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 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.

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.

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.

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.

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.

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.

Stroke and osteoporosis: a Taiwan cohort study.

BACKGROUND: Osteoporosis and stroke are major health problems that have potentially overlapping pathophysiological mechanisms. The aim of this study was to estimate osteoporosis risk in Taiwan patientswho had a stroke. METHOD: This study retrieved data contained in the Taiwan National Health Insurance Research Database for a population-based sample of consecutive patients either hospitalised for stroke or treated for stroke on an outpatient basis. A total of 7550 newly diagnosed patientswho had a stroke were enrolled during 1996-2010. Osteoporosis risk in these patients was then compared with a matched group of patients who had not had a stroke randomly selected from the database at a ratio of 1:4 (n=30 200). The relationship between stroke history and osteoporosis risk was estimated with Cox proportional hazard regression models. RESULTS: During the follow-up period, osteoporosis developed in 1537 patients who had a stroke and in 5830 patients who had not had a stroke. The incidence of osteoporosis for cohorts with and without stroke was 32.97 and 14.28 per 1000 person-years, respectively. After controlling for covariates, the overall risk of osteoporosis was 1.82-fold higher in the stroke group than in the non-stroke group. The relative osteoporosis risk contributed by stroke had apparently greater impact among male gender and younger age groups. CONCLUSION: History of stroke is a risk factor for osteoporosis in Taiwan. Much attention to stroke-targeted treatment modalities might minimise adverse outcomes of osteoporosis.

The association between keloid and osteoporosis: real-world evidence.

BACKGROUND: Keloids are characterized by disturbance of fibroblast proliferation and apoptosis, deposition of collagen, and upregulation of dermal inflammation cells. This benign dermal fibro-proliferative scarring condition is a recognized skin inflammation disorder. Chronic inflammation is a well-known contributor to bone loss and its sequelae, osteoporosis. They both shared a similar pathogenesis through chronic inflammation. We assessed whether keloids increase osteoporosis risk through using National Health Insurance Research Database. METHODS: The 42,985 enrolled patients included 8597 patients with keloids but no history of osteoporosis; 34,388 controls without keloids were identified from the general population and matched at a one-to-four ratio by age, gender. Kaplan-Meier method was applied to determine cumulative incidence of osteoporosis. Cox proportional hazard regression analysis was performed after adjustment of covariates to estimate the effect of keloids on osteoporosis risk. RESULTS: Of the 8597 patients with keloids, 178 (2.07%) patients were diagnosed with osteoporosis while in the 34,388 controls, 587 (1.71%) were diagnosed with osteoporosis. That is, the keloids patients had 2.64-fold higher risk of osteoporosis compared to controls after adjustment for age, gender, Charlson Comorbidity Index and related comorbidities. The association between keloids and osteoporosis was strongest in patients younger than 50 years (hazard ratio = 7.06%) and in patients without comorbidities (hazard ratio = 4.98%). In the keloids patients, a high incidence of osteoporosis was also associated with advanced age, high Charlson Comorbidity Index score, hyperlipidemia, chronic liver disease, stroke, and depression. CONCLUSIONS: Osteoporosis risk was higher in patients with keloids compared to controls, especially in young subjects and subjects without comorbidities.

Impact of Hepatoma-Derived Growth Factor Blockade on Resiniferatoxin-Induced Neuropathy.

Resiniferatoxin is an ultrapotent capsaicin analog that mediates nociceptive processing; treatment with resiniferatoxin can cause an inflammatory response and, ultimately, neuropathic pain. Hepatoma-derived growth factor, a growth factor related to normal development, is associated with neurotransmitters surrounding neurons and glial cells. Therefore, the study aims to investigate how blocking hepatoma-derived growth factor affects the inflammatory response in neuropathic pain. Serum hepatoma-derived growth factor protein expression was measured via ELISA. Resiniferatoxin was administrated intraperitoneally to induce neuropathic pain in 36 male Sprague-Dawley rats which were divided into three groups (resiniferatoxin+recombinant hepatoma-derived growth factor antibody group, resiniferatoxin group, and control group) (n = 12/group). The mechanical threshold response was tested with calibration forceps. Cell apoptosis was measured by TUNEL assay. Immunofluorescence staining was performed to detect apoptosis of neuron cells and proliferation of astrocytes in the spinal cord dorsal horn. RT-PCR technique and western blot were used to measure detect inflammatory factors and protein expressions. Serum hepatoma-derived growth factor protein expression was higher in the patients with sciatica compared to controls. In resiniferatoxin-group rats, protein expression of hepatoma-derived growth factor was higher than controls. Blocking hepatoma-derived growth factor improved the mechanical threshold response in rats. In dorsal root ganglion, blocking hepatoma-derived growth factor inhibited inflammatory cytokines. In the spinal cord dorsal horn, blocking hepatoma-derived growth factor inhibited proliferation of astrocyte, apoptosis of neuron cells, and attenuated expressions of pain-associated proteins. The experiment showed that blocking hepatoma-derived growth factor can prevent neuropathic pain and may be a useful alternative to conventional analgesics.

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.

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.

Association between suicide risk and traumatic brain injury in adults: a population based cohort study.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability worldwide, and its treatment is potentially a heavy economic burden. Suicide is another global public health problem and the second leading cause of death in young adults. Patients with TBI are known to have higher than normal rates of non-fatal deliberate self-harm, suicide and all-cause mortality. The aim of this study was to explore the association between TBI and suicide risk in a Chinese cohort. METHOD: This study analysed data contained in the Taiwan National Health Insurance Research Database for 17 504 subjects with TBI and for 70 016 subjects without TBI matched for age and gender at a ratio of 1 to 4. Cox proportional hazard regression analysis was used to estimate subsequent suicide attempts in the TBI group. Probability of attempted suicide was determined by Kaplan-Meier method. RESULTS: The overall risk of suicide attempts was 2.23 times higher in the TBI group compared with the non-TBI group (0.98 vs 0.29 per 1000 person-years, respectively) after adjustment for covariates. Regardless of gender, age or comorbidity, the TBI group tended to have more suicide attempts, and the risk attempted suicide increased with the severity of TBI. Depression and alcohol attributed disease also increased the risk of attempted suicide in the TBI group. CONCLUSION: Suicide is preventable if risk factors are recognised. Hence, TBI patients require special attention to minimise their risk of attempted suicide.

EXPRESS: NGF-trkA signaling modulates the analgesic effects of prostatic acid phosphatase in resiniferatoxin-induced neuropathy.

BACKGROUND: Neuropathic pain in small-fiber neuropathy results from injury to and sensitization of nociceptors. Functional prostatic acid phosphatase (PAP) acts as an analgesic effector. However, the mechanism responsible for the modulation of PAP neuropathology, which leads to loss of the analgesic effect after small-fiber neuropathy, remains unclear. RESULTS: We used a resiniferatoxin (RTX)-induced small-fiber neuropathy model to examine whether functional PAP(þ) neurons are essential to maintain the analgesic effect. PAP(þ) neurons were categorized into small to medium neurons (25th-75th percentile: 17.1-23.7 mm); these neurons were slightly reduced by RTX (p»0.0003). By contrast, RTX-induced activating transcription factor 3 (ATF3), an injury marker, in PAP(þ) neurons (29.0%5.6% vs. 0.2%0.2%, p»0.0043), indicating PAP neuropathology. Moreover, the high-affinity nerve growth factor (NGF) receptor (trkA) colocalized with PAP and showed similar profiles after RTX-induced neuropathy, and the PAP/trkA ratios correlated with the degree of mechanical allodynia (r»0.62, p»0.0062). The NGF inducer 4-methylcatechol (4MC) normalized the analgesic effects of PAP; specifically, it reversed the PAP and trkA profiles and relieved mechanical allodynia. Administering 2.5S NGF showed similar results to those of administering 4MC. This finding suggests that the analgesic effect of functional PAP is mediated by NGF-trkA signaling, which was confirmed by NGF neutralization. CONCLUSIONS: This study revealed that functional PAP(þ) neurons are essential for the analgesic effect, which is mediated by NGF-trkA signaling.

Traumatic Brain Injury and Substance Related Disorder: A 10-Year Nationwide Cohort Study in Taiwan.

Whether traumatic brain injury (TBI) is causally related to substance related disorder (SRD) is still debatable, especially in persons with no history of mental disorders at the time of injury. This study analyzed data in the Taiwan National Health Insurance Research Database for 19,109 patients aged ≥18 years who had been diagnosed with TBI during 2000-2010. An additional 19,109 randomly selected age and gender matched patients without TBI (1 : 1 ratio) were enrolled in the control group. The relationship between TBI and SRD was estimated with Cox proportional hazard regression models. During the follow-up period, SRD developed in 340 patients in the TBI group and in 118 patients in the control group. After controlling for covariates, the overall incidence of SRD was 3.62-fold higher in the TBI group compared to the control group. Additionally, patients in the severe TBI subgroup were 9.01 times more likely to have SRD compared to controls. Notably, patients in the TBI group were prone to alcohol related disorders. The data in this study indicate that TBI is significantly associated with the subsequent risk of SRD. Physicians treating patients with TBI should be alert to this association to prevent the occurrence of adverse events.

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.

MicroRNA-195-5p Attenuates Intracerebral-Hemorrhage-Induced Brain Damage by Inhibiting MMP-9/MMP-2 Expression.

Intracerebral hemorrhage (ICH) remains a devastating disease with high mortality, and there is a lack of effective strategies to improve functional outcomes. The primary injury of ICH is mechanical damage to brain tissue caused by the hematoma. Secondary injury, resulting from inflammation, red cell lysis, and thrombin production, presents a potential target for therapeutic intervention. Inflammation, crucial in secondary brain injury, involves both cellular and molecular components. MicroRNAs (miRNAs) are vital regulators of cell growth, differentiation, and apoptosis. Their deregulation may lead to diseases, and modulating miRNA expression has shown therapeutic potential, especially in cancer. Recent studies have implicated miRNAs in the pathogenesis of stroke, affecting endothelial dysfunction, neurovascular integrity, edema, apoptosis, inflammation, and extracellular matrix remodeling. Preclinical and human studies support the use of miRNA-directed gene modulation as a therapeutic strategy for ICH. Our study focused on the effects of miR-195 in ICH models. Neurological tests, including the corner turn and grip tests, indicated that miR-195 treatment led to improvements in motor function impairments caused by ICH. Furthermore, miR-195-5p significantly reduced brain edema in the ipsilateral hemisphere and restored blood-brain barrier (BBB) integrity, as shown by reduced Evans blue dye extravasation. These results suggest miR-195-5p's potential in attenuating ICH-induced apoptosis, possibly related to its influence on MMP-9 and MMP-2 expression, enzymes associated with secondary brain injury. The anti-apoptotic effects of miR-195-5p, demonstrated through TUNEL assays, further underscore its therapeutic promise in addressing the secondary brain injury and apoptosis associated with ICH. In conclusion, miR-195-5p demonstrates a significant neuroprotective effect against ICH-induced neural damage, brain edema, and BBB disruption, primarily through the downregulation of MMP-9 and MMP-2. Our findings indicate that miR-195-5p holds therapeutic potential in managing cerebral cell death following ICH.

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.