CDDO regulates central and peripheral sensitization to attenuate post-herpetic neuralgia by targeting TRPV1/PKC-δ/p-Akt signals.

Postherpetic neuralgia (PHN) is a notorious neuropathic pain featuring persistent profound mechanical hyperalgesia with significant negative impact on patients' life quality. CDDO can regulate inflammatory response and programmed cell death. Its derivative also protects neurons from damages by modulating microglia activities. As a consequence of central and peripheral sensitization, applying neural blocks may benefit to minimize the risk of PHN. This study aimed to explore whether CDDO could generate analgesic action in a PHN-rats' model. The behavioural test was determined by calibrated forceps testing. The number of apoptotic neurons and degree of glial cell reaction were assessed by immunofluorescence assay. Activation of PKC-δ and the phosphorylation of Akt were measured by western blots. CDDO improved PHN by decreasing TRPV1-positive nociceptive neurons, the apoptotic neurons, and reversed glial cell reaction in adult rats. It also suppressed the enhanced PKC-δ and p-Akt signalling in the sciatic nerve, dorsal root ganglia (DRG) and spinal dorsal horn. Our research is the promising report demonstrating the analgesic and neuroprotective action of CDDO in a PHN-rat's model by regulating central and peripheral sensitization targeting TRPV1, PKC-δ and p-Akt. It also is the first study to elucidate the role of oligodendrocyte in PHN.

RTA-408 Regulates p-NF-κB/TSLP/STAT5 Signaling to Ameliorate Nociceptive Hypersensitivity in Chronic Constriction Injury Rats.

Neuropathic pain following nerve injury is a complex condition, which often puts a negative impact on life and remains a sustained problem. To make pain management better is of great significance and unmet need. RTA 408 (Omaveloxone) is a traditional Asian medicine with a valid anti-inflammatory property. Thus, we aim to investigate the therapeutic effect of RTA-408 on mechanical allodynia in chronic constriction injury (CCI) rats as well as the underlying mechanisms. Neuropathic pain was induced by using CCI of the rats' sciatic nerve (SN) and the behavior testing was measured by calibrated forceps testing. Activation of Nrf-2, the phosphorylation of nuclear factor-κB (NF-κB), and the inflammatory response were assessed by western blots. The number of apoptotic neurons and degree of glial cell reaction were examined by immunofluorescence assay. RTA-408 exerts an analgesic effect on CCI rats. RTA-408 reduces neuronal apoptosis and glial cell activation by increasing Nrf-2 expression and decreasing the inflammatory response (TNF-α/ p-NF-κB/ TSLP/ STAT5). These data suggest that RTA-408 is a candidate with potential to reduce nociceptive hypersensitivity after CCI by targeting TSLP/STAT5 signaling.

A Novel Synthetic Oleanolic Acid Derivative Inhibits Glioma Cell Proliferation by Regulating Cell Cycle G2/M Arrest.

2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid-9,11-dihydro-trifluoroethyl amide (CDDO-dhTFEA) has antioxidant and anti-inflammatory activities; however, whether CDDO-dhTFEA has anticancer effects is unclear. The objective of this research was to investigate the possibility of CDDO-dhTFEA as a potential cancer-fighting treatment in glioblastoma cells. Our experiments were performed on U87MG and GBM8401 cells, and we found that CDDO-dhTFEA was effective in reducing cell proliferation in both cell lines, in a manner that was dependent on both time and concentration. Additionally, we observed that CDDO-dhTFEA had a significant impact on the regulation of cell proliferation, which was evident in the increase in DNA synthesis that was observed in both cell types. CDDO-dhTFEA induced G2/M cell cycle arrest and mitotic delay, which may be associated with the inhibition of proliferation. Treatment with CDDO-dhTFEA led to cell cycle G2/M arrest and inhibited proliferation of U87MG and GBM8401 cells by regulating G2/M cell cycle proteins and gene expression in GBM cells in vitro.

The Use of San-Huang-Xie-Xin-Tang Reduces the Mortality Rate among Breast Cancer Patients.

Globally, breast cancer is the most common cause of cancer deaths. In Taiwan, it is the most prevalent cancer among females. Since San-Huang-Xie-Xin-Tang (SHXXT) exerts not only an anti-inflammatory but an immunomodulatory effect, it may act as a potent anti-tumor agent. Herein, the study aimed to explore the influence of SHXXT and its constituents on the mortality rate among breast cancer patients in Taiwan regarding the component effect and the dose-relationship effect. By using the Taiwan National Health Insurance (NHI) Research Database (NHIRD), the study analyzed 5387 breast cancer patients taking Chinese herbal medicine (CHM) and 5387 breast cancer patients not using CHM. CHM means SHXXT and its constituents in the study. The Kaplan-Meier method was utilized to determine the mortality probabilities among patients. Whether the CHM influences the mortality rate among patients was estimated by Cox proportional hazard regression analysis. The use of CHM could lower the cancer mortality rate by 59% in breast cancer patients. The protective effect was parallel to the cumulative days of CHM use and the annual average CHM dose. In addition, the mortality rate was lower in patients who used SHXXT compared to those who only used one of its constituents. SHXXT and its constituents were all promising therapeutic weapons against breast cancer.

RTA dh404 Induces Cell Cycle Arrest, Apoptosis, and Autophagy in Glioblastoma Cells.

RTA dh404 is a novel synthetic oleanolic acid derivative that has been reported to possess anti-allergic, neuroprotective, antioxidative, and anti-inflammatory properties, and exerts therapeutic effects on various cancers. Although CDDO and its derivatives have anticancer effects, the actual anticancer mechanism has not been fully explored. Therefore, in this study, glioblastoma cell lines were exposed to different concentrations of RTA dh404 (0, 2, 4, and 8 µM). Cell viability was evaluated using the PrestoBlue™ reagent assay. The role of RTA dh404 in cell cycle progression, apoptosis, and autophagy was analyzed using flow cytometry and Western blotting. The expression of cell cycle-, apoptosis-, and autophagy-related genes was detected by next-generation sequencing. RTA dh404 reduces GBM8401 and U87MG glioma cell viability. RTA dh404 treated cells had a significant increase in the percentage of apoptotic cells and caspase-3 activity. In addition, the results of the cell cycle analysis showed that RTA dh404 arrested GBM8401 and U87MG glioma cells at the G2/M phase. Autophagy was observed in RTA dh404-treated cells. Subsequently, we found that RTA dh404-induced cell cycle arrest, apoptosis, and autophagy were related to the regulation of associated genes using next-generation sequencing. Our data indicated that RTA dh404 causes G2/M cell cycle arrest and induces apoptosis and autophagy by regulating the expression of cell cycle-, apoptosis-, and autophagy-related genes in human glioblastoma cells, suggesting that RTA dh404 is a potential drug candidate for the treatment of glioblastoma.

Linalyl Acetate Ameliorates Mechanical Hyperalgesia Through Suppressing Inflammation by TSLP/IL-33 Signaling.

Neuropathic pain is a debilitating chronic disorder, significantly causing personal and social burdens, in which activated neuroinflammation is one major contributor. Thymic stromal lymphopoietin (TSLP) and interleukin (IL)-33 is important for chronic inflammation. Linalyl acetate (LA) is main component of lavender oil with an anti-inflammatory property through TSLP signaling. The aim of the study is to investigate how LA regulates mechanical hyperalgesia after sciatic nerve injury (SNI). Adult Sprague-Dawley male rats were separated into 3 groups: control group, SNI group and SNI with LA group. LA was administrated intraperitoneally one day before SNI. Pain behavior test was evaluated through calibration forceps testing. Ipsilateral sciatic nerves (SNs), dorsal root ganglions (DRGs) and spinal cord were collected for immunofluorescence staining and Western blotting analyses. SNI rats were more sensitive to hyperalgesia response to mechanical stimulus since operation, which was accompanied by spinal cord glial cells reactions and DRG neuro-glial interaction. LA could relieve the pain sensation, proinflammatory cytokines and decrease the expression of TSLP/TSLPR complex. Also, LA could reduce inflammation through reducing IL-33 signaling. This study is the first to indicate that LA can modulate pain through TSLP/TSLPR and IL-33 signaling after nerve injury.

Prognostic Impact of Low-Level p53 Expression on Brain Astrocytomas Immunopositive for Epidermal Growth Factor Receptor.

Although the expression of p53 and epidermal growth factor receptor (EGFR) is associated with therapeutic resistance and patient outcomes in many malignancies, the relationship in astrocytomas is unclear. This study aims to correlate p53 and EGFR expression in brain astrocytomas with overall patient survival. Eighty-two patients with astrocytomas were enrolled in the study. Semi-quantitative p53 and EGFR immunohistochemical staining was measured in tumor specimens. The mean follow-up after astrocytoma surgery was 18.46 months. The overall survival rate was 83%. Survival was reduced in EGFR-positive patients compared with survival in EGFR-negative patients (p < 0.05). However, no significant differences in survival were detected between patients with high and low p53 expression. In patients with low p53 expression, positive EGFR staining was associated with significantly worse survival compared with patients with negative EGFR staining (log-rank test: p < 0.001). Survival rates in positive and negative EGFR groups with high p53 protein expression were similar (log-rank test: p = 0.919). The IC50 of an EGFR inhibitor was higher in GBM cells with high p53 protein expression compared with the IC50 in cells with low p53 expression. Combined EGFR and p53 expression may have prognostic significance in astrocytomas.

Impact of seborrheic dermatitis on osteoporosis risk: A population-based cohort study.

Osteoporosis is a systemic bone-resorbing disease that easily causes subsequent risk of fracture. Hence, the substantial physical burden of osteoporosis makes it an important public health issue. Seborrheic dermatitis (SD) is a chronic, recurrent, inflammatory skin disease. Despite the advances in medication for treating osteoporosis, identifying undiagnosed osteoporosis patients is still challenging. Since osteoporosis and SD share a similar pathobiology, e.g. inflammation and hormonal imbalance, we aimed to investigate whether the existence of SD increases osteoporosis risk by using the Taiwan National Health Insurance Research Database. A total of 7831 patients aged 18-50 years with SD and a control group of 31 324 patients without SD matched by age, gender, Charlson Comorbidity Index, and index date at a ratio of 1:4 during 1996-2010 were recruited in the study. To measure the cumulative incidence and compare the hazard ratios of osteoporosis between each group, the Kaplan-Meier method and Cox proportional hazard regression models were utilized. It was found that 0.98% of SD patients had osteoporosis. Compared to the non-SD group, the SD group had a 5.95-fold higher osteoporosis risk after adjustment for variables. The impact of SD on osteoporosis risk was largest in the female and young age groups. In addition, the presence of hyperlipidemia, hyperthyroidism, and epilepsy synergistically increased osteoporosis incidence in the SD group. This first large cohort study demonstrated an association between SD and osteoporosis. Since the effect on bone health in SD patients with concomitant diseases is largest in early life, diet or lifestyle recommendations as well as regular bone examinations are advised during follow-up of SD.

Potential Roles of Teamwork and Unmet Needs on Surgical Learning Curves of Spinal Robotic Screw Placement.

Background: The aim of this study was to investigate the learning curve of robotic spine surgery quantitatively with the well-described power law of practice. Methods: Kaohsiung Medical University Hospital set up a robotic spine surgery team by the neurosurgery department in 2013 and the orthopedic department joined the well-established team in 2014. A total of consecutive 150 cases received robotic assisted spinal surgery. The 150 cases, with 841 transpedicular screws were enrolled into 3 groups: the first 50 cases performed by neurosurgeons, the first 50 cases by orthopedic surgeons, and 50 cases by neurosurgeons after the orthopedic surgeons joined the team. The time per screw and accuracy by each group and individual surgeon were analyzed. Results: The time per screw for each group was 9.56 ± 4.19, 7.29 ± 3.64, and 8.74 ± 5.77 minutes, respectively, with p-value 0.0017. The accuracy was 99.6% (253/254), 99.5% (361/363), and 99.1% (222/224), respectively, with p-value 0.77. Though the first group took time significantly more on per screw placement but without significance on the nonlinear parallelism F-test. Analysis of 5 surgeons and their first 10 cases of short segment surgery showed the time per screw by each surgeon was 12.28 ± 5.21, 6.38 ± 1.54, 8.68 ± 3.10, 6.33 ± 1.90, and 6.73 ± 1.81 minutes. The first surgeon who initiated the robotic spine surgery took significantly more time per screw, and the nonlinear parallelism test also revealed only the first surgeon had a steeper learning curve. Conclusion: This is the first study to demonstrate that differences of learning curves between individual surgeons and teams. The roles of teamwork and the unmet needs due to lack of active perception are discussed.

Trigeminal Neuralgia Is a Dementia Risk Factor: A Retrospective Cohort Study.

Background: Dementia, a worldwide public-health issue, is regarded as a disorder rather than a normal aging process. Trigeminal neuralgia (TN) is a chronic debilitating pain disorder that impairs daily activities. Both are most prevalent in females and in patients older than 50 years. Recent studies reveal that pain and dementia may have a reciprocal interaction with each other. Objective: In response, we estimated whether adults with TN have an increased dementia risk. Methodology: By means of Taiwan's National Health Insurance Research Database, between 1996 and 2010, 762 patients aged over 50 years in the TN group were matched with 3048 patients in the non-TN group at a ratio of 1:4. Kaplan-Meier method and Cox proportional hazard regression models were also used to determine the cumulative incidence and compare the hazard ratios of dementia in each group. Results: The incidence of dementia was higher in the TN group compared to the non-TN group. After adjusting for covariates, the TN group had a 4.47-fold higher risk of dementia compared to the non-TN group. Additionally, the impact of TN on dementia risk was larger in young-aged patients than in old-aged patients. As well, the age at the time of dementia diagnosis was younger in the TN group compared to the non-TN group. Conclusions: TN is a dementia risk factor. Given the lack of a curative therapy for dementia, early identification of TN patients may help to prevent dementia sequelae.

The Risk of Trigeminal Neuralgia Following Osteoporosis.

Background and objectives: Managing people with trigeminal neuralgia (TN) and osteoporosis is challenging due to their debilitating conditions. Currently, the exact association between TN and osteoporosis in patients remains unknown, although there is potential overlapping of pathophysiological mechanisms. In response, we calculated TN risk in patients who have osteoporosis. Materials and Methods: 45,393 patients aged over 50 years diagnosed with osteoporosis were matched with 45,393 non-osteoporosis patients aged over 50 years (1:1 ratio) who were used as the control group, using data from 1996 to 2010 from Taiwan's National Health Insurance Research Database. The cumulative incidences of subsequent TN and the hazard ratio were estimated using Cox proportional hazards modeling and the Kaplan-Meier method, respectively. Results: Among the total sample, 333 patients were diagnosed with TN during the follow-up period: 205 in the osteoporosis cohort and 128 in the control cohort. Through covariate adjustment, the overall TN incidence showed a 1.80-fold increase in the osteoporosis cohort in comparison with the control cohort (0.60 vs. 0.18 per 1000 person-years, respectively). The High Charlson Comorbidity Index, hypertension, and migraines were risk factors of TN. Conclusions: Osteoporosis patients had a higher TN risk than that of the control cohort. Therefore, early recognition of pain and symptoms in osteoporotic people may help to identify possible TN patients who need prompt therapy.

The Contribution of TSLP Activation to Hyperalgesia in Dorsal Root Ganglia Neurons of a Rat.

Peripheral nerve injury involves divergent alterations within dorsal root ganglia (DRG) neurons sensitized by persistent inflammation. Thymic stromal lymphopoietin (TSLP) production is crucial in the development of chronic inflammatory responses. Herein, we investigate the changes of TSLP expression in rats' DRG neurons between injured and uninjured sides in the same rat. Linalyl acetate (LA) was served as a TSLP inhibitor and given intraperitoneally. Rats were assigned to be group of chronic constriction injury (CCI) of the sciatic nerve and the group of CCI of the sciatic nerve administrated with LA. Over 14 days, the rats were measured for paw withdrawal thresholds. DRGs were collected to assess morphological changes via immunofluorescence study. After receiving CCI, the rats rapidly developed mechanical hyperalgesia. TSLP expression at DRG, on the ipsilateral injured side, was consistent with changes in pain behaviors. TSLP appeared in nerve fibers with both small diameters and large diameters. Additionally, TSLP was expressed mostly in transient receptor potential vanilloid-1 (TRPV1)-positive nociceptive neurons. Administration with LA can attenuate the pain behaviors and expression of TSLP in DRG neurons, and in apoptotic neurons at the injured side, but not in the contra-lateral uninjured side. Overall, these results imply that altered expressions of TSLP in nociceptive DRG neurons contributed to mechanical hyperalgesia in a CCI rat model.

2-PMAP Ameliorates Cerebral Vasospasm and Brain Injury after Subarachnoid Hemorrhage by Regulating Neuro-Inflammation in Rats.

A subarachnoid hemorrhage (SAH), leading to severe disability and high fatality in survivors, is a devastating disease. Neuro-inflammation, a critical mechanism of cerebral vasospasm and brain injury from SAH, is tightly related to prognoses. Interestingly, studies indicate that 2-[(pyridine-2-ylmethyl)-amino]-phenol (2-PMAP) crosses the blood-brain barrier easily. Here, we investigated whether the vasodilatory and neuroprotective roles of 2-PMAP were observed in SAH rats. Rats were assigned to three groups: sham, SAH and SAH+2-PMAP. SAHs were induced by a cisterna magna injection. In the SAH+2-PMAP group, 5 mg/kg 2-PMAP was injected into the subarachnoid space before SAH induction. The administration of 2-PMAP markedly ameliorated cerebral vasospasm and decreased endothelial apoptosis 48 h after SAH. Meanwhile, 2-PMAP decreased the severity of neurological impairments and neuronal apoptosis after SAH. Furthermore, 2-PMAP decreased the activation of microglia and astrocytes, expressions of TLR-4 and p-NF-κB, inflammatory markers (TNF-α, IL-1ß and IL-6) and reactive oxygen species. This study is the first to confirm that 2-PMAP has vasodilatory and neuroprotective effects in a rat model of SAH. Taken together, the experimental results indicate that 2-PMAP treatment attenuates neuro-inflammation, oxidative stress and cerebral vasospasm, in addition to ameliorating neurological deficits, and that these attenuating and ameliorating effects are conferred through the TLR-4/NF-κB pathway.

Migraines and keloids: a 15-year Taiwan claim database analysis.

BACKGROUND: Fibroproliferative lesions with intractable pruritus, pain and hyperesthesia that cause uncontrolled scar growth are known as keloids. Migraines are common upsetting headache disorders characterised by frequent recurrence and attacks aggravated by physical activity. Both keloids and migraines can cause physical exhaustion and discomfort in patients; they have similar pathophysiological pathways, that is, the transforming growth factor-ß1 gene and neurogenic inflammation. OBJECTIVE: To investigate subsequent development of migraines in patients with keloids. Methods Data were retrieved from the Taiwan National Health Insurance Research Database. The keloids group included patients aged 20 years and older with a recent diagnosis of keloids(n=9864). The non-keloids group included patients without keloids matched for gender and age at 1-4 ratio (n=39 456). Migraine risk between groups was measured by Cox proportional hazards regression models. Incidence rates and hazard ratios were calculated. RESULTS: During the study period, 103 keloids patients and 323 non-keloids patients developed migraines. The keloids patients had a 2.29-fold greater risk of developing migraines compared with the non-keloids group after adjustment for covariates (1.81 vs 0.55 per 1000 person-years, respectively). In the keloids group, female or patients younger than 50 years were prone to developing migraines. CONCLUSION: The higher tendency to develop migraines in the keloids group in comparison with the non-keloids group suggests that keloids could be a predisposing risk factor for migraine development in adults. Keloids patients who complain of headaches should be examined for migraines.

Blocking Hepatoma-Derived Growth Factor Attenuates Vasospasm and Neuron Cell Apoptosis in Rats Subjected to Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is an important subcategory of stroke due to its unacceptably high mortality rate as well as the severe complications it causes, such as cerebral vasospasm, neurological deficits, and cardiopulmonary abnormality. Hepatoma-derived growth factor (HDGF) is a growth factor related to normal development and is involved in liver development and regeneration. This study explored the relationship between SAH and HDGF. Sixty rats were divided into five groups (n = 12/group): (A) control group; (B) rHDGF ab only group [normal animals treated with 50 µM recombinant HDGF antibodies (rHDGF ab)]; (C) SAH group; (D) SAH + pre-rHDGF ab group (SAH animals pre-treated with 50 µM rHDGF ab into the subarachnoid space within 24 h before SAH); and (E) SAH + post-rHDGF ab group (SAH animals post-treated with 50 µM rHDGF ab into the subarachnoid space within 24 h after SAH). At 48 h after SAH, serum and cerebrospinal fluid (CSF) samples were collected to measure the levels of pro-inflammatory factors by ELISA, and rat cortex tissues were used to measure protein levels by western blot analysis. Immunofluorescence staining for Iba-1, GFAP, TUNEL, and NeuN was detected proliferation of microglia and astrocyte and apoptosis of neuron cells. Neurological outcome was assessed by ambulation and placing/stepping reflex responses. Morphology assay showed that pre-treatment and post-treatment with rHDGF ab attenuated vasospasm after SAH. SAH up-regulated the levels of TNF-α, IL-1ß, and IL-6 in both the CSF and serum samples, and both pre- and post-treatment with rHDGF ab inhibited the up-regulation of these pro-inflammatory factors, except for the serum IL-6 levels. Western blot analysis demonstrated that SAH up-regulated pro-BDNF and NFκB protein levels, and both pre- and post-treatment with rHDGF ab significantly reduced the up-regulation. The result from immunofluorescence staining showed that SAH induced proliferation of microglia and astrocyte and apoptosis of neuron cells. Both pre- and post-treatment with rHDGF ab significantly attenuated proliferation of microglia and astrocyte and inhibited apoptosis of neuron cells. Furthermore, treatment with rHDGF ab significantly improved neurological outcome. Blocking HDGF attenuates neuron cell apoptosis and vasospasm through inhibiting inflammation in brain tissue at early phase after SAH.

Valproic Acid Reduces Vasospasm through Modulation of Akt Phosphorylation and Attenuates Neuronal Apoptosis in Subarachnoid Hemorrhage Rats.

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating emergent event associated with high mortality and morbidity. Survivors usually experience functional neurological sequelae caused by vasospasm-related delayed ischemia. In this study, male Sprague-Dawley rats were randomly assigned to five groups: sham (non-SAH) group, SAH group, and three groups with SAH treated with different doses of valproic acid (VPA) (10, 20, 40 mg/kg, once-daily, for 7 days). The severity of vasospasm was determined by the ratio of cross-sectional areas to intima-media thickness of the basilar arteries (BA) on the seventh day after SAH. The BA showed decreased expression of phospho-Akt proteins. The dentate gyrus showed increased expression of cleaved caspase-3 and Bax proteins and decreased expression of Bcl-2, phospho-ERK 1/2, phospho-Akt and acetyl-histone H3 proteins. The incidence of SAH-induced vasospasm was significantly lower in the SAH group treated with VPA 40 mg/kg (p < 0.001). Moreover, all groups treated with VPA showed reversal of the above-mentioned protein expression in BA and the dentate gyrus. Treatment with VPA upregulated histone H3 acetylation and conferred anti-vasospastic and neuro-protective effects by enhancing Akt and/or ERK phosphorylation. This study demonstrated that VPA could alleviate delayed cerebral vasospasm induced neuro-apoptosis after SAH.

Increased Expression of Thymic Stromal Lymphopoietin in Chronic Constriction Injury of Rat Nerve.

Thymic stromal lymphopoietin (TSLP) is a well-known cytokine for T helper 2 inflammatory responses. A nerve injury activates the neuroinflammation cascade and neuron-glia interaction in dorsal root ganglions (DRG)s, leading to neuropathic pain. Therefore, this study was to investigate the role of TSLP after nerve injury. Male Sprague-Dawley rats were divided as an experimental group with chronic constriction injury (CCI) to the sciatic nerve and a control group. The mechanical pain threshold response was determined by calibration forceps. After assessment of mechanical allodynia, the ipsilateral spinal cord, DRG, sciatic nerve and skin were harvested. Immunofluorescence staining was performed to identify cell types with various markers. Western blot analyses were performed to evaluate protein expressions. Mechanical allodynia developed after CCI and persisted for the next 14 days. Astrocyte reactions occurred and continued until day 14, too. After CCI, DRG and the sciatic nerve also had significantly increased expressions of TSLP/TSLP-R/STAT5. The TSLPR was localized to sensory neuronal endings innervating the skin. This study is the first to demonstrate that the TSLP complex and the STAT5 pathway in nerve are potential therapeutic targets because of their roles in pain regulation after nerve injury.

GLUT-1 Enhances Glycolysis, Oxidative Stress, and Fibroblast Proliferation in Keloid.

A keloid is a fibroproliferative skin tumor. Proliferating keloid fibroblasts (KFs) demand active metabolic utilization. The contributing roles of glycolysis and glucose metabolism in keloid fibroproliferation remain unclear. This study aims to determine the regulation of glycolysis and glucose metabolism by glucose transporter-1 (GLUT-1), an essential protein to initiate cellular glucose uptake, in keloids and in KFs. Tissues of keloids and healthy skin were explanted for KFs and normal fibroblasts (NFs), respectively. GLUT-1 expression was measured by immunofluorescence, RT-PCR, and immunoblotting. The oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were measured with or without WZB117, a GLUT-1 inhibitor. Reactive oxygen species (ROS) were assayed by MitoSOX immunostaining. The result showed that glycolysis (ECAR) was enhanced in KFs, whereas OCR was not. GLUT-1 expression was selectively increased in KFs. Consistently, GLUT-1 expression was increased in keloid tissue. Treatment with WZB117 abolished the enhanced ECAR, including glycolysis and glycolytic capacity, in KFs. ROS levels were increased in KFs compared to those in NFs. GLUT-1 inhibition suppressed not only the ROS levels but also the cell proliferation in KFs. In summary, the GLUT-1-dependent glycolysis and ROS production mediated fibroblast proliferation in keloids. GLUT1 might be a potential target for metabolic reprogramming to treat keloids.

Risk of cancer development in patients with keloids.

Keloid is a skin disease characterized by exaggerated scar formation, excessive fibroblast proliferation, and excessive collagen deposition. Cancers commonly arise from a fibrotic microenvironment; e.g., hepatoma arises from liver cirrhosis, and oral cancers arise from submucosal fibrosis. As keloids are a prototypic fibroproliferative disease, this study investigated whether patients with keloids have an increased cancer risk. In a matched, population-based study, first 17,401 patients treated for keloids during 1998-2010 with 69,604 controls without keloids at a ratio of 1:4 were evaluated. The association between keloids and risk of cancer was estimated by logistic regression or Cox proportional hazard regression models after adjustment of covariates. In total, 893 first-time cases of cancer were identified in the 17,401 patients with keloids. The overall cancer risk was 1.49-fold higher in the keloids group compared to controls. Regarding specific cancers, the keloids group, had a significantly higher risk of skin cancer compared to controls (Relative risk = 1.73). The relative risk for skin cancer was even higher for males with keloids (Relative risk = 2.16). Further stratified analyses also revealed a significantly higher risk of developing pancreatic cancer in female patients with keloids compared to controls (Relative risk = 2.19) after adjustment for known pancreatic cancer risk factors. This study indicates that patients with keloids have a higher than normal risk for several cancer types, especially skin cancers (both genders) and pancreatic cancer (females). Therefore, patients with keloids should undergo regular skin examinations, and females with keloids should regularly undergo abdominal ultrasonography.