PD-Like Pathogenesis in Caenorhabditis elegans Intestinally Infected with Nocardia farcinica and the Underlying Molecular Mechanisms.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the abnormal aggregation of α-synuclein (α-syn) and the loss of dopaminergic neurons. Although microbial infection has been implicated in the pathogenesis of PD, the associated virulence factors and the underlying molecular mechanisms require further elucidation. Here, we found that intestinal infection with Nocardia farcinica induced a series of PD-like symptoms in Caenorhabditis elegans, such as the accelerated degeneration of dopaminergic neurons, impaired locomotion capacity, and enhanced α-syn aggregation, through the disturbance of mitochondrial functions. To identify the potential virulence factors involved in these effects, we knocked out the nbtB/C and nbtS genes in N. farcinica, which are localized in the gene clusters responsible for nocobactin biosynthesis. The deletion of either gene partially rescued the degenerative effects of wild-type N. farcinica on dopaminergic neurons by attenuating mitochondrial dysfunction. LC-MS analysis further identified a decrease in the abundance of several siderophores in the two mutants, including nocobactin NA-a, nocobactin NA-b, and nocardimicin B. Collectively, our results demonstrated that intestinal N. farcinica infection in C. elegans facilitates PD-like pathogenesis and provides novel evidence for the involvement of pathogenic bacteria in neurodegenerative diseases via non-neuroinvasive mechanisms.

Valeric acid reduction by chitosan oligosaccharide induces autophagy in a Parkinson's disease mouse model.

Parkinson's disease (PD) is a central nervous system disease with the highest disability and mortality rate worldwide, and it is caused by a variety of factors. The most common medications for PD have side effects with limited therapeutic outcomes. Many studies have reported that chitosan oligosaccharide (COS) crossed blood-brain barrier to achieve a neuroprotective effect in PD. However, the role of COS in PD remains unclear. The present study demonstrated that COS increased dopaminergic neurons in the substantia nigra (SN) and ameliorated dyskinesia in a PD mouse model. Moreover, COS reduced gut microbial diversity and faecal short-chain fatty acids. Valeric acid supplementation enhanced the inflammatory response in the colon and SN, and it reversed COS - suppressed dopamine neurons damage. Autophagy was involved in COS modulating inflammation through valeric acid. These results suggest that COS reduces bacterial metabolites - valeric acid, which diminishes inflammation via activating autophagy, ultimately alleviating PD.

Iron-inhibited autophagy via transcription factor ZFP27 in Parkinson's disease.

Parkinson's disease (PD) is a challenge because of the ageing of the population and the disease's complicated pathogenesis. Accumulating evidence showed that iron and autophagy were involved in PD. Nevertheless, the molecular mechanism and role of iron and autophagy in PD are not yet elucidated. In the present study, it was shown that PD mice had significant motor dysfunction, increased iron content, less dopamine neurons and more α-synuclein accumulation in the substantia nigra. Meanwhile, PD mice treated with deferoxamine exhibited less iron content, relieved the dyskinesia and had a significant increase in dopamine neurons and a significant decrease in α-synuclein. Autophagy induced by LC3 was inhibited in PD models with iron treatment. Following verification showed that iron aggregation restrained insulin-like growth factor 2 (IGF2) and transcription factor zinc finger protein 27 (ZFP27) in PD models. In addition, LC3-induced autophagy flux was reduced with ZFP27 knockdown. Furthermore, ZFP27 affected autophagy by regulating LC3 promoter activity. These data suggest that iron deposition inhibits IGF2 and ZFP27 to reduce LC3-induced autophagy, and ultimately decrease dopamine neurons, accelerating PD progression. Our findings provide a novel insight that ZFP27-mediated iron-related autophagy and IGF2 may activate the downstream kinase gene to trigger autophagy in the PD model.

Small G protein RAC-2 regulates forgetting via the JNK-1 signalling pathway in Caenorhabditis elegans.

Although forgetting was once regarded as a passive decline in memory and an occasional source of embarrassment, recent research suggests that it is an active biological process of removing outdated or irrelevant memories via activation of specific genes and signal transduction pathways. Rho family G proteins are known to have a role in synaptic plasticity mediated by the actin cytoskeleton. However, the current study reveals that another Rho guanosine triphosphate enzyme (GTPase), RAC-2, facilitates the occurrence of forgetting in Caenorhabditis elegans independent of actin dynamics. Functioning downstream of RAC-2 in the same signalling pathway, JNK-1 and its phosphorylated protein are required to positively regulate forgetting. The pan-neuronal rescue of RAC-2 or JNK-1, instead of AWC neuron-specific expression, reverses the delayed forgetting caused by the rac-2 mutation, which indicates that the involvement of RAC-2/JNK-1 in more than AWCs must be required. In summary, our work elucidates the action of the Rho GTPase RAC-2 and downstream JNK-1 as a potential novel pathway in forgetting in C. elegans.

Comprehensive analysis of m6A/m5C/m1A-related gene expression, immune infiltration, and sensitivity of antineoplastic drugs in glioma.

This research aims to develop a prognostic glioma marker based on m6A/m5C/m1A genes and investigate the potential role in the tumor immune microenvironment. Data for patients with glioma were downloaded from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA). The expression of genes related to m6A/m5C/m1A was compared for normal and glioma groups. Gene Ontology and Kyoto Encyclopedia of Genes and Gene enrichment analysis of differentially expressed genes were conducted. Consistent clustering analysis was performed to obtain glioma subtypes and complete the survival analysis and immune analysis. Based on TCGA, Lasso regression analysis was used to obtain a prognostic model, and the CGGA database was used to validate the model. The model-based risk scores and the hub genes with the immune microenvironment, clinical features, and antitumor drug susceptibility were investigated. The clinical glioma tissues were collected to verify the expression of hub genes via immunohistochemistry. Twenty genes were differentially expressed, Consensus cluster analysis identified two molecular clusters. Overall survival was significantly higher in cluster 2 than in cluster 1. Immunological analysis revealed statistically significant differences in 26 immune cells and 17 immune functions between the two clusters. Enrichment analysis detected multiple meaningful pathways. We constructed a prognostic model that consists of WTAP, TRMT6, DNMT1, and DNMT3B. The high-risk and low-risk groups affected the survival prognosis and immune infiltration, which were related to grade, gender, age, and survival status. The prognostic value of the model was validated using another independent cohort CGGA. Clinical correlation and immune analysis revealed that four hub genes were associated with tumor grade, immune cells, and antitumor drug sensitivity, and WTAP was significantly associated with microsatellite instability(MSI). Immunohistochemistry confirmed the high expression of WTAP, DNMT1, and DNMT3B in tumor tissue, but the low expression of TRMT6. This study established a strong prognostic marker based on m6A/m5C/m1A methylation regulators, which can accurately predict the prognosis of patients with gliomas. m6A/m5C/m1A modification mode plays an important role in the tumor microenvironment, can provide valuable information for anti-tumor immunotherapy, and have a profound impact on the clinical characteristics.

Protective Effects of Polysaccharides in Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) are characterized by progressive degeneration and necrosis of neurons, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease and others. There are no existing therapies that correct the progression of these diseases, and current therapies provide merely symptomatic relief. The use of polysaccharides has received significant attention due to extensive biological activities and application prospects. Previous studies suggest that the polysaccharides as a candidate participate in neuronal protection and protect against NDs. In this review, we demonstrate that various polysaccharides mediate NDs, and share several common mechanisms characterized by autophagy, apoptosis, neuroinflammation, oxidative stress, mitochondrial dysfunction in PD and AD. Furthermore, this review reveals potential role of polysaccharides in vitro and in vivo models of NDs, and highlights the contributions of polysaccharides and prospects of their mechanism studies for the treatment of NDs. Finally, we suggest some remaining questions for the field and areas for new development.

6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 acts as a protein kinase to regulate glioblastoma progression by activating the AKT/forkhead box O1 pathway.

Abnormal expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) is closely related to the occurrence and development of tumors, and PFKFB4 has been shown to function as a protein kinase. However, the molecular mechanisms through which PFKFB4 functions in glioblastoma (GBM) remain poorly understood. Accordingly, in this study, we assessed the roles of PFKFB4 in GBM. Compared to in adjacent tissues, PFKFB4 was highly expressed in GBM, and its expression level was negatively correlated with the overall survival time. In addition, knockdown of PFKFB4 inhibited the proliferation and invasion of GBM cells and promoted apoptosis. In a xenograft tumor model, tumor growth was inhibited by knockdown of PFKFB4 using short hairpin RNA. Further studies demonstrated that PFKFB4 is involved in regulating the AKT signaling pathway. Thus, PFKFB4 acts as a protein kinase to regulate GBM progression by activating the AKT/forkhead box O1 pathway, which may be a potential therapeutic target in GBM.

PD-1 Involvement in Peripheral Blood CD8+ T Lymphocyte Dysfunction in Patients with Acute-on-chronic Liver Failure.

BACKGROUND AND AIMS: Programmed cell death-1 (PD-1) plays an important role in downregulating T lymphocytes but the mechanisms are still poorly understood. This study aimed to explore the role of PD-1 in CD8+ T lymphocyte dysfunction in hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). METHODS: Thirty patients with HBV-ACLF and 30 healthy controls (HCs) were recruited. The differences in the numbers and functions of CD8+ T lymphocytes, PD-1 and glucose transporter-1 (Glut1) expression from the peripheral blood of patients with HBV-ACLF and HCs were analyzed. In vitro, the CD8+ T lymphocytes from HCs were cultured (HC group) and the CD8+ T lymphocytes from ACLF patients were cultured with PD-L1-IgG (ACLF+PD-1 group) or IgG (ACLF group). The numbers and functions of CD8+ T lymphocytes, PD-1 expression, glycogen uptake capacity, and Glut1, hexokinase-2 (HK2), and pyruvate kinase (PKM2) expression were analyzed among the HC group, ACLF group and ACLF+ PD-1group. RESULTS: The absolute numbers of CD8+ T lymphocytes in the peripheral blood from patients with HBV-ACLF were lower than in the HCs (p<0.001). The expression of PD-1 in peripheral blood CD8+ T lymphocytes was lower in HCs than in patients with HBV-ACLF (p=0.021). Compared with HCs, PD-1 expression was increased (p=0.021) and Glut1 expression was decreased (p=0.016) in CD8+ T lymphocytes from the HBV-ACLF group. In vitro, glycogen uptake and functions of ACLF CD8+ T lymphocytes were significantly lower than that in HCs (p=0.017; all p<0.001). When PD-1/PD-L1 was activated, the glycogen uptake rate and expression levels of Glut1, HK2, and PKM2 showed a decreasing trend (ACLF+PD-1 group compared to ACLF group , all p<0.05). The functions of CD8+ T lymphocytes in the ACLF+PD-1 group [using biomarkers of Ki67, CD69, IL-2, interferon-gamma, and tumor necrosis factor-alpha- were lower than in the ACLF group (all p<0.05). CONCLUSIONS: CD8+ T lymphocyte dysfunction is observed in patients with HBV-ACLF. PD-1-induced T lymphocyte dysfunction might involve glycolysis inhibition.

Multiple olfactory pathways contribute to the lure process of Caenorhabditis elegans by pathogenic bacteria.

Chemosensation is indispensable for the survival of Caenorhabditis elegans to discriminate food and pathogenic bacteria in their living environment. Food-like odors emitted by the pathogen Bacillus nematocida B16 for trapping its hosts and an olfactory signaling pathway responsible to sense the attractant 2-heptanone were identified in our previous study. Here, we further explore how the worms recognize the attractive molecules indole and 2-ethyl hexanol, which have different chemical properties and modest nematode-luring ability. We show that the chemotaxis toward indole and 2-ethyl hexanol requires the G protein-coupled receptors encoded by str-193 on AWC and str-7 on AWA. In a further genetic screen for downstream effectors in olfactory signaling cascades, the Gα subunit GSA-1, guanylyl cyclase ODR-1 and DAF-11 and the cGMP-gated channel TAX-2/TAX-4 were found to be necessary for indole sensation, whereas the TRPV channels OSM-9/OCR-2 and the PLC pathway activated by GPA-6 are responsible for the detection of 2-ethyl hexanol. Altogether, our current work further clarifies the distinct olfactory signaling pathways through which C. elegans senses different chemicals and is lured by B. nematocida B16, improving our comprehensive understanding of the mechanisms by which bacterial pathogens effectively infect their hosts.

An Intracranial Tuberculoma with Discharging Scalp Sinus.

Our report highlights a case of intracranial tuberculoma in an elderly woman with chronic discharging sinus. A 77-year-old woman had a mass lesion extending to the scalp through a chronic discharging sinus for 2 years with an intermittent, non-radiating, dull, low-grade headache. Based on our survey of central nervous system tuberculosis, this case is a rare event of documented intracranial tuberculoma with concomitant discharge of the scalp sinus similar to the periodic geyser eruptions in developing countries.

Combined use of murine double minute-2 promoter methylation and serum AFP improves diagnostic efficiency in hepatitis B virus-related hepatocellular carcinoma.

Objective: Hepatocellular carcinoma (HCC) accounts for approximately 85% of all cases of liver cancer. In China, chronic hepatitis B virus-related HCC (HBV-related HCC) is the most common type of HCC. However, the majority of HBV-related HCC patients are asymptomatic, and the best opportunities for treating these patients are missed. The precise diagnosis of HBV-related HCC is crucial. The main purpose of this study was to evaluate the diagnostic value of murine double minute-2 (MDM2) promoter methylation in HBV-related HCC patients. Methods: The methylation status of the MDM2 promoter was detected by methylation-specific PCR. The MDM2 expression levels were validated by quantitative real-time PCR. Enzyme-linked immunosorbent assay was used to determine the levels of interleukin-6 (IL-6) and tumor-necrosis factor-α (TNF-α) in plasma. Results: The methylation frequency of the MDM2 promoter was decreased in HBV-related HCC patients. The MDM2 mRNA levels of patients with HBV-related HCC were higher than those of patients with liver cirrhosis and chronic hepatitis B. The plasma levels of IL-6 and TNF-α were significantly higher in HBV-related HCC patients than that in liver cirrhosis and chronic hepatitis B patients. The TNF-α levels were higher in the unmethylated MDM2 promoter group than in the methylated MDM2 promoter group in HBV-related HCC patients. Moreover, the combination of MDM2 promoter methylation and alpha-fetoprotein (AFP) improved the diagnosis of HBV-related HCC. Conclusions: Our study indicates, for the first time, that MDM2 promoter hypomethylation is present in HBV-related HCC patients. The combination of MDM2 promoter methylation and AFP can greatly improve diagnostic efficiency in HBV-related HCC, which might provide a new method for HBV-related HCC diagnosis.

Rehabilitation therapy for patients with glioma: A PRISMA-compliant systematic review and meta-analysis.

BACKGROUND: Glioma is the most common type of brain tumor because of the destructiveness of the disease itself and the side effects of treatment, patients often leave symptoms of neurological defects. At present, rehabilitation treatment is not popular in glioma patients. There is a lack of definite evidence to prove the benefits of rehabilitation therapy for glioma patients. The purpose of this meta-analysis is to determine whether rehabilitation therapy can significantly improve the prognosis of neurological function and improve the quality of life of patients with glioma. METHODS: The articles about rehabilitation treatment of glioma in Cochrane, PubMed, and Embase, Web of Science, and Medline database from January 1990 to May 2020 were searched. Before rehabilitation as the control group, after rehabilitation as the experimental group. The Functional Independence Measure (FIM) was used as the outcome index, including total FIM, motor FIM, and cognitive FIM. Use STATA12.0 for meta-analysis. RESULTS: A total of 8 articles were included in the study, with a total of 375 glioma patients. Meta-analysis of total FIM (SMD = 0.96, 95%CI = 0.66-1.26, P < .001), motor FIM (SMD = 0.75, 95%CI = 0.54-0.96, P < .001) and cognitive FIM (SMD = 0.35, 95%CI = 0.19-0.50, P < .001) indicated that the neurological function of rehabilitation was significantly improved in total, motor and consciousness. CONCLUSION: The published studies show that rehabilitation therapy can improve the functional prognosis and quality of life of glioma patients. More attention should be paid to the therapeutic value of rehabilitation for glioma patients in the future. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42020188740.

A trade-off switch of two immunological memories in Caenorhabditis elegans reinfected by bacterial pathogens.

Recent studies have suggested that innate immune responses exhibit characteristics associated with memory linked to modulations in both vertebrates and invertebrates. However, the diverse evolutionary paths taken, particularly within the invertebrate taxa, should lead to similarly diverse innate immunity memory processes. Our understanding of innate immune memory in invertebrates primarily comes from studies of the fruit fly Drosophila melanogaster, the generality of which is unclear. Caenorhabditis elegans typically inhabits soil harboring a variety of fatal microbial pathogens; for this invertebrate, the innate immune system and aversive behavior are the major defensive strategies against microbial infection. However, their characteristics of immunological memory remains infantile. Here we discovered an immunological memory that promoted avoidance and suppressed innate immunity during reinfection with bacteria, which we revealed to be specific to the previously exposed pathogens. During this trade-off switch of avoidance and innate immunity, the chemosensory neurons AWB and ADF modulated production of serotonin and dopamine, which in turn decreased expression of the innate immunity-associated genes and led to enhanced avoidance via the downstream insulin-like pathway. Therefore, our current study profiles the immune memories during C. elegans reinfected by pathogenic bacteria and further reveals that the chemosensory neurons, the neurotransmitter(s), and their associated molecular signaling pathways are responsible for a trade-off switch between the two immunological memories.

TNIP1-mediated TNF-α/NF-κB signalling cascade sustains glioma cell proliferation.

As a malignant tumour of the central nervous system, glioma exhibits high incidence and poor prognosis. Although TNIP1 and the TNF-α/NF-κB axis play key roles in immune diseases and inflammatory responses, their relationship and role in glioma remain unknown. Here, we revealed high levels of TNIP1 and TNF-α/NF-κB in glioma tissue. Glioma cell proliferation was activated with TNF-α treatment and showed extreme sensitivity to the TNF receptor antagonist. Furthermore, loss of TNIP1 disbanded the A20 complex responsible for IκB degradation and NF-κB nucleus translocation, and consequently erased TNFα-induced glioma cell proliferation. Thus, our investigation uncovered a vital function of the TNIP1-mediated TNF-α/NF-κB axis in glioma cell proliferation and provides novel insight into glioma pathology and diagnosis.

Diagnostic value of NKG2D promoter methylation in hepatitis B virus-associated hepatocellular carcinoma.

Aim: Natural killer cell receptor group 2D (NKG2D) plays an important role in the immune regulation of tumors. We speculate that DNA methylation are involved in the regulation of NKG2D gene. Methods: We investigated the methylation status of the NKG2D promoter in peripheral blood mononuclear cells of hepatocellular carcinoma (HCC) patients, chronic hepatitis B patients and healthy controls by methylation-specific PCR and the mRNA expression level was examined by real-time quantitative PCR. Results: The methylation frequency of NKG2D promoter in HCC patients was higher than that of chronic hepatitis B patients and healthy controls. NKG2D promoter methylation has a good predictive value for HCC diagnosis. Conclusion: NKG2D promoter methylation can be used as a noninvasive marker for detecting HCC.

Gastrodin protects dopaminergic neurons via insulin-like pathway in a Parkinson's disease model.

BACKGROUND: Recently, the use of traditional Chinese medicine (TCM) has become more generally accepted, including by the Food and Drug Administration. To expand the use of TCM worldwide, it is important to study the molecular mechanisms by which TCM and its active ingredients produce effects. Gastrodin is an active ingredient from Gastrodia elata Blume. It is reported that gastrodin has neuroprotective function in Parkinson's disease. But its mechanisms of neuroprotection remain not clear in PD. Here, we build two C. elegans PD model using 6-OHDA and transgenic animal to observe the changes of PD worms treated with or without gastrodin to confirm the function of gastrodin, then utilize mutant worms to investigate DAF-2/DAF-16 signaling pathway, and finally verify the mechanism of gastrodin in PD. RESULTS: Gastrodin attenuates the accumulation of α-synuclein and the injury of dopaminergic neurons, improves chemotaxis behavior in Parkinson's disease models, then recovers chemotaxis behavior by insulin-like pathway. DAF-2/DAF-16 is required for neuroprotective effect of dopamine neuron in PD. CONCLUSIONS: Our study demonstrated that gastrodin rescued dopaminergic neurons and reduced accumulation of α-synuclein protein, and the activity of gastrodin against Parkinson's disease depended on the insulin-like DAF-2/DAF-16 signaling pathway. Our findings revealed that this insulin-like pathway mediates neuroprotection of gastrodin in a Parkinson's disease model.

Resection of Meningiomas Involving Major Dural Venous Sinuses: Classification, Technique, and Long-Term Results.

OBJECTIVE: Management of meningiomas with major dural venous sinus involvement is challenging. We present our case series and perspective on reconstruction of the sinuses. METHODS: Fifty-five patients underwent operations between 2005 and 2016 and the retrospective data were collected and analyzed. RESULTS: The cohort was younger with a mean of 51.3 years (range, 19-72 years) predominantly involving the superior sagittal sinus (44 patients). Sinus involvement was classified into group 1 (<50% of sinus, n = 28), group 2 (50%-99%, n = 8), and group 3 (total occlusion, n = 19). Venous collateralization was present in 100% of group 2 and 3 and in 36% of group 1 occlusions. Sinus pericranii was seen in 22 patients. Gross total resection was achieved in 87.2%, and sinus reconstruction followed in 38 patients (24 by direct suture and 14 by a patch graft). Pathology showed 36 (65%) World Health Organization grade I, 18 (33%) grade II, and 1 (2%) grade III tumors. During the mean follow-up of 60 months (range, 1-132 months), sinus was patent (74%) or narrowed but patent (24%) in 98%; 2 recurrences (3.6%) were observed (at 24 and 120 months). The mean preoperative/postoperative Karnofsky Performance Status and Kaplan-Meier cumulative overall/recurrence-free survival were 84.2%/88.1% and 90.9%/80.1%, respectively. CONCLUSIONS: These meningiomas present in a younger population, are more likely to be World Health Organization grade II or III, necessitating a more aggressive tumor resection strategy. Aggressive resection coupled with sinus reconstruction results in good long-term surgical outcome and low recurrence rates.

The Signaling Pathway of Caenorhabditis elegans Mediates Chemotaxis Response to the Attractant 2-Heptanone in a Trojan Horse-like Pathogenesis.

The nematode Caenorhabditis elegans exhibits behavioral responses to a wide range of odorants associated with food and pathogens. A previous study described a Trojan Horse-like strategy of pathogenesis whereby the bacterium Bacillus nematocida B16 emits the volatile organic compound 2-heptanone to trap C. elegans for successful infection. Here, we further explored the receptor for 2-heptanone as well as the pathway involved in signal transduction in C. elegans Our experiments showed that 2-heptanone sensing depended on the function of AWC neurons and a GPCR encoded by str-2 Consistent with the above observation, the HEK293 cells expressing STR-2 on their surfaces showed a transient elevation in intracellular Ca2+ levels after 2-heptanone applications. After combining the assays of RNA interference and gene mutants, we also identified the Gα subunits and their downstream components in the olfactory signal cascade that are necessary for responding to 2-heptanone, including Gα subunits of egl-30 and gpa-3, phospholipase C of plc-1and egl-8, and the calcium channel of cmk-1 and cal-1. Our work demonstrates for the first time that an integrated signaling pathway for 2-heptanone response in C. elegans involves recognition by GPCR STR-2, activation by Gα subunits of egl-30/gpa-3 and transfer to the PLC pathway, indicating that a potentially novel olfactory pathway exists in AWC neurons. Meanwhile, since 2-heptanone, a metabolite from the pathogenic bacterium B. nematocida B16, can be sensed by C. elegans and thus strongly attract its host, our current work also suggested coevolution between the pathogenic microorganism and the chemosensory system in C. elegans.

One sided bypass for bilateral Moyamoya disease, a case report and review of the literatures.

BACKGROUND: Moyamoya disease (MMD) is a rare condition, where the most appropriate treatment for it is yet to be determined. Surgery remains an important method of choice although it is considered a form of palliative care. The outcome following surgery is very difficult to judge, and there is no standardised measurement to assess it. It is therefore important to know which approach for such patient is adequate. CLINICAL PRESENTATION: A 21-year-old male patient presented with signs and symptoms of intracranial haemorrhage. Upon investigation, a diagnosis of bilateral MMD was made, and one sided direct bypass surgery was subsequently performed. At 3-year follow-up, there is no evidence of recurrent cerebral vascular event. CONCLUSION: This case provided further evidence that direct bypass surgery is beneficial for patient in terms of blood flow improvement and symptom relieve. Although there is no consensus on whether bilateral surgical intervention is mandatory for patient with bilateral MMD, unilateral bypass might be sufficient enough. Further study is required to evaluate the best approach for such group of patient.