Taohong Siwu decoction alleviates cognitive impairment by suppressing endoplasmic reticulum stress and apoptosis signaling pathway in vascular dementia rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Taohong Siwu Decoction (TSD), a classic traditional Chinese medicine formula, is used for the treatment of vascular diseases, including vascular dementia (VD). However, the mechanisms remain unclear. AIM OF STUDY: This study aimed to investigate whether TSD has a positive effect on cognitive impairment in VD rats and to confirm that the mechanism of action is related to the Endoplasmic Reticulum stress (ERs) and cell apoptosis signaling pathway. MATERIALS AND METHODS: A total of 40 male adult Sprague-Dawley rats were divided into four groups: sham-operated group (Sham), the two-vessel occlusion group (2VO), the 2VO treated with 4.5 g/kg/d TSD group (2VO + TSD-L), the 2VO treated with 13.5 g/kg/d TSD group (2VO + TSD-H). The rats underwent either 2VO surgery or sham surgery. Postoperative TSD treatment was given for 4 consecutive weeks. Behavioral tests were initiated at the end of gastrulation. Open-field test (OFT) was used to detect the activity level. The New Object Recognition test (NOR) was used to test long-term memory. The Morris water maze (MWM) test was used to examine the foundation of spatial learning and memory. As a final step, the hippocampus was taken for molecular testing. The protein levels of GRP78 (Bip), p-PERK, PERK, IRE1α, p-IRE1α, ATF6, eIF2α, p-eIF2α, ATF4, XBP1, Bcl-2 and Bax were determined by Western blot. Immunofluorescence visualizes molecular expression. RESULTS: In the OFT, residence time in the central area was significantly longer in both TSD treatment groups compared to the 2VO group. In the NOR, the recognition index was obviously elevated in both TSD treatment groups. The 2VO group had a significantly longer escape latency and fewer times in crossing the location of the platform compared with the Sham group in MWM. TSD treatment reversed this notion. Pathologically, staining observations confirmed that TSD inhibited hippocampal neuronal loss and alleviated the abnormal reduction of the Nissl body. In parallel, TUNEL staining illustrated that TSD decelerated neuronal apoptosis. Western Blot demonstrated that TSD reduces the expression of ERs and apoptotic proteins. CONCLUSION: In this study, the significant ameliorative effect on cognitive impairment of TSD has been determined by comparing the behavioral data of the 4 groups of rats. Furthermore, it was confirmed that this effect of TSD was achieved by suppressing the ERs-mediated apoptosis signaling pathway.

In-situ synthesized MgIn2S4/CdWO4 type-II heterojunction as a light-driven photoelectrochemical sensor for ultrasensitive detection of catechol in environmental water samples.

As an essential chemical intermediate, catechol (CC) residues may have adverse effects on human health. Herein, an effective and facile photoelectrochemical sensor platform based on MgIn2S4/CdWO4 composite is constructed for monitoring CC. MgIn2S4 increases light absorption range and activity, while CdWO4 enhances photoelectronic stability, and the type-II heterojunction formed can significantly enhance photocurrent response. Due to the autoxidation process, CC is converted into oligomeric products, which increase the spatial site resistance and attenuate the overall photocurrent response. It is worth noting that the cauliflower-like structure of MgIn2S4 can provide a large specific surface area, and the presence of Mg2+ promotes autoxidation, thus providing a suitable condition for detecting CC. Under optimal conditions, the MgIn2S4/CdWO4/GCE photoelectrochemical sensor has a prominent linear relationship in the range of CC concentration from 2 nM to 7 µM, with a limit of detection of 0.27 nM. With satisfactory selectivity, excellent stability, and remarkable reproducibility, this sensor provides a crucial reference value for effectively and rapidly detecting pollutants in environmental water samples.

Ethanol extract of Evodia lepta Merr. ameliorates cognitive impairment through inhibiting NLRP3 inflammasome in scopolamine-treated mice.

Evodia lepta Merr. (Evodia lepta) is a well-known traditional Chinese medicine, which has been widely used in herbal tea. We previously reported that the coumarin compounds from the root of Evodia lepta exhibited neuroprotective effects. However, whether Evodia lepta could inhibit NLRP3 inflammasome in dementia was still unknown. In this study, the components of the Evodia lepta extract were identified by HPLC-Q-TOF HRMS. We employed a scopolamine-treated mouse model. Evodia lepta extract (10 or 20 mg/kg) and donepezil were treated by gavage once a day for 14 consecutive days. Following the behavioral tests, oxidative stress levels were measured. Then, Western blot and immunofluorescence analysis were used to evaluate the expressions of NLRP3 inflammasome. 14 major components of the Evodia lepta extract were identified by HPLC-Q-TOF HRMS. The results of Morris water maze, object recognition task and open field test indicated that Evodia lepta extract could ameliorate cognitive impairment in scopolamine-treated mice. Evodia lepta extract improved cholinergic system. Moreover, Evodia lepta extract improved the expressions of PSD95 and BDNF. Evodia lepta extract suppressed neuronal oxidative stress and apoptosis. In addition, Evodia lepta extract inhibited NLRP3 inflammasome in the hippocampus of scopolamine-treated mice. Evodia lepta extract could protect against cognitive impairment by inhibiting NLRP3 inflammasome in scopolamine-treated mice.

Water-Level Fluctuation Control of the Trophic Structure of a Yangtze River Oxbow.

Seasonal water-level fluctuations can profoundly impact nutrient dynamics in aquatic ecosystems, influencing trophic structures and overall ecosystem functions. The Tian-e-Zhou Oxbow of the Yangtze River is China's first ex situ reserve and the world's first successful case of ex situ conservation for cetaceans. In order to better protect the Yangtze finless porpoise, the effects of water-level fluctuations on the trophic structure in this oxbow cannot be ignored. Therefore, we employed stable isotope analysis to investigate the changes in the trophic position, trophic niche, and contribution of basal food sources to fish during the wet and dry seasons of 2021-2022. The research results indicate that based on stable isotope analysis of the trophic levels of different dietary fish species, fish trophic levels during the wet season were generally higher than those during the dry season, but the difference was not significant (p > 0.05). Fish communities in the Tian-e-Zhou Oxbow exhibited broader trophic niche space and lower trophic redundancy during the wet season (p < 0.05), indicating a more complex and stable food web structure. In both the wet and dry seasons, fish in the oxbow primarily relied on endogenous carbon sources, but there were significant differences in the way they were utilized between the two seasons (p < 0.05). In light of the changes in the trophic structure of the fish during the wet and dry seasons, and to ensure the stable development of the Yangtze finless porpoise population, we recommend strengthening the connectivity between the Tian-e-Zhou Oxbow and the Yangtze River.

[Occurrence Characteristics and Risk Assessment of Microplastics in Water and Sediments of Anhui Section of Huaihe River Basin].

The occurrence characteristics and ecological risk level of microplastics in the water and sediments of the Anhui section of Huaihe River Basin were analyzed via field sampling, stereomicroscopy, scanning electron microscopy, Fourier transform infrared spectroscopy (FTIR), risk index (H), and pollution load index (PLI) model. The current situation of microplastics in the water and sediments of the basin was analyzed, and the ecological risk assessment of microplastics was conducted. The results showed that the detection rate of microplastics at each site in the basin was 100%. The average abundance of microplastics in surface water and sediments was (39800±3367) n·m-3 and (5078±447) n·kg-1, respectively. The average abundance of microplastics in the downstream was higher than that in the upstream and midstream. The particle size of microplastics in water and sediments was primarily 20-150 µm, accounting for 82.96% and 80.77%, respectively. The microplastics were primarily fiber (water 76.05%, sediment 84.53%), film (water 21.83%, sediment 15.43%), and debris (water 2.12%, sediment 0.04%). The microplastics in water and sediments were primarily transparent, accounting for 63.31% and 83.69%, respectively. Polyethylene (65.74% in water and 80.62% in sediment) and polypropylene (18.43% in water and 9.71% in sediment) were the major components of water and sediments. Microplastics were primarily derived from agricultural films, abandoned fishing gear and nets, and artificially abandoned plastic bags in ports. The microplastic risk index (H) model assessment revealed that the risk index of some sites was high, and the risk level of microplastics in the Anhui section of Huaihe River Basin was grade II. The pollution load index (PLI) model assessment revealed that the ecological risk of surface water and sediments in the basin was generally low.

Kai-Xin-San Improves Cognitive Impairment via Wnt/ß-Catenin and IRE1/XBP1s Signalings in APP/PS1 Mice.

Alzheimer's disease (AD) is the most common type of dementia with an insidious onset and slow progression. Kai-Xin-San (KXS) has been reported to be effective in improving cognitive impairment in AD. However, the mechanism is still confused. In this study, we employed APP/PS1 mice to explore the neuroprotective mechanism of KXS. Forty-eight male APP/PS1 mice were randomly divided into model group, KXS groups (0.7, 1.4, and 2.8 g/kg/d, p.o.) and the wild-type mice were assigned to the normal control group (n = 12 in each group). Y-maze and novel object recognition tests were carried out after continuous intragastric administration for 2 months. The abilities of learning, memory, and new object recognition in the APP/PS1 mice were enhanced significantly after KXS treatment. KXS can reduce the deposition of Aß40 and Aß42 in APP/PS1 mice brain. KXS decreased the levels of serum inflammatory cytokines, tumor necrosis factor-α, interleukin-1ß, and interleukin-6. KXS increased the activities of superoxide dismutase and glutathione peroxidase significantly, whereas it inhibited the contents of reactive oxygen species and malondialdehyde significantly. In addition, we also detected Wnt/ß-catenin signaling related proteins, such as Wnt7a, ß-catenin, low-density lipoprotein receptor-related protein 6 (LRP6), glycogen synthase kinase-3ß (GSK-3ß), nuclear factor kappa-B (NF-κB), postsynaptic density 95 (PSD95), microtubule associated protein-2 (MAP-2), and endoplasmic reticulum stress (IRE1 pathway) related proteins, such as inositol-requiring enzyme 1 (IRE1), phosphorylated IRE1(p-IRE1), spliced X-box-binding protein 1 (XBP1s), immunoglobulin binding protein (BIP), and protein disulfide isomerase (PDI) in the hippocampus. Results showed that KXS decreased the expression of GSK-3ß, NF-kB, p-IRE1/IRE1 ratio, XBP1s, and BIP; increased the expression of Wnt7a, ß-catenin, LRP6, PSD95, MAP2, and PDI. In conclusion, KXS improved cognitive impairment by activating Wnt/ß-catenin signaling, inhibiting the IRE1/XBP1s pathway in APP/PS1 mice.

Raman mapping of piezoelectric poly(l-lactic acid) films for force sensors.

Poly-l-lactic acid (PLLA) is a synthetic, biocompatible, biodegradable polymer with good piezoelectric properties. The prepared PLLA films were annealed in the oven at 140 °C for 0 h, 3 h, 12 h, and 24 h, respectively. The influences of temperature treatment time on the optoelectronic properties of the PLLA films and piezoelectric sensors based on them were investigated. The morphology and crystal structure of the PLLA films obtained under various post-processing conditions were examined by scanning electron microscopy, X-ray diffraction, Raman spectroscopy, and ATR-FTIR spectroscopy. The micromechanical equipment for tension-compression measurements was built in the laboratory for the tested piezoelectric sensors. The analysis of the structure shows that the increase in the crystallite size of the PLLA film influences the growth of the piezoelectric signal of the sensors based on them. The vibrational analysis of the PLLA films confirmed their crystal structure. The improvement in the structure and the stretching of the dipole C[double bond, length as m-dash]O for the film obtained after 3 h treatment increased the piezoelectric properties of the PLLA films. The analysis of Raman mapping added information that the area of the ordered phase of the PLLA films depends on the time of temperature treatment. The maximum value of the piezoelectric signal was 0.98 mV for sensors prepared on films annealed for 3 h at a load of 20 N. For films without temperature annealing at the same load, the maximum value was 0.45 mV. Thus, efficient converters of mechanical energy into electrical energy were obtained, which opens new innovative perspectives for the creation of flexible pressure sensors based on PLLA.

Salvianolic acid B ameliorates non-alcoholic fatty liver disease by inhibiting hepatic lipid accumulation and NLRP3 inflammasome in ob/ob mice.

Non-alcoholic fatty liver disease (NAFLD) has high occurrence in the global world, which poses serious threats to human health. Salvianolic acid B (SalB), an extract of the root of Salvia miltiorrhiza, has the protective effect on metabolic homeostasis. However, the mechanism is still unknown. In this study, we used ob/ob mice, a model of NAFLD, to explore the hepatoprotective effects of SalB. The results showed that SalB significantly reduced the body weights and liver weights, and ameliorated plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), hepatic free fatty acid (FFA), total cholesterol (TC) levels, and hepatic TG and TC levels in ob/ob mice. SalB reduced the number of lipid droplets and inhibited hepatic lipogenesis by regulating peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid synthase (FASN), stearoyl-Co A desaturase 1 (SCD1), and cluster of differentiation 36 (CD36). Compared to ob/ob mice, the lower expressions of the pro-inflammatory cytokines, such as interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and F4/80, were observed after SalB treatment. Importantly, SalB treatment inhibited the activation of NLRP3 inflammasome and reduced the severity of liver inflammation. Our findings suggested that SalB improved NAFLD pathology in ob/ob mice by reducing hepatic lipid accumulation and NLRP3 inflammasome activation, which might be the potential hepatoprotective mechanism of SalB.

Cost-effectiveness Analysis of Dienogest Compared With Gonadotropin-Releasing Hormone Agonist After Conservative Surgery for Endometriosis in China.

PURPOSE: Although the clinical effect of dienogest for endometriosis after conservative surgery has been proven, the cost-effectiveness of this new pharmacotherapy remains to be determined. We aimed to assess the health economic implications of dienogest versus a gonadotropin-releasing hormone agonist (GnRH-a; goserelin in the Chinese setting. METHODS: A decision tree model was developed to evaluate the cost-effectiveness of dienogest compared with a GnRH-a (goserelin) after conservative surgery for endometriosis during a 2-year time horizon from the perspective of a health care system in China. The cost of drugs, use of outpatient care facilities, administration of medications, routine laboratory work and imaging studies, and treatment of drug-related adverse events were considered. We obtained clinical efficacy data from the peer-reviewed literature. Base case findings were further tested with 1-way and probabilistic sensitivity analyses. FINDINGS: The model projects that treatment with dienogest would result in a modest incremental 0.02 quality-adjusted life-year gains compared with a GnRH-a (goserelin) (1.48 vs 1.46) at a cost saving of ¥7274 (¥22,809 vs ¥30,164). Probabilistic sensitivity analysis found that dienogest has a 100% probability of % being considered cost-effective compared with a GnRH-a (goserelin) at the willingness-to-pay threshold of 3 times the gross domestic product per capita (¥64,644 × 3) of China in 2018 (¥1 = US$0.1454 and €0.1248). IMPLICATIONS: Dienogest is more effective and cost-saving compared with a GnRH-a (goserelin) in the treatment of patients with endometriosis after conservative surgery in China.

Single scrotal incision orchiopexy versus the inguinal approach in children with palpable undescended testis: a systematic review and meta-analysis.

PURPOSE: We performed a systematic review and meta-analysis to compare the efficacy and safety between single-incision, transscrotal orchidopexy, and the traditional inguinal orchidopexy in children. METHODS: A systematic search of the electronic databases was conducted to identify studies compared the transscrotal orchidopexy (SO) and inguinal orchidopexy (IO) for children. Parameters, such as operative time, the incidence of patent processus vaginalis, and postoperative complications, including wound infection, testicular atrophy, testicular reascent, hernia, or hydrocele, were pooled and compared by meta-analysis. RESULTS: Among the 1376 children with palpable undescended testes (UDTs) included in the eight studies, 697 had received SO and 679 IO. There were shorter operative times with the SO approach compared with IO. However, no significant difference was found between SO and IO in the incidence of patent processus vaginalis and postoperative complications, including wound infection, testicular atrophy, testicular reascent, and hernia. CONCLUSION: SO is a safe and effective surgical approach alternative to IO for pediatric UDTs. Compared with IO, SO has the advantage of shorter operative times. Besides, the incidence of postoperative wound infection may be slightly lower in SO. We suggest that SO should be considered as an acceptable option for children with UDTs.

Laparoscopic versus open splenectomy in children: a systematic review and meta-analysis.

PURPOSE: We conducted a systematic review and meta-analysis to compare the clinical outcomes between laparoscopic splenectomy and the traditional open splenectomy in children. METHODS: Literature searches were conducted to identify studies having compared the laparoscopic splenectomy (LS) and open splenectomy (OS) for children. Parameters such as operative time, blood loss, length of postoperative stay, the removal of accessory spleens and postoperative complications including postoperative high fever, acute chest syndrome (ACS), and ileus were pooled and compared by meta-analysis. RESULTS: Among the 922 pediatric participants included in the 10 studies, 508 had received LS and 414 OS. There were shorter length of hospital stays, less blood loss, and longer operative times with the LS approach compared with OS. However, no significant difference was found between LS and OS in the secondary outcome, such as the removal of accessory spleens or postoperative complications including postoperative high fever, ACS, and ileus. CONCLUSION: LS is a feasible, safe, and effective surgical procedure alternative to OS for pediatric patients. Compared with OS, LS has the advantage of shorter hospital stay and less blood loss. Besides, total postoperative complications may be slightly lower in LS. We conclude that LS should be considered an acceptable option for children.

[Infantile polycystic kidney disease: a case report and literature review].

OBJECTIVE: To summarize the clinical characteristics, diagnosis, treatments and outcomes of perinatal autosomal recessive polycystic kidney disease. METHODS: The clinical data of one case with infantile polycystic kidney disease diagnosed in perinatal stage and the reports of 11 cases seen in the past 15 years searched in Pubmed, OVID and Elsevier and CNKI, Wanfang database by using the polycystic kidney disease, infant, perinatal, autosomal recessive and case report as keyword were reviewed and analyzed. RESULTS: The infant was characterized by huge kidneys, severe respiratory and renal compromise. The kidneys were symmetrically enlarged and highly echogenic by ultrasonographic examination and showed high-signal intensity on T2-weighted images by MRI. Histologic analysis showed pulmonary hypoplasia, numerous dilated and elongated tubular structures in the kidney and dilated intrahepatic biliary ducts. Among the 12 cases, 8 cases' presumptive diagnosis was made by prenatal ultrasound revealed enlarged kidneys and oligohydramnios. All cases suffered respiratory distress after birth, and 5 cases complicated pneumothorax. 6 cases died in neonatal stage because of respiratory failure.1 case died 2 m after birth because of renal failure. Five cases are alive and underwent dialysis, nephrectomy or renal transplant. CONCLUSION: Newborn infants with perinatal autosomal recessive polycystic kidney disease often have poor outcome and died from respiratory and renal failure. Aggressive respiratory support and renal replacement therapy (including nephrectomy, dialysis and transplantation) may give these infants a favorable outcome.

ER stress and ASK1-JNK activation contribute to oridonin-induced apoptosis and growth inhibition in cultured human hepatoblastoma HuH-6 cells.

Oridonin, the main active component of Rabdosia rubescens, has antitumor activities in experimental and clinical settings. The aims of the current study were to explore the anticancer abilities of oridonin in hepatoblastoma (HB) HuH-6 cells and to investigate the underlying mechanisms. We found that oridonin inhibited HuH-6 cell in vitro growth in a dose- and time-dependent manner. Further, oridonin induced HuH-6 cell apoptosis and G2/M cell cycle arrest. Upon studying the mechanism, we found that oridonin treatment caused endoplasmic reticulum (ER) stress activation. Meanwhile, ER stress inhibitor salubrinal- or inositol-requiring enzyme 1 (IRE-1) shRNA silencing inhibited oridonin's anti-HuH-6 effects, while ER stress inducers thapsigargin (Tg) and tunicamycin (Tm) mimicked oridonin's actions on HuH-6 cells. Oridonin also activated apoptosis signal regulating kinase 1 (ASK1)-c-Jun N-terminal kinase 1 (JNK1) signaling in cultured HuH-6 cells, which was inhibited by IRE-1 silencing. Importantly, the JNK inhibitors suppressed oridonin-induced growth inhibition and apoptosis in HuH-6 cells. In conclusion, our results suggest that oridonin induces growth inhibition and apoptosis in cultured HuH-6 cells involving ER stress and ASK1/JNK signaling pathways, which enhances our understanding of the molecular mechanisms of oridonin in HB management.

Primary mixed germ cell tumor arising in the pancreatic head.

Germ cell tumors, comprised of gonadal and extra-gonadal types, are relatively rare tumors arising from primordial germ cells. Extra-gonadal germ cell tumors have been reported to occur at many non-gonadal locations, from the brain to the sacrococcygeal region. However, primary germ cell tumors in the pancreas are extremely rare. Herein, we present the first case of a 12-month-old girl with a primary mixed germ cell tumor, consisting of both endodermal sinus tumor and mature teratoma, in the pancreatic head.

PGMapper: a web-based tool linking phenotype to genes.

SUMMARY: With the availability of whole genome sequence in many species, linkage analysis, positional cloning and microarray are gradually becoming powerful tools for investigating the links between phenotype and genotype or genes. However, in these methods, causative genes underlying a quantitative trait locus, or a disease, are usually located within a large genomic region or a large set of genes. Examining the function of every gene is very time consuming and needs to retrieve and integrate the information from multiple databases or genome resources. PGMapper is a software tool for automatically matching phenotype to genes from a defined genome region or a group of given genes by combining the mapping information from the Ensembl database and gene function information from the OMIM and PubMed databases. PGMapper is currently available for candidate gene search of human, mouse, rat, zebrafish and 12 other species. AVAILABILITY: Available online at http://www.genediscovery.org/pgmapper/index.jsp.

TNF-alpha induces leukemic clonal evolution ex vivo in Fanconi anemia group C murine stem cells.

The molecular pathogenesis of the myeloid leukemias that frequently occur in patients with Fanconi anemia (FA) is not well defined. Hematopoietic stem cells bearing inactivating mutations of FA complementation group C (FANCC) are genetically unstable and hypersensitive to apoptotic cytokine cues including IFN-gamma and TNF-alpha, but neoplastic stem cell clones that arise frequently in vivo are resistant to these cytokines. Reasoning that the combination of genetic instability and cytokine hypersensitivity might create an environment supporting the emergence of leukemic stem cells, we tested the leukemia-promoting effects of TNF-alpha in murine stem cells. TNF-alpha exposure initially profoundly inhibited the growth of Fancc-/- stem cells. However, longer-term exposure of these cells promoted the outgrowth of cytogenetically abnormal clones that, upon transplantation into congenic WT mice, led to acute myelogenous leukemia. TNF-alpha induced ROS-dependent genetic instability in Fancc-/- but not in WT cells. The leukemic clones were TNF-alpha resistant but retained their characteristic hypersensitivity to mitomycin C and exhibited high levels of chromosomal instability. Expression of FANCC cDNA in Fancc-/- stem cells protected them from TNF-alpha-induced clonal evolution. We conclude that TNF-alpha exposure creates an environment in which somatically mutated preleukemic stem cell clones are selected and from which unaltered TNF-alpha-hypersensitive Fancc-/- stem cells are purged.

Inflammatory ROS promote and cooperate with the Fanconi anemia mutation for hematopoietic senescence.

The proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) inhibits hematopoietic stem cell (HSC) expansion, interferes with HSC self-renewal and compromises the ability of HSC to reconstitute hematopoiesis. We have investigated mechanisms by which TNFalpha suppresses hematopoiesis using the genomic instability syndrome Fanconi anemia mouse model deficient for the complementation-group-C gene (Fancc). Examination of senescence makers, such as senescence-associated beta-galactosidase, HP1-gamma, p53 and p16(INK4A) shows that TNFalpha induces premature senescence in bone marrow HSCs and progenitor cells as well as other tissues of Fancc-/- mice. TNFalpha-induced senescence correlates with the accumulation of reactive oxygen species (ROS) and oxidative DNA damage. Neutralization of TNFalpha or deletion of the TNF receptor in Fancc-/- mice (Fancc-/-;Tnfr1-/-) prevents excessive ROS production and hematopoietic senescence. Pretreatment of TNFalpha-injected Fancc-/- mice with a ROS scavenger significantly reduces oxidative base damage, DNA strand breaks and senescence. Furthermore, HSCs and progenitor cells from TNFalpha-treated Fancc-/- mice show increased chromosomal aberrations and have an impaired oxidative DNA-damage repair. These results indicate an intimate link between inflammatory reactive oxygen species and DNA-damage-induced premature senescence in HSCs and progenitor cells, which may play an important role in aging and anemia.

Inflammatory reactive oxygen species-mediated hemopoietic suppression in Fancc-deficient mice.

Patients with the genomic instability syndrome Fanconi anemia (FA) commonly develop progressive bone marrow (BM) failure and have a high risk of cancer. Certain manifestations of the disease suggest that the FA immune system is dysfunctional and may contribute to the pathogenesis of both BM failure and malignancies. In this study, we have investigated inflammation and innate immunity in FA hemopoietic cells using mice deficient in Fanconi complementation group C gene (Fancc). We demonstrate that Fancc-deficient mice exhibit enhanced inflammatory response and are hypersensitive to LPS-induced septic shock as a result of hemopoietic suppression. This exacerbated inflammatory phenotype is intrinsic to the hemopoietic system and can be corrected by the re-expression of a wild-type FANCC gene, suggesting a potential role of the FANCC protein in innate immunity. LPS-mediated hemopoietic suppression requires two major inflammatory agents, TNF-alpha and reactive oxygen species. In addition, LPS-induced excessive accumulation of reactive oxygen species in Fancc(-/-) BM cells overactivates the stress kinase p38 and requires prolonged activation of the JNK. Our data implicate a role of inflammation in pathogenesis of FA and BM failure diseases in general.