Irisin inhibits microglial senescence via TFAM-mediated mitochondrial metabolism in a mouse model of tauopathy.

BACKGROUND: The accumulation of senescent microglia has been highlighted as a critical contributor to the progression of tauopathies. Irisin, a muscle-derived hormone produced by the proteolytic cleavage of Fibronectin-domain III containing 5 (FNDC5), mediates the pleiotropic effects of exercise on the physical body. Herein, we investigate the potential role of irisin in microglial senescence in tauopathies. METHODS: To model tauopathies both in vivo and in vitro, we utilized P301S tau transgenic mice and tau K18 fibril-treated microglia BV2 cells, respectively. We first examined the expression of the irisin expression and senescence phenotypes of microglia in tauopathies. Subsequently, we investigated the impact of irisin on microglial senescence and its underlying molecular mechanisms. RESULT: We observed a reduction in irisin levels and an onset of premature microglial senescence both in vivo and in vitro. Irisin administration was found to counteract microglial senescence and ameliorate cognitive decline in P301S mice. Mechanistically, irisin effectively inhibited microglial senescence by stimulating the expression of mitochondrial transcription factor A (TFAM), a master regulator of mitochondrial respiratory chain biogenesis, thereby enhancing mitochondrial oxidative phosphorylation (OXPHOS). Silencing TFAM eliminated the inhibitory effect of irisin on microglial senescence as well as the restorative effect of irisin on mitochondrial OXPHOS. Furthermore, the SIRT1/PGC1α signaling pathway appeared to be implicated in irisin-mediated upregulation of TFAM. CONCLUSION: Taken together, our study revealed that irisin mitigated microglial senescence via TFAM-driven mitochondrial biogenesis, suggesting a promising new avenue for therapeutic strategies targeting tauopathies.

SIRT3 ameliorates diabetes-associated cognitive dysfunction via regulating mitochondria-associated ER membranes.

BACKGROUND: Diabetes is associated with an increased risk of cognitive decline and dementia. These diseases are linked with mitochondrial dysfunction, most likely as a consequence of excessive formation of mitochondria-associated membranes (MAMs). Sirtuin3 (SIRT3), a key mitochondrial NAD+-dependent deacetylase, is critical responsible for mitochondrial functional homeostasis and is highly associated with neuropathology. However, the role of SIRT3 in regulating MAM coupling remains unknown. METHODS: Streptozotocin-injected diabetic mice and high glucose-treated SH-SY5Y cells were established as the animal and cellular models, respectively. SIRT3 expression was up-regulated in vivo using an adeno-associated virus in mouse hippocampus and in vitro using a recombinant lentivirus vector. Cognitive function was evaluated using behavioural tests. Hippocampus injury was assessed using Golgi and Nissl staining. Apoptosis was analysed using western blotting and TUNEL assay. Mitochondrial function was detected using flow cytometry and confocal fluorescence microscopy. The mechanisms were investigated using co-immunoprecipitation of VDAC1-GRP75-IP3R complex, fluorescence imaging of ER and mitochondrial co-localisation and transmission electron microscopy of structural analysis of MAMs. RESULTS: Our results demonstrated that SIRT3 expression was significantly reduced in high glucose-treated SH-SY5Y cells and hippocampal tissues from diabetic mice. Further, up-regulating SIRT3 alleviated hippocampus injuries and cognitive impairment in diabetic mice and mitigated mitochondrial Ca2+ overload-induced mitochondrial dysfunction and apoptosis. Mechanistically, MAM formation was enhanced under high glucose conditions, which was reversed by genetic up-regulation of SIRT3 via reduced interaction of the VDAC1-GRP75-IP3R complex in vitro and in vivo. Furthermore, we investigated the therapeutic effects of pharmacological activation of SIRT3 in diabetic mice via honokiol treatment, which exhibited similar effects to our genetic interventions. CONCLUSIONS: In summary, our findings suggest that SIRT3 ameliorates cognitive impairment in diabetic mice by limiting aberrant MAM formation. Furthermore, targeting the activation of SIRT3 by honokiol provides a promising therapeutic candidate for diabetes-associated cognitive dysfunction. Overall, our study suggests a novel role of SIRT3 in regulating MAM coupling and indicates that SIRT3-targeted therapies are promising for diabetic dementia patients.

Clemastine fumarate attenuates tauopathy and meliorates cognition in hTau mice via autophagy enhancement.

Clemastine fumarate, which has been identified as a promising agent for remyelination and autophagy enhancement, has been shown to mitigate Aß deposition and improve cognitive function in the APP/PS1 mouse model of Alzheimer's disease. Based on these findings, we investigated the effect of clemastine fumarate in hTau mice, a different Alzheimer's disease model characterized by overexpression of human Tau protein. Surprisingly, clemastine fumarate was effective in reducing pathological deposition of Tau protein, protecting neurons and synapses from damage, inhibiting neuroinflammation, and improving cognitive impairment in hTau mice. Interestingly, chloroquine, an autophagy inhibitor, had a significant impact on total and Sarkosyl fractions of autophagy, demonstrating that it can interrupt autophagy. Notably, after administration of chloroquine, levels of Tau protein were significantly increased. When clemastine fumarate was co-administered with chloroquine, the protective effects were reversed, indicating that clemastine fumarate indeed triggered autophagy and promoted the degradation of Tau protein, while also inhibiting further Tauopathy-related neuroinflammation and synapse loss to improve cognitive function in hTau mice.

Identification of Two Novel Carbapenemase-Encoding Hybrid Plasmids Harboring blaNDM-5 and blaKPC-2 in a Clinical ST11-KL47 Klebsiella pneumoniae.

Background: Emergence of blaKPC and blaNDM co-harboring Klebsiella pneumoniae has escalated the threat of Carbapenem-resistant Klebsiella pneumoniae (CRKP) to healthcare. It remains unknown the prevalence and molecular characteristics of CRKP co-producing KPC and NDMs carbapenemases in Henan. Methods and Results: Twenty-seven CRKP strains isolated from different times were selected randomly in affiliated cancer hospital of Zhengzhou University from January 2019 to January 2021, among which one KPC-2 and NDM-5 positive CRKP named K9 was isolated from an abdominal pus sample of a 63-year-old male patient with leukemia. Sequencing of K9 determined that K9 belonged to ST11-KL47, which is resistant to antibiotics such as meropenem, ceftazidime-avibactam and tetracycline. K9 carried two different plasmids that contained blaNDM-5 and blaKPC-2. Both plasmids were shown to be novel hybrid plasmids and IS26 played an important role in generation of two plasmids. Gene blaKPC-2 was flanked by the NTEKPC-Ib-like genetic structure (IS26-ΔTn3-ISKpn8-blaKPC-2-ISKpn6-IS26) and was located on a conjugative IncFII/R/N type hybrid plasmid. Conclusion: The resistance gene blaNDM-5 located on a region organized as IS26-blaNDM-5-ble-trpF-dsbD-ISCR1-sul1-aadA2-dfrA12-IntI1-IS26 was carried by a phage-plasmid. We described a clinical CRKP co-producing KPC-2 and NDM-5 and emphasized an urgent need to control their further spread.

Complement C3a receptor antagonist alleviates tau pathology and ameliorates cognitive deficits in P301S mice.

Human tauopathies, including Alzheimer's disease (AD), are a major class of neurodegenerative diseases characterized by intracellular deposition of pathological hyperphosphorylated forms of Tau protein. Complement system is composed of many proteins, which form a complex regulatory network to modulate the immune activity in the brain. Emerging studies have demonstrated a critical role of complement C3a receptor (C3aR) in the development of tauopathy and AD. The underlying mechanisms by which C3aR activation mediates tau hyperphosphorylation in tauopathies, however, remains largely unknown. Here, we observed that the expression of C3aR is upregulated in the brains of P301S mice - a mouse model of tauopathy and AD. Pharmacologic blockade of C3aR ameliorates synaptic integrity and reduced tau hyperphosphorylation in P301S mice. Besides, the administration of C3aR antagonist (C3aRA: SB 290157) improved spatial memory as tested in the Morris water maze. Moreover, C3a receptor antagonist inhibited tau hyperphosphorylation by regulating p35/CDK5 signaling. In summary, results suggest that the C3aR plays an essential role in the accumulation of hyperphosphorylated Tau and behavioral deficits in P301S mice. C3aR could be a feasible therapeutic target for the treatment of tauopathy disorders, including AD.

AdipoRon mitigates tau pathology and restores mitochondrial dynamics via AMPK-related pathway in a mouse model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a complicated and refractory neurodegenerative disease that is typically characterized by memory loss and multiple cognitive impairments. Multiple neuropathology including hyperphosphorylated tau formation and accumulation, dysregulated mitochondrial dynamics, and synaptic damage have been well implicated in the progression of AD. So far, there are few valid and effective therapeutic modalities for treatment. AdipoRon, a specific adiponectin (APN) receptor agonist, is reported to be associated with cognitive deficits improvement. In the present study, we attempt to explore the potential therapeutic effects of AdipoRon on tauopathy and related molecular mechanisms. METHODS: In this study, P301S tau transgenic mice were used. The plasma level of APN was detected by ELISA. The level of APN receptors was qualified by western blot and immunofluorescence. 6-month-old mice were treated with AdipoRon or vehicle by oral administration daily for 4 months. The benefits of AdipoRon on tau hyperphosphorylation, mitochondrial dynamics, and synaptic function were detected by western blot, immunohistochemistry, immunofluorescence, Golgi staining and transmission electron microscopy. Morris water maze test and novel object recognition test were conducted to explore memory impairments. RESULTS: Compared with wild-type mice, the expression of APN in plasma in 10-month-old P301S mice was obviously decreased. APN receptors in the hippocampus were increased in the hippocampus. AdipoRon treatment significantly rescued memory deficits in P301S mice. Besides, AdipoRon treatment was also detected to improve synaptic function, enhance mitochondrial fusion, and mitigate hyperphosphorylated tau accumulation in P301S mice and SY5Y cells. Mechanistically, AMPK/SIRT3 and AMPK/GSK3ß signaling pathways are demonstrated to be involved in AdipoRon-mediated benefits on mitochondrial dynamics and tau accumulation, respectively, and inhibition of AMPK related pathways showed counteracted effects. CONCLUSION: Our results demonstrated that AdipoRon treatment could significantly mitigate tau pathology, improve synaptic damage, and restore mitochondrial dynamics via the AMPK-related pathway, which provides a novel potential therapeutic approach to retard the progression of AD and other tauopathies diseases.

Dual Role of Inositol-requiring Enzyme 1α-X-box Binding protein 1 Signaling in Neurodegenerative Diseases.

The prevalence of neurodegenerative disease has increased as an outcome of the aging population, and effective clinical treatments for such diseases are lacking. Endoplasmic reticulum dysfunction has been identified as a causative factor in various neurological disorders. The inositol-requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1) signaling pathway is the most conserved branch of the unfolded protein response, functioning in both physiological and pathological processes. The modulation of IRE1α-XBP1 signaling via genetic manipulation or drug administration has opposite effects in multiple disease models of neurodegeneration, indicating the complex and heterogeneous role of IRE1α-XBP1 signaling among neurodegenerative diseases and even at different stages within the same disease. Herein, we focus on the multifaceted nature of IRE1α-XBP1 signaling and provide a detailed overview of the latest findings regarding its biological relevance in brain physiology and neurodegenerative disease pathobiology. Moreover, the possible pharmacological targets in the IRE1α-XBP1 axis are discussed.

HSPB8 Overexpression Ameliorates Cognitive Impairment in Diabetic Mice via Inhibiting NLRP3 Inflammation Activation.

Type 2 diabetes mellitus (T2DM) is associated with an elevated risk of cognitive impairment. And the underlying mechanism remains unillustrated. HSPB8 is a member of the small heat shock protein family. In this study, we found that the expression of HSPB8 was upregulated in the hippocampus of high - fat diet (HFD) + streptozotocin (STZ) - induced diabetic mice and N2a cells exposed to high glucose. Overexpression of HSPB8 relieved cognitive decline in DM mice. Mechanically, HSPB8 overexpression in the hippocampus of diabetic mice inhibited NOD-like receptor protein 3 (NLRP3) inflammasome activation via dephosphorylating mitochondrial fission-associated protein dynamin-related protein 1 (DRP1) at the phosphorylated site Ser616 (p-Drp1S616). Furthermore, HSPB8 overexpression increased mitochondrial membrane potential (MMP) and reduced oxidative stress. These results indicate a protective effect of HSPB8 in the hippocampus of diabetic mice and N2a cells exposed to high glucose. Overexpression of HSPB8 might be a useful strategy for treating T2DM-related cognitive decline.

(-)-Epicatechin Reduces Neuroinflammation, Protects Mitochondria Function, and Prevents Cognitive Impairment in Sepsis-Associated Encephalopathy.

Sepsis-associated encephalopathy is a common neurological complication of sepsis. Despite advances in pathological and diagnostic investigations, its treatment remains a major challenge. In sepsis-associated encephalopathy, neuroinflammatory overactivation and mitochondrial damage are thought to contribute to cognitive and behavioral impairments. In this study, we found that administration of (-)-Epicatechin, a dietary flavonoid of the flavan-3-ol subgroup, improves memory deficits and behavior performance by ameliorating neuroinflammation, regulating mitochondria function, enhancing synaptic plasticity, and reducing neuronal loss in a mouse model of lipopolysaccharide-induced sepsis. We further show that the AMPK signaling pathway might be among the mechanisms involved in the beneficial memory effects. Our data demonstrated the potential of (-)-Epicatechin as a new drug candidate for the treatment of sepsis-associated cognitive impairment by targeting AMPK.

Corrigendum: Acute Administration of Metformin Protects Against Neuronal Apoptosis Induced by Cerebral Ischemia-Reperfusion Injury via Regulation of the AMPK/CREB/BDNF Pathway.

[This corrects the article DOI: 10.3389/fphar.2022.832611.].

Analysis of the molecular characteristics of a blaKPC-2-harbouring untypeable plasmid in Serratia marcescens / Análisis de las características moleculares de un plásmido no tipificable que alberga blaKPC-2 en Serratia marcescens

Introduction: Serratia marcescens has attracted increasing attention worldwide as a neglected opportunistic pathogen of public health concern, especially due to its antimicrobial resistance features, which usually cause nosocomial infections in immunocompromised or critically ill patients. Methods: In our study, four carbapenem-resistant Serratia marcescens (CRSM) clinical isolates were characterized in our hospital from February 2018 to May 2018. The conjugation experiment confirmed the transferability of the carbapenem resistance gene. The types of carbapenem resistance genes were detected by PCR. The homology of the strains was analysed by pulsed field gel electrophoresis (PFGE). The characteristics of the plasmid and environment of carbapenem resistance genes were analysed after whole genome sequencing was performed. Then, we compared the amino acid sequence of the replication initiation protein and constructed a dendrogram by the neighbour-joining method. Results: All four isolates showed carbapenem resistance conferred by a blaKPC-2-harbouring plasmid. They had exactly the same bands confirmed by PFGE and were defined as the homologous strains. The blaKPC-2 genes in all of the isolates were located in a 42,742 bp plasmid, which was located in the core region of antibiotic resistance and was composed of Tn3 family transposons, recombinant enzyme genes, ISKpn6 and ISKpn27. The core region of antibiotic resistance formed a ‘Tn3-ISKpn6-blaKPC-ISKpn27-Tn3’ structure, which was an independent region as a movable element belonging to transposon Tn6296 and its derivatives. The plasmid had a similar skeleton to incX6 plasmids and a similar amino acid sequence to the replication initiation protein. The plasmid was defined as an untypeable blaKPC-2-harbouring plasmid named the ‘IncX6-like’ plasmid. Conclusion: The four CRSM isolates were mainly clonally disseminated with a blaKPC-2-harbouring plasmid in our hospital. The pKPC-2-HENAN1602 plasmid...(AU)

Acute Administration of Metformin Protects Against Neuronal Apoptosis Induced by Cerebral Ischemia-Reperfusion Injury via Regulation of the AMPK/CREB/BDNF Pathway.

Metformin is a first-line anti-diabetic agent with a powerful hypoglycemic effect. Several studies have reported that metformin can improve the prognosis of stroke patients and that this effect is independent of its hypoglycemic effect; however, the specific mechanism remains unclear. In this research, we explored the effect and specific mechanism of metformin in cerebral ischemia-reperfusion (I/R) injury by constructing a transient middle cerebral artery occlusion model in vivo and a glucose and oxygen deprivation/reoxygenation (OGD/R) model in vitro. The results of the in vivo experiments showed that acute treatment with low-dose metformin (10 mg/kg) ameliorated cerebral edema, reduced the cerebral infarction volume, improved the neurological deficit score, and ameliorated neuronal apoptosis in the ischemic penumbra. Moreover, metformin up-regulated the brain-derived neurotrophic factor (BDNF) expression and increased phosphorylation levels of AMP-activated protein kinase (AMPK) and cAMP-response element binding protein (CREB) in the ischemia penumbra. Nevertheless, the above-mentioned effects of metformin were reversed by Compound C. The results of the in vitro experiments showed that low metformin concentrations (20 µM) could reduce apoptosis of human umbilical vein endothelial cells (HUVECs) under OGD/R conditions and promote cell proliferation. Moreover, metformin could further promote BDNF expression and release in HUVECs under OGD/R conditions via the AMPK/CREB pathway. The Transwell chamber assay showed that HUVECs treated with metformin could reduce apoptosis of SH-SY5Y cells under OGD/R conditions and this effect could be partially reversed by transfection of BDNF siRNA in HUVECs. In summary, our results suggest that metformin upregulates the level of BDNF in the cerebral ischemic penumbra via the AMPK/CREB pathway, thereby playing a protective effect in cerebral I/R injury.

Umbilical Cord Mesenchymal Stem Cells Derived Neurospheres Promote Long-term functional recovery But Aggravate Acute Phase Inflammation in Experimental Stroke.

Human umbilical cord mesenchymal stem cells (UC-MSCs) transplantation has been shown to ameliorate intracerebral hemorrhage (ICH) in animal and clinical studies. We previously reported an easy one-step method to induce UC-MSCs into neurospheres with much enhanced neurogenic and angiogenic potential. In the present study, we further evaluated the neuro-protective effects of these UC-MSCs derived neurospheres (UC-MSCs-NS) using a murine collagenase induced ICH model. We compared the effects of UC-MSCs or UC-MSCs-NS transplantation at two different time-points: 3 h after ICH induction (early transplantation) or three days after ICH induction (delayed transplantation). The results showed that UC-MSCs exhibited favorable effects at both time-points whereas UC-MSCs-NS early delivery led to increased cell apoptosis, exacerbated brain edema, enlarged ICH volume and deteriorated neurological function. In vivo inflammatory cytokine analysis indicated UC-MSCs transplantation was able to attenuate the acute phase secretion of inflammatory cytokines TNF-α and IL-1ß whereas UC-MSCs-NS immediate transplantation led to increased levels of these cytokines. However, long-term follow-up experiment showed delayed UC-MSCs-NS transplantation was superior to UC-MSCs transplantation alone in terms of increased neurogenic reconstitution. Our results suggest both UC-MSCs and UC-MSCs-NS can exert favorable effects in ICH therapy but the infusion of UC-MSCs-NS should avoid the super-early phase of ICH. We believe UC-MSCs derived neurospheres should be further exploited for chronic refractory neurological disorders such as chronic phase of stroke and various neurodegenerative disorders such as Alzheimer's disease.

Analysis of the molecular characteristics of a blaKPC-2-harbouring untypeable plasmid in Serratia marcescens.

INTRODUCTION: Serratia marcescens has attracted increasing attention worldwide as a neglected opportunistic pathogen of public health concern, especially due to its antimicrobial resistance features, which usually cause nosocomial infections in immunocompromised or critically ill patients. METHODS: In our study, four carbapenem-resistant Serratia marcescens (CRSM) clinical isolates were characterized in our hospital from February 2018 to May 2018. The conjugation experiment confirmed the transferability of the carbapenem resistance gene. The types of carbapenem resistance genes were detected by PCR. The homology of the strains was analysed by pulsed field gel electrophoresis (PFGE). The characteristics of the plasmid and environment of carbapenem resistance genes were analysed after whole genome sequencing was performed. Then, we compared the amino acid sequence of the replication initiation protein and constructed a dendrogram by the neighbour-joining method. RESULTS: All four isolates showed carbapenem resistance conferred by a blaKPC-2-harbouring plasmid. They had exactly the same bands confirmed by PFGE and were defined as the homologous strains. The blaKPC-2 genes in all of the isolates were located in a 42,742 bp plasmid, which was located in the core region of antibiotic resistance and was composed of Tn3 family transposons, recombinant enzyme genes, ISKpn6 and ISKpn27. The core region of antibiotic resistance formed a 'Tn3-ISKpn6-blaKPC-ISKpn27-Tn3' structure, which was an independent region as a movable element belonging to transposon Tn6296 and its derivatives. The plasmid had a similar skeleton to incX6 plasmids and a similar amino acid sequence to the replication initiation protein. The plasmid was defined as an untypeable blaKPC-2-harbouring plasmid named the 'IncX6-like' plasmid. CONCLUSION: The four CRSM isolates were mainly clonally disseminated with a blaKPC-2-harbouring plasmid in our hospital. The pKPC-2-HENAN1602 plasmid (CP047392) in our study was first reported in Serratia marcescens, which belongs to an untypeable group named the 'IncX6-like' plasmid. The carbapenem-resistant gene structure surrounding blaKPC-2 as a sole accessory module can be acquired by horizontal gene transfer and might lead to serious nosocomial infection.

Corrigendum: Dl-3-n-Butylphthalide Reduces Cognitive Deficits and Alleviates Neuropathology in P301S Tau Transgenic Mice.

[This corrects the article DOI: 10.3389/fnins.2021.620176.].

Dl-3-n-Butylphthalide Reduces Cognitive Deficits and Alleviates Neuropathology in P301S Tau Transgenic Mice.

Alzheimer's disease (AD) is a destructive and burdensome neurodegenerative disease, one of the most common characteristics of which are neurofibrillary tangles (NFTs) that are composed of abnormal tau protein. Animal studies have suggested that dl-3-n-butylphthalide (dl-NBP) alleviates cognitive impairment in mouse models of APP/PS1 and SAMP8. However, the underlying mechanisms related to this remain unclear. In this study, we examined the effects of dl-NBP on learning and memory in P301S transgenic mice, which carry the human tau gene with the P301S mutation. We found that dl-NBP supplementation effectively improved behavioral deficits and rescued synaptic loss in P301S tau transgenic mice, compared with vehicle-treated P301S mice. Furthermore, we also found that it markedly inhibited the hyperphosphorylated tau at the Ser262 site and decreased the activity of MARK4, which was associated with tau at the Ser262 site. Finally, dl-NBP treatment exerted anti-inflammatory effects and reduced inflammatory responses in P301S mice. In conclusion, our results provide evidence that dl-NBP has a promising potential for the therapy of tauopathies, including AD.

Complement C3a receptor antagonist attenuates tau hyperphosphorylation via glycogen synthase kinase 3ß signaling pathways.

Neurofibrillary tangles aggregated from hyperphosphorylated tau protein are the main pathological feature of Alzheimer's disease (AD). Complement C3 (or C3a) is the core component of the complement system and is associated with AD pathological processes. However, it remains unclear whether C3a or the C3a receptor has any effect on tau phosphorylation. In this study, we found that exposure of SH-SY5Y cells to okadaic acid (OA) decreased cell viabilities and induced tau hyperphosphorylation. These effects were alleviated by C3a receptor antagonist SB290157 and were further validated by C3a receptor siRNA in OA-treated SH-SY5Y cells. In addition, our results demonstrated that SB290157 markedly inhibited the activities of glycogen synthase kinase 3ß (GSK3ß), but had no effect on protein phosphatase 2A C subunit (PP2Ac) and cyclin-dependent kinases 5 (CDK5). Our findings here indicate the unique role of the C3a receptor in regulating tau phosphorylation via GSK3ß signaling pathways and suggest that the C3a receptor may be a viable target for treating AD.

Increase in Candida Parapsilosis Candidemia in Cancer Patients.

This study aimed to identify the risk factors of candidemia and asses possible clinically significant differences between Candida parapsilosis and other Candida species in a Chinese tertiary cancer center over six years. A total of 323 cancer patients were enrolled and analyzed from 2012 to 2018. Among the isolates, the species most frequently isolated was C. parapsilosis (37.15%, 120/323), and C. albicans only accounted for 34.37%. Based on statistical analysis, when candidemia patients who had C. parapsilosis were compared with other Candida spp., the following factors were found to be significantly associated with C. parapsilosis fungemia: parenteral nutrition (p < 0.001), neutropenia (p < 0.001), receipt of chemotherapy (p = 0.002), and previous antifungal use (p < 0.001). Parenteral nutrition was a factor that independently predicted C. parapsilosis candidemia (OR, 0.183; 95% CI, 0.098-0.340; p < 0.001).In short, C. parapsilosis as the leading non-albicans Candida spp. isolates in candidemia are posing a major threat for cancer patients. The study highlights the urgent need to evaluate the possibility of development of C. parapsilosis candidemia in cancer patients exposed to these risk factors effective and prevention strategies against this causative agent transmitted through nosocomial route should be implemented.