Effectiveness of Chinese Herbal Medicine as a Complementary Treatment for Neutropenia Prevention and Immunity Modulation During Chemotherapy in Patients With Breast Cancer: Protocol for a Real-World Pragmatic Clinical Trial.

BACKGROUND: In recent years, advancements in cancer treatment have enabled cancer cell inhibition, leading to improved patient outcomes. However, the side effects of chemotherapy, especially leukopenia, impact patients' ability to tolerate their treatments and affect their quality of life. Traditional Chinese medicine is thought to provide complementary cancer treatment to improve the quality of life and prolong survival time among patients with cancer. OBJECTIVE: This study aims to evaluate the effectiveness of Chinese herbal medicine (CHM) as a complementary treatment for neutropenia prevention and immunity modulation during chemotherapy in patients with breast cancer. METHODS: We will conduct a real-world pragmatic clinical trial to evaluate the effectiveness of CHM as a supplementary therapy to prevent neutropenia in patients with breast cancer undergoing chemotherapy. Patients will be classified into CHM or non-CHM groups based on whether they received CHM during chemotherapy. Using generalized estimating equations or repeated measures ANOVA, we will assess differences in white blood cell counts, absolute neutrophil counts, immune cells, and programmed cell death protein 1 (PD-1) expression levels between the 2 groups. RESULTS: This study was approved by the research ethics committee of Hualien Tzu Chi Hospital (IRB 110-168-A). The enrollment process began in September 2021 and will stop in December 2024. A total of 140 patients will be recruited. Data cleaning and analysis are expected to finish in the middle of 2025. CONCLUSIONS: Traditional Chinese medicine is the most commonly used complementary medicine, and it has been reported to significantly alleviate chemotherapy-related side effects. This study's findings may contribute to developing effective interventions targeting chemotherapy-related neutropenia among patients with breast cancer in clinical practice. TRIAL REGISTRATION: International Traditional Medicine Clinical Trial Registry ITMCTR2023000054; https://tinyurl.com/yc353hes. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55662.

Anti-inflammatory effects of powdered product of Bu Yang Huan Wu decoction: Possible role in protecting against Transient Focal Cerebral Ischemia.

Bu Yang Huan Wu decoction (BYHW) is a traditional Chinese medicine (TCM) that consists of several herbs and has been used in patients with ischemic stroke for centuries. Although powdered formula of BYHW has widely been prescribed in clinic nowadays, evidence-based effectiveness and mechanism of action of BYHW powdered product in stroke remain to be characterized. Adult male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 90 min followed by reperfusion for 24 h (ischemia/reperfusion; I/R) or sham surgery. After I/R, the rats were then given low dose (0.5 g/kg) and high dose (2.5 g/kg) of BYHW or vehicle by oral gavage twice a day for seven consecutive days. The results showed that I/R induced obvious cerebral infarction and neurobehavioral defects, in parallel with histological aberrations and extensive signaling of proinflammatory cytokines, including tumor necrosis factor (TNF-α) and interleukin-6 (IL-6), in the stroke model. Post-I/R treatment with BYHW powdered product significantly reduced the infarct area and ameliorated neurofunctional defects in a dose-dependent manner. The dose dependence was associated with TNF-α downregulation and interleukin-10 (IL-10) induction. In summary, the present findings demonstrated that BYHW powdered product exhibited therapeutic efficacy for experimental stroke and a higher dose treatment may strengthen the effectiveness via inflammatory modulation.

Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide on Gastric Cancer: Implications for REDD1 Activation and mTOR Inhibition.

BACKGROUND/AIMS: Radix Angelica Sinensis (danggui in Chinese) is widely used in traditional chinese medicine (TCM). N-butylidenephthalide (BP), a bioactive compound in danggui, is a potential antitumor agent for various cancer types. However, its clinical effect and mechanism in the treatment of gastric cancer remain undetermined. METHODS: The in vivo protective effect of danggui in patients with gastric cancer were validated using data from Taiwan's National Health Insurance Research Database (NHIRD). The genes induced by BP-treatment were analyzed by whole transcriptome RNA sequencing (RNA-seq) and validated by real-time PCR, western blot and siRNA transfection. The effect of BP on AGS cell migration and invasion was evaluated in transwell assays. The antitumor effects of BP were evaluated in vivo in an AGS xenograft animal model. RESULTS: Danggui users were found to have an increased survival rate when compared with danggui nonusers (log-rank test p = 0.002) . The use of danggui highly associated with decreased mortality (the adjusted hazard ratio (HR) of danggui user was 0.72 [95 % CI, 0.57-0.92] (p = 0.009). The in vitro results showed that BP inhibited gastric cancer cell proliferation, and triggered cellular apoptosis depending on the activation of mitochondrial apoptotic pathway. Using RNA-seq analysis we found that REDD1 was the highest transcript induced by BP in gastric cancer cells. BP induce an increase of REDD1 expression that inhibits mTOR signaling, thus inhibiting gastric cancer growth. We used RNA interference to demonstrate that the knock-down of REDD1 attenuated the BP-induced mTORC1 activation and growth inhibition. BP suppressed the growth of AGS xenografts tumor in vivo. CONCLUSION: Danggui can prolong the survival rate of gastric cancer patients in Taiwan. BP caused gastric cancer cell death through the activation of mitochondria-intrinsic pathway and induced the REDD1 expression leading to mTOR signal pathway inhibition in gastric cancer cells. BP inhibited the in vivo growth of AGS xenograft tumors. These results may provide the basis for a new therapeutic approach toward the treatment of gastric cancer progression.

Potential therapeutic effects of N-butylidenephthalide from Radix Angelica Sinensis (Danggui) in human bladder cancer cells.

BACKGROUND: N-butylidenephthalide (BP) isolated from Radix Angelica Sinensis (Danggui) exhibits anti-tumorigenic effect in various cancer cells both in vivo and in vitro. The effect of BP in bladder cancer treatment is still unclear and worth for further investigate. METHODS: Changes of patients with bladder cancer after Angelica Sinensis exposure were evaluated by analysis of Taiwan's National Health Insurance Research Database (NHIRD) database. The anti-proliferative effect of BP on human bladder cancer cells was investigated and their cell cycle profiles after BP treatment were determined by flow cytometry. BP-induced apoptosis was demonstrated by Annexin V-FITC staining and TUNEL assay, while the expressions of apoptosis-related proteins were determined by western blot. The migration inhibitory effect of BP on human bladder cancer cells were shown by trans-well and wound healing assays. Tumor model in NOD-SCID mice were induced by injection of BFTC human bladder cancer cells. RESULTS: The correlation of taking Angelica sinensis and the incidence of bladder cancer in NHIRD imply that this herbal product is worth for further investigation. BP caused bladder cancer cell death in a time- and dose- dependent manner and induced apoptosis via the activation of caspase-9 and caspase-3. BP also suppressed the migration of bladder cancer cells as revealed by the trans-well and wound healing assays. Up-regulation of E-cadherin and down-regulation of N-cadherin were evidenced by real-time RT-PCR analysis after BP treatment in vitro. Besides, in combination with BP, the sensitivity of these bladder cancer cells to cisplatin increased significantly. BP also suppressed BFTC xenograft tumor growth, and caused 44.2% reduction of tumor volume after treatment for 26 days. CONCLUSIONS: BP caused bladder cancer cell death through activation of mitochondria-intrinsic pathway. BP also suppressed the migration and invasion of these cells, probably by modulating EMT-related genes. Furthermore, combination therapy of BP with a lower dose of cisplatin significantly inhibited the growth of these bladder cancer cell lines. The incidence of bladder cancer decreased in patients who were exposed to Angelica sinensis, suggesting that BP could serve as a potential adjuvant in bladder cancer therapy regimen.

Beneficial effects of calcitriol on hypertension, glucose intolerance, impairment of endothelium-dependent vascular relaxation, and visceral adiposity in fructose-fed hypertensive rats.

Besides regulating calcium homeostasis, the effects of vitamin D on vascular tone and metabolic disturbances remain scarce in the literature despite an increase intake with high-fructose corn syrup worldwide. We investigated the effects of calcitriol, an active form of vitamin D, on vascular relaxation, glucose tolerance, and visceral fat pads in fructose-fed rats. Male Wistar-Kyoto rats were divided into 4 groups (n = 6 per group). Group Con: standard chow diet for 8 weeks; Group Fru: high-fructose diet (60% fructose) for 8 weeks; Group Fru-HVD: high-fructose diet as Group Fru, high-dose calcitriol treatment (20 ng / 100 g body weight per day) 4 weeks after the beginning of fructose feeding; and Group Fru-LVD: high-fructose diet as Group Fru, low-dose calcitriol treatment (10 ng / 100 g body weight per day) 4 weeks after the beginning of fructose feeding. Systolic blood pressure was measured twice a week by the tail-cuff method. Blood was examined for serum ionized calcium, phosphate, creatinine, glucose, triglycerides, and total cholesterol. Intra-peritoneal glucose intolerance test, aortic vascular reactivity, the weight of visceral fat pads, adipose size, and adipose angiotensin II levels were analyzed at the end of the study. The results showed that the fructose-fed rats significantly developed hypertension, impaired glucose tolerance, heavier weight and larger adipose size of visceral fat pads, and raised adipose angiotensin II expressions compared with the control rats. High- and low-dose calcitriol reduced modestly systolic blood pressure, increased endothelium-dependent aortic relaxation, ameliorated glucose intolerance, reduced the weight and adipose size of visceral fat pads, and lowered adipose angiotensin II expressions in the fructose-fed rats. However, high-dose calcitriol treatment mildly increased serum ionized calcium levels (1.44 ± 0.05 mmol/L). These results suggest a protective role of calcitriol treatment on endothelial function, glucose tolerance, and visceral adiposity in fructose-fed rats.

Reduction of motor disorder in 6-OHDA-induced severe parkinsonism rats by post treatment with granulocyte-colony stimulating factor.

Granulocyte-colony stimulating factor (G-CSF) induced regeneration of dopaminergic neurons and improved behavior deficit in moderate Parkinson's disease (PD) model mice. Post treatment of G-CSF in severe PD model has not been addressed. A very severe PD model in rats was induced by a high dose 6-hydroxydopamine (6-OHDA) injected into the right medial forebrain bundle to evaluate therapeutic effects of G-CSF. G-CSF (50 microg/kg/day for five days) was given on the 9th day after the 6-OHDA injection. Rotational behavior was examined on the 9th and 28th days. Rats were killed on the 28th day and survival dopaminergic neurons in the substantia nigra, dopaminergic axons and dopaminergic receptor 2 in the striatum were examined. We, for the first time, demonstrated that post treatment with G-CSF reduced abnormal rotational behavior and increased the lesion to non-lesion ratio of dopaminergic fibers in the striatum, but the treatment promoted neither the increase in survival dopaminergic neurons nor the increase in dopaminergic receptor 2 expression. We conclude that post treatment with G-CSF can reduce the abnormal rotational behavior of severe PD rats primarily through relative increases in dopaminergic fibers of the lesion side in the striatum. Results of our study suggest therapeutic potentials of G-CSF for treating severe PD patients.

Adolescent toluene exposure produces enduring social and cognitive deficits in mice: an animal model of solvent-induced psychosis.

OBJECTIVES: Abuse of toluene-containing volatile solvents by adolescents is a significant public health problem. The present study characterized the long-term behavioural and neurochemical consequences of toluene exposure during adolescence. METHODS: Male NMRI mice received one injection per day of either toluene (600 mg/kg) or corn oil during postnatal days (PN) 35-37 and (750 mg/kg) during PN38-39 and PN42-46. A variety of psychiatric disorder-relevant behavioural tests were examined at PN56-P84. RESULTS: The toluene-exposed mice were significantly deficient in the social interaction test, nesting behaviour, social dominance tube test, and novel objective recognition test. However, toluene exposure did not affect locomotor activity and behavioural profiles in the forced swimming test, tail suspension test, emergence test and elevated plus maze. Neurochemically, the turnover rates of dopamine in the prefrontal cortex, striatum and nucleus accumbens were reduced in toluene-treated mice. CONCLUSIONS: Adolescent toluene exposure leads to social deficits and cognitive impairment at adulthood as well as neurochemical dysfunction in mice, which correlate with the symptoms observed in patients suffering from solvent-induced psychosis. These findings highlight the need for understanding the effects of solvent abuse on the developing nervous system and reveal an animal model suitable for research into pathophysiology of neurological and psychiatric consequences of solvent abuse.

The association of methylation in the promoter of APC and MGMT and the prognosis of Taiwanese CRC patients.

AIMS: The purpose of this study was to investigate the association of methylation in the promoter regions of adenomatous polyposis coli (APC) and O(6)-methylguanine-DNA methyltransferase (MGMT) and the survival of Taiwanese colorectal cancer (CRC) subjects who received 5-fluorouracil (5-FU) adjuvant chemotherapy. RESULTS: DNA isolated from tumor tissue of 117 CRC subjects was analyzed for the existence of methylation in the promoter regions of APC and MGMT by methylation-specific PCR. Various characteristics of the 117 subjects were recorded and used in the Cox proportional-hazard model analyses. Methylation in the promoter region is 62.4% (73/117) for APC and 60.7% (71/117) for MGMT in our CRC patients. Subjects presenting methylation in the APC promoter demonstrate significantly lower hazards for all causes of death (hazard ratios=0.378, p=0.011) or CRC deaths (hazard ratios=0.426, p=0.039). However, no significant correlation is found between the methylation of MGMT promoter and the prognosis of CRC subjects. In addition, no interaction between 5-FU adjuvant chemotherapy and methylation of the two genes are observed. CONCLUSIONS: Methylation in the APC promoter may serve as a predictor for the prognosis of Taiwanese CRC patients.

Prognostic significance of interaction between somatic APC mutations and 5-fluorouracil adjuvant chemotherapy in Taiwanese colorectal cancer subjects.

OBJECTIVE: The correlations between adenomatous polyposis coli (APC) mutations and 5-fluorouracil (5-FU) adjuvant chemotherapy and colorectal cancer (CRC) patients' prognosis are not well known. We performed an exploratory study to investigate the association between APC mutations and the survival of Taiwanese CRC subjects who received 5-FU adjuvant chemotherapy. METHODS: Full-length APC gene isolated from tumor tissue and adjacent normal colon tissue from 117 CRC subjects was sequenced. Various characteristics of the 117 subjects were recorded and used in the Cox proportionalhazard model analyses. RESULTS: Although the subject survival rate was associated with the cancer stage, but not with the occurrence of APC mutations, we demonstrate a significant interaction between the somatic APC mutations and 5-FU adjuvant chemotherapy to the prognosis of CRC subjects. Subjects carrying APC mutation(s) and receiving 5-FU adjuvant chemotherapy demonstrate increased hazards (vs. no APC mutation or chemotherapy) for all cause (hazard ratios = 5.565; P = 0.042) or CRC deaths (hazard ratios = 6.920; P = 0.043). 5-FU adjuvant chemotherapy only decreases hazards in CRC subjects without APC mutation(s) for all cause death (hazard ratios = 0.257; P = 0.003) or CRC death (hazard ratios = 0.342; P = 0.028). CONCLUSIONS: 5-FU adjuvant chemotherapy only prevents CRC subjects without somatic APC mutation(s) from all cause death or CRC death. It needs further studies with larger sample size and longer follow-up time to confirm these results.

Functional recovery of stroke rats induced by granulocyte colony-stimulating factor-stimulated stem cells.

BACKGROUND: Stroke is a leading cause of death and disability worldwide; however, no effective treatment currently exists. METHODS AND RESULTS: Rats receiving subcutaneous granulocyte colony-stimulating factor (G-CSF) showed less cerebral infarction, as evaluated by MRI, and improved motor performance after right middle cerebral artery ligation than vehicle-treated control rats. Subcutaneous administration of G-CSF enhanced the availability of circulating hematopoietic stem cells to the brain and their capacity for neurogenesis and angiogenesis in rats with cerebral ischemia. CONCLUSIONS: G-CSF induced increases in bone marrow cell mobilization and targeting to the brain, reducing the volume of cerebral infarction and improving neural plasticity and vascularization.