshold and P2X3 receptor expression in vlPAG in a dose-dependent manner. A-317491 microinjection into vlPAG significantly reduced the analgesic effects of neurotropin in the rats with osteocarcinoma pain. CONCLUSION: Through these findings, it is shown that vlPAG P2X3 receptor activation participates in neurotropin-mediated analgesia mechanism in osteocarcinoma pain.

Sympathetic Nerves Positively Regulate Eosinophil-Driven Allergic Conjunctivitis via α1-Adrenergic Receptor Signaling.

Eosinophils are a major cause of tissue injury in allergic conjunctivitis. The biological nature of eosinophils in the conjunctiva and the mechanisms that control eosinophils' responses in allergic conjunctivitis are currently not completely understood. This study reports that conjunctival eosinophils comprise two populations-Siglec-Fint and Siglec-Fhi-in different life stages. Siglec-Fint eosinophils partly expressed CD34 and were in the immature (or steady) state. Siglec-Fhi eosinophils did not express CD34, sharply increased in number after short ragweed (SRW) pollen challenge, and were in the mature (or activated) state. Moreover, chemical sympathectomy by 6-hydroxydopamine reduced the recruitment and activation of eosinophils, whereas the activation of the sympathetic nerve system (SNS) with restraint stress accelerated the recruitment and activation of eosinophils in SRW-induced conjunctivitis. It was also found that two eosinophil populations expressed alpha-1a-adrenergic receptors (α1a-ARs); in SRW-induced conjunctivitis, treatment with an α1a-AR antagonist decreased eosinophil responses, whereas treatment with an α1a-AR agonist aggravated eosinophil responses. Thus, eosinophil responses in conjunctivitis are regulated by the SNS via α1a-AR signaling. SNS inputs or α1a-AR function may be potential targets for the treatment of allergic conjunctivitis.

Antibiotic-induced dysbiosis of gut microbiota impairs corneal development in postnatal mice by affecting CCR2 negative macrophage distribution.

Antibiotics are extremely useful, but they can cause adverse impacts on host bodies. We found that antibiotic treatment altered the composition of the gut microbiota and the gene expression profile in the corneal tissues of postnatal mice and decreased the corneal size and thickness, the angiogenesis of limbal blood vessels, and the neurogenesis of corneal nerve fibers. The reconstitution of the gut microbiota with fecal transplants in antibiotic-treated mice largely reversed these impairments in corneal development. Furthermore, C-C chemokine receptor type 2 negative (CCR2-) macrophages were confirmed to participate in corneal development, and their distribution in the cornea was regulated by the gut microbiota. We propose that the CCR2- macrophage population is a crucial mediator through which gut microbiota affect corneal development in postnatal mice. In addition, probiotics were shown to have the potential effect of restoring corneal development in antibiotic-treated mice. Abx-induced gut dysbiosis has significant, long-term effects on the development of the cornea, and reversal of these suppressive effects takes a long time.

Acute tobacco smoke exposure exacerbates the inflammatory response to corneal wounds in mice via the sympathetic nervous system.

Exposure to tobacco smoke is a major public health concern that can also affect ophthalmic health. Based on previous work demonstrating the important role of the sympathetic nervous system (SNS) in corneal wound repair, we postulated that acute tobacco smoke exposure (ATSE) may act through the SNS in the impairment of corneal wound repair. Here we find that ATSE rapidly increases the markers of inflammatory response in normal corneal limbi. After an abrasion injury, ATSE exaggerates inflammation, impairs wound repair, and enhances the expression of nuclear factor-κB (NF-κB) and inflammatory molecules such as interleukin-6 (IL-6) and IL-17. We find that chemical SNS sympathectomy, local adrenergic receptor antagonism, NF-κB1 inactivation, and IL-6/IL-17A neutralization can all independently attenuate ATSE-induced excessive inflammatory responses and alleviate their impairment of the healing process. These findings highlight that the SNS may represent a major molecular sensor and mediator of ATSE-induced inflammation.

Antibiotic-Induced Dysbiosis of Gut Microbiota Impairs Corneal Nerve Regeneration by Affecting CCR2-Negative Macrophage Distribution.

Although antibiotics are useful, they can also bring negative effects. We found that antibiotic-treated mice exhibit an alteration in the gene expression profile of corneal tissues and a decrease in corneal nerve density. During corneal wound healing, antibiotic treatment was found to impair corneal nerve regeneration, an effect that could be largely reversed by reconstitution of the gut microbiota via fecal transplant. Furthermore, CCR2- corneal macrophages were found to participate in the repair of damaged corneal nerves, and a decrease in CCR2- corneal macrophages in antibiotic-treated mice, which could be reversed by fecal transplant, was observed. Adoptive transfer of CCR2- corneal macrophages promoted corneal nerve regeneration in antibiotic-treated mice. The application of probiotics after administration of antibiotics also restored the proportion of CCR2- corneal macrophages and increased the regeneration of corneal nerve fibers after epithelial abrasion. These results suggest that dysbiosis of the gut microbiota induced by antibiotic treatment impairs corneal nerve regeneration by affecting CCR2- macrophage distribution in the cornea. This study also indicates the potential of probiotics as a therapeutic strategy for promoting the regeneration of damaged corneal nerve fibers when the gut microbiota is in dysbiosis.

The mouse autonomic nervous system modulates inflammation and epithelial renewal after corneal abrasion through the activation of distinct local macrophages.

Inflammation and reepithelialization after corneal abrasion are critical for the rapid restoration of vision and the prevention of microbial infections. However, the endogenous regulatory mechanisms are not completely understood. Here we report that the manipulation of autonomic nervous system (ANS) regulates the inflammation and healing processes. The activation of sympathetic nerves inhibited reepithelialization after corneal abrasion but increased the influx of neutrophils and the release of inflammatory cytokines. Conversely, the activation of parasympathetic nerves promoted reepithelialization and inhibited the influx of neutrophils and the release of inflammatory cytokines. Furthermore, we observed that CD64+CCR2+ macrophages in the cornea preferentially expressed the ß-2 adrenergic receptor (AR), whereas CD64+CCR2- macrophages preferentially expressed the α-7 nicotinic acetylcholine receptor (α7nAChR). After abrasion, the topical administration of a ß2AR agonist further enhanced the expression of the proinflammatory genes in the CD64+CCR2+ cell subset sorted from injured corneas. In contrast, the topical administration of an α7nAChR agonist further enhanced the expression of the anti-inflammatory genes in the CD64+CCR2- subset. Thus crosstalk between the ANS and local macrophage populations is necessary for the progress of corneal wound repair. Manipulation of ANS inputs to the wounded cornea may represent an alternative approach to the treatment of impaired wound healing.