Cardiopulmonary Exercise Test With Comorbidity Index Before Allogeneic Hematopoietic Stem Cell Transplantation.

PURPOSE: To evaluate the role of the cardiopulmonary exercise test (CPET) with comorbidity index as a predictor of overall survival (OS) and non-relapse mortality (NRM) in patients with hematological malignancies who undergo allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: We retrospectively analyzed consecutive adult patients with hematological malignancies who underwent HLA-matched donor-HSCT at Chungnam National University Hospital (Daejeon, South Korea) between January 2014 and December 2020. Maximal oxygen consumption (VO2max) was classified using the recommendations of the Mayo Clinic database. RESULTS: Of 72 patients, 38 (52.8%) had VO2max values lower than the 25th percentile (VO2max ≤ 25th) of an age- and sex-matched normal population. Patients with VO2max ≤ 25th had no significant differences both OS and NRM (30 month OS 29.8% vs 41%, P = .328; and 30 month NRM 16% vs 3.3%, P = .222), compared with other patients. VO2max ≤ 25th was assigned a weight of 1 when added to the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) to form a composite comorbidity/CPET index (HCT-CI/CPET). Patients with HCT-CI/CPET scores of 0 to 1 demonstrated significantly better OS and NRM than did patients with HCT-CI/CPET scores ≥2 [median OS not reached vs 6 months, P < .001 and 30 month NRM 7.4% vs 33.3%, P = .006]. An HCT-CI/CPET score ≥2 was the only adverse risk factor for NRM on multivariate analysis [hazard ratio (HR) of NRM 10.36 (95% CI 1.486-2.25, P = .018)]. CONCLUSION: The composite HCT-CI/CPET score can predict the survival and mortality of patients with hematological malignancies who undergo allogeneic HSCT.

DA-9805 protects dopaminergic neurons from endoplasmic reticulum stress and inflammation.

Parkinson's disease (PD) is a multifactorial neurodegenerative disease with damages to mitochondria and endoplasmic reticulum (ER), followed by neuroinflammation. We previously reported that a triple herbal extract DA-9805 in experimental PD toxin-models had neuroprotective effects by alleviating mitochondrial damage and oxidative stress. In the present study, we investigated whether DA-9805 could suppress ER stress and neuroinflammation in vitro and/or in vivo. Pre-treatment with DA-9805 (1 µg/ml) attenuated upregulation of glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and cleaved caspase-3 in SH-SY5Y neuroblastoma cells treated with thapsigargin (1 µg/ml) or tunicamycin (2 µg/ml). In addition, DA-9805 prevented the production of IL-1ß, IL-6, TNF-α and nitric oxide through inhibition of NF-κB activation in BV2 microglial cells stimulated with lipopolysaccharides (LPS). Intraperitoneal injection of LPS (10 mg/kg) into mice can induce acute neuroinflammation and dopaminergic neuronal cell death. Oral administration of DA-9805 (10 or 30 mg/kg/day for 3 days before LPS injection) prevented loss of dopaminergic neurons and activation of microglia and astrocytes in the substantia nigra in LPS-injected mouse models. Taken together, these results indicate that DA-9805 can effectively prevent ER stress and neuroinflammation, suggesting that DA-9805 is a multitargeting and disease-modifying therapeutic candidate for PD.

Qi-activating quercetin alleviates mitochondrial dysfunction and neuroinflammation in vivo and in vitro.

Parkinson's disease (PD) is a multifactorial neurodegenerative disease manifesting mitochondrial damages and neuroinflammation. Qi is defined as a natural power that can regulate the energy flow in Oriental medicine, whereas mitochondria generate energy power in Western medicine. We investigated whether Qi-enhancing component in Oriental herb medicines could activate mitochondrial activities. Quercetin was found as a major bioactive compound in most Qi-activating Oriental herb medicines through online search for active compounds in several Oriental Medicine databases. We then investigated if quercetin could reverse 1-methyl-4-phenylpyridinium (MPP+)-induced mitochondrial dysfunction and lipopolysaccharide (LPS)-induced neuroinflammation. Mitochondrial activities were monitored based on complex 1 NADH dehydrogenase activities, ATP contents, mitochondrial membrane potential, cellular/mitochondrial reactive oxygen species, and oxygen consumption rate in SH-SY5Y cells. Quercetin at concentration up to 20 µg/ml was not cytotoxic to SH-SY5Y cells. Pre-treatment with quercetin significantly protected mitochondrial damages in 1 mM MPP+- or 100 ng/ml LPS-treated cells. Quercetin increased expression levels of tyrosine hydroxylase and mitochondria controlling proteins. When in vivo effects of quercetin were assessed by immunohistochemical staining of tissue sections from LPS-injected mice brains, quercetin reduced the activation of microglia and astrocytes in the hippocampus and substantia nigra of LPS-injected mice. Our data suggest that Qi-activating quercetin might be therapeutically effective for neuroinflammation-mediated neurodegeneration by alleviating mitochondrial damages.

Triple herbal extract DA-9805 exerts a neuroprotective effect via amelioration of mitochondrial damage in experimental models of Parkinson's disease.

Moutan cortex, Angelica Dahurica root, and Bupleurum root are traditional herbal medicines used in Asian countries to treat various diseases caused by oxidative stress or inflammation. Parkinson's disease (PD) has been associated with mitochondrial dysfunction, but no effective treatment for mitochondrial dysfunction has yet been identified. In this study we investigated the neuroprotective effects of the triple herbal extract DA-9805 in experimental models of PD. DA-9805 was prepared by extracting three dried plant materials (Moutan cortex, Angelica Dahurica root, and Bupleurum root in a 1:1:1 mixture) with 90% ethanol on a stirring plate for 24 h at room temperature and fingerprinted using high-performance liquid chromatography. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridinium (MPP+), which both exert neurotoxic effects on dopaminergic neurons by inhibiting mitochondrial oxidative phosphorylation (OXPHOS) complex I, were used to make experimental models of PD. In MPP+-treated SH-SY5Y cells, DA-9805 ameliorated the suppression of tyrosine hydroxylase expression and mitochondrial damage on OXPHOS complex 1 activity, mitochondrial membrane potential, reactive oxygen species (ROS) generation, and oxygen consumption rate. In the MPTP-induced subacute PD model mice, oral administration of DA-9805 recovered dopamine content as well as bradykinesia, as determined by the rotarod test. DA-9805 protected against neuronal damage in the substantia nigra pars compacta (SNpc) and striatum. In both in vitro and in vivo models of PD, DA-9805 normalized the phosphorylation of AKT at S473 and T308 on the insulin signaling pathway and the expression of mitochondria-related genes. These results demonstrate that the triple herbal extract DA-9805 showed neuroprotective effects via alleviating mitochondria damage in experimental models of PD. We propose that DA-9805 may be a suitable candidate for disease-modifying therapeutics for PD.

Ethanol extract of Bupleurum falcatum and saikosaponins inhibit neuroinflammation via inhibition of NF-κB.

ETHNOPHARMACOLOGICAL RELEVANCE: The root of Bupleurum falcatum L. (BF) has been used in traditional Korean and Chinese medicines for over 2000 years to treat infections, fever, and chronic liver diseases. Among the many active compounds in BF ethanol extract (BFE), saikosaponins exert pharmacological activities including anti-inflammatory effects. Activated microglial cells release a variety of pro-inflammatory substances, leading to neuronal cell death and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The aim of the present study was to investigate the mechanism of the anti-neuroinflammatory effects of BFE using lipopolysaccharide (LPS)-stimulated microglial cells and LPS-intraperitoneal injected C57BL/6 mice. MATERIALS AND METHODS: Dried roots of BF were extracted with 70% ethanol (tenfold volume) on a stirring plate for 24h at room temperature to prepare BFE. Pure saikosaponins (SB3, SB4, and SD) were prepared by solvent extraction and column chromatography fractionation. BV2 murine microglial cells were treated with BFE or saikosaponins for 4h and stimulated with LPS. Generation of nitric oxide (NO), inflammatory cytokines, and reactive oxygen species (ROS) from activated microglial cells were monitored. The effects of BFE on NF-κB activation were determined using RT-PCR, reporter assay, and immunostaining. The in vivo effects of BFE were also assessed by immunohistochemical staining of tissue sections from LPS-injected mouse brains. RESULTS: Treatment with BFE or saikosaponins dose-dependently attenuated LPS-induced production of NO, iNOS mRNA, and ROS by 30-50%. They reduced LPS-mediated increases in the mRNA levels of IL-6, IL-1ß, and TNF-α by approximately 30-70% without affecting cell viability, and decreased LPS-mediated NF-κB activity via reducing p65/RELA mRNA, transcriptional activity, and nuclear localization of NF-κB. BFE also reduced LPS-induced activation of microglia and astrocytes in the hippocampus and substantia nigra of LPS-injected mice. CONCLUSION: Our data suggest that BFE may be effective for reducing neuroinflammation-mediated neurodegeneration through suppressing NF-κB-mediated inflammatory pathways.