High paternal homocysteine causes ventricular septal defects in mouse offspring.

Maternal hyperhomocysteinemia is widely considered as an independent risk of congenital heart disease (CHD). However, whether high paternal homocysteine causes CHD remains unknown. Here, we showed that increased homocysteine levels of male mice caused decreased sperm count, sperm motility defect and ventricular septal defect of the offspring. Moreover, high levels of paternal homocysteine decrease sperm DNMT3A/3B, accompanied with changes in DNA methylation levels in the promoter regions of CHD-related genes. Folic acid supplement could decrease the occurrence of VSD in high homocysteine male mice. This study reveals that increased paternal homocysteine level increases VSD risk in the offspring, indicating that decreasing paternal homocysteine may be an intervening target of CHD.

Ketogenic diet-produced ß-hydroxybutyric acid accumulates brain GABA and increases GABA/glutamate ratio to inhibit epilepsy.

Ketogenic diet (KD) alleviates refractory epilepsy and reduces seizures in children. However, the metabolic/cell biologic mechanisms by which the KD exerts its antiepileptic efficacy remain elusive. Herein, we report that KD-produced ß-hydroxybutyric acid (BHB) augments brain gamma-aminobutyric acid (GABA) and the GABA/glutamate ratio to inhibit epilepsy. The KD ameliorated pentetrazol-induced epilepsy in mice. Mechanistically, KD-produced BHB, but not other ketone bodies, inhibited HDAC1/HDAC2, increased H3K27 acetylation, and transcriptionally upregulated SIRT4 and glutamate decarboxylase 1 (GAD1). BHB-induced SIRT4 de-carbamylated and inactivated glutamate dehydrogenase to preserve glutamate for GABA synthesis, and GAD1 upregulation increased mouse brain GABA/glutamate ratio to inhibit neuron excitation. BHB administration in mice inhibited epilepsy induced by pentetrazol. BHB-mediated relief of epilepsy required high GABA level and GABA/glutamate ratio. These results identified BHB as the major antiepileptic metabolite of the KD and suggested that BHB may serve as an alternative and less toxic antiepileptic agent than KD.

Crown-ether threaded covalent organic polyrotaxane framework (COPF) towards synergistic crown/Zn2+/photothermal/photodynamic antibacterial and infected wound healing therapy.

Controllable preparation of materials with new structure has always been the top priority of polymer materials science research. Here, the supramolecular binding strategy is adopted to develop covalent organic frameworks (COFs) with novel structures and functions. Based on this, a two-dimensional crown-ether ring threaded covalent organic framework (COF), denoted as Crown-COPF with intrinsic photothermal (PTT) and photodynamic (PDT) therapeutic capacity, was facilely developed using crown-ether threaded rotaxane and porphyrin as building blocks. Crown-COPF with discrete mechanically interlocked blocks in the open pore could be used as a molecular machine, in which crown-ether served as the wheel sliding along the axle under the laser stimulation. As a result, Crown-COPF combining with the bactericidal power of crown ether displayed a significant photothermal and photodynamic antibacterial activity towards both the Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus), far exceeding the traditional Crown-free COF. Noteworthily, the bactericidal performance could be further enhanced via impregnation of Zn2+ ions (Crown-COPF-Zn) flexible coordinated with the multiple coordination sites (crown-ether, bipyridine, and porphyrin), which not only endow the positive charge with the skeleton, enhancing its ability to bind to the bacterial membrane, but also introduce the bactericidal ability of zinc ions. Notably, in vivo experiments on mice with back infections indicates Crown-COPF-Zn with self-adaptive multinuclear zinc center, could effectively promote the repairing of wounds. This study paves a new avenue for the effectively preparation of porous polymers with brand new structure, which provides opportunities for COF and mechanically interlocked polymers (MIPs) research and applications.

Associations of liver function with plasma biomarkers for Alzheimer's Disease.

BACKGROUND: Blood-based biomarkers for Alzheimer's disease (AD) are promising to be used in clinical settings. The liver is an important degradation organ of the body. Whether liver function affects the levels of AD biomarkers needs to be studied. OBJECTIVE: To investigate the associations between liver function and the plasma levels of AD biomarkers. METHODS: We conducted an ADNI cohort-based cross-sectional study. Thirteen liver function markers commonly used in clinical settings were analyzed: total protein (TP), albumin (AL), globulin (GL), AL/GL ratio (A/G), total bilirubin (TB), direct bilirubin (DB), indirect bilirubin (IB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST/ALT ratio, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and γ-glutamyltransferase (GGT). Liquid chromatography-tandem mass spectrometry was used to detect the plasma Aß42 and Aß40 concentrations. Single Molecule array technique was used to measure the plasma p-tau181 and NfL concentrations. We used linear regression models to analyze the associations between liver function markers and the levels of AD plasma biomarkers. RESULTS: ALP was positively associated with the levels of plasma Aß42 (ß = 0.16, P = 0.018) and Aß40 (ß = 0.21, P = 0.004). LDH was positively associated with the levels of plasma p-tau181 (ß = 0.09, P = 0.022). While NfL was correlated with multiple liver function markers, including AL, A/G, ALT, AST/ALT, and LDH. CONCLUSION: Liver function was associated with the plasma levels of AD biomarkers. It needs to consider the potential influence of liver function on the reference ranges and the interpretation of results for AD biomarkers before clinical use.

Heterodimers of Aromadendrane Sesquiterpenoid with Benzoquinone from the Chinese Liverwort Mylia nuda.

Mylnudones A-G (1-7), unprecedented 1,10-seco-aromadendrane-benzoquinone-type heterodimers, and a highly rearranged aromadendrane-type sesquiterpenoid (8), along with four known analogs (9-12), were isolated from the liverwort Mylia nuda. Compounds 1-6 and 7, bearing tricyclo[6.2.1.02,7] undecane and tricyclo[5.3.1.02,6] undecane backbones, likely formed via a Diels-Alder reaction and radical cyclization, respectively. Their structures were determined by spectroscopic analysis, computational calculation, and single-crystal X-ray diffraction analysis. Dimeric compounds displayed cytoprotective effects against glutamic acid-induced neurological deficits.

The preservation of right cingulum fibers in subjective cognitive decline of preclinical phase of Alzheimer's disease.

Introduction: Subjective cognitive decline (SCD) with a positive amyloid burden has been recognized as the earliest clinical symptom of the preclinical phase of Alzheimers disease (AD), providing invaluable opportunities to improve our understanding of the natural history of AD and determine strategies for early therapeutic interventions. Methods: The microstructure of white matter in patients showing SCD in the preclinical phase of AD (SCD of pre-AD) was evaluated using diffusion images, and voxel-wise fractional anisotropy (FA), mean diffusivity (MD), and axial and radial diffusivities were assessed and compared among participant groups. Significant clusters in the tracts were extracted to determine their associations with alterations in the cognitive domains. Results: We found that individuals with SCD of pre-AD may have subclinical episodic memory impairment associated with the global amyloid burden. Meanwhile, we found significantly reduced FA and λ1 in the right cingulum (cingulate and hippocampus) in AD dementia, while significantly increased FA and decreased MD as well as λ23 in the SCD of pre-AD group in comparison with the HC group. Discussion: In conclusion, increased white matter microstructural integrity in the right cingulum (cingulate and hippocampus) may indicate compensation for short-term episodic memory in individuals with SCD of pre-AD in comparison with individuals with AD and healthy elderly individuals.

Identification of novel diagnostic panel for mild cognitive impairment and Alzheimer's disease: findings based on urine proteomics and machine learning.

BACKGROUND: Alzheimer's disease is a prevalent disease with a heavy global burden. Proteomics is the systematic study of proteins and peptides to provide comprehensive descriptions. Aiming to obtain a more accurate and convenient clinical diagnosis, researchers are working for better biomarkers. Urine is more convenient which could reflect the change of disease at an earlier stage. Thus, we conducted a cross-sectional study to investigate novel diagnostic panels. METHODS: We firstly enrolled participants from China-Japan Friendship Hospital from April 2022 to November 2022, collected urine samples, and conducted an LC-MS/MS analysis. In parallel, clinical data were collected, and clinical examinations were performed. After statistical and bioinformatics analyses, significant risk factors and differential urinary proteins were determined. We attempt to investigate diagnostic panels based on machine learning including LASSO and SVM. RESULTS: Fifty-seven AD patients, 43 MCI patients, and 62 CN subjects were enrolled. A total of 3366 proteins were identified, and 608 urine proteins were finally included in the analysis. There were 33 significantly differential proteins between the AD and CN groups and 15 significantly differential proteins between the MCI and CN groups. AD diagnostic panel included DDC, CTSC, EHD4, GSTA3, SLC44A4, GNS, GSTA1, ANXA4, PLD3, CTSH, HP, RPS3, CPVL, age, and APOE ε4 with an AUC of 0.9989 in the training test and 0.8824 in the test set while MCI diagnostic panel included TUBB, SUCLG2, PROCR, TCP1, ACE, FLOT2, EHD4, PROZ, C9, SERPINA3, age, and APOE ε4 with an AUC of 0.9985 in the training test and 0.8143 in the test set. Besides, diagnostic proteins were weakly correlated with cognitive functions. CONCLUSIONS: In conclusion, the procedure is convenient, non-invasive, and useful for diagnosis, which could assist physicians in differentiating AD and MCI from CN.

The silkworm (Bombyx mori) gut microbiota is involved in metabolic detoxification by glucosylation of plant toxins.

Herbivores have evolved the ability to detoxify feed components through different mechanisms. The oligophagous silkworm feeds on Cudrania tricuspidata leaves (CTLs) instead of mulberry leaves for the purpose of producing special, high-quality silk. However, CTL-fed silkworms are found to have smaller bodies, slower growth and lower silk production than those fed mulberry leaves. Here, we show that the high content of prenylated isoflavones (PIFs) that occurred in CTLs is converted into glycosylated derivatives (GPIFs) in silkworm faeces through the silkworm gut microbiota, and this biotransformation is the key process in PIFs detoxification because GPIFs are found to be much less toxic, as revealed both in vitro and in vivo. Additionally, adding Bacillus subtilis as a probiotic to remodel the gut microbiota could beneficially promote silkworm growth and development. Consequently, this study provides meaningful guidance for silk production by improving the adaptability of CTL-fed silkworms.

Depressive symptom trajectories and new-onset arthritis in a middle-aged and elderly Chinese population.

OBJECTIVE: Previous studies reported that depression was associated with a high risk of arthritis. However, the effect of different long-term depressive symptom trajectory patterns on the risk of arthritis has not been evaluated. Our study aimed to explore the association between depressive symptom trajectories and the risk of arthritis. METHODS: A total of 5583 participants from the China Health and Retirement Longitudinal Study from 2011 to 2018 were included in this analysis. Group-based trajectory modeling was used to identify depressive symptom trajectories, and a multivariable competitive Cox regression model was used to examine the association of depressive symptom trajectories with arthritis during follow-up. RESULTS: Five depressive symptom trajectories were identified in our research: stable-high, decreasing, increasing, stable-moderate and stable-low. Compared with participants in the stable-low trajectory group, those in the stable-moderate, increasing, decreasing and stable-high trajectory groups had a higher cumulative risk of arthritis, with HRs (95% CIs) for arthritis of 1.64 (1.30, 2.07), 1.86 (1.30, 2.66), 1.99 (1.41, 2.80) and 2.19 (1.38, 3.48), respectively. Participants with the stable-high symptoms trajectory had the highest cumulative risk of arthritis. There was still a high risk of arthritis, although the depression state was reduced and remained at a level that is generally considered reasonable. CONCLUSIONS: The higher depressive symptoms trajectories were significantly associated with the increased risk of arthritis, and the long-term depressive symptoms trajectories may be a strong predictor of having arthritis.

Global, regional, and national burden of cardiovascular diseases in youths and young adults aged 15-39 years in 204 countries/territories, 1990-2019: a systematic analysis of Global Burden of Disease Study 2019.

BACKGROUND: Understanding the temporal trends in the burden of overall and type-specific cardiovascular diseases (CVDs) in youths and young adults and its attributable risk factors is important for effective and targeted prevention strategies and measures. We aimed to provide a standardized and comprehensive estimation of the prevalence, incidence, disability-adjusted life years (DALY), and mortality rate of CVDs and its associated risk factors in youths and young adults aged 15-39 years at global, regional, and national levels. METHODS: We applied Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2019 analytical tools to calculate the age-standardized incidence, prevalence, DALY, and mortality rate of overall and type-specific CVDs (i.e., rheumatic heart disease, ischemic heart disease, stroke, hypertensive heart disease, non-rheumatic valvular heart disease, cardiomyopathy and myocarditis, atrial fibrillation and flutter, aortic aneurysm, and endocarditis) among youths and young adults aged 15-39 years by age, sex, region, sociodemographic index and across 204 countries/territories from 1990 to 2019, and proportional DALY of CVDs attributable to associated risk factors. RESULTS: The global age-standardized DALY (per 100,000 population) for CVDs in youths and young adults significantly decreased from 1257.51 (95% confidence interval 1257.03, 1257.99) in 1990 to 990.64 (990.28, 990.99) in 2019 with an average annual percent change (AAPC) of - 0.81% (- 1.04%, - 0.58%, P < 0.001), and the age-standardized mortality rate also significantly decreased from 19.83 (19.77, 19.89) to 15.12 (15.08, 15.16) with an AAPC of - 0.93% (- 1.21%, - 0.66%, P < 0.001). However, the global age-standardized incidence rate (per 100,000 population) moderately increased from 126.80 (126.65, 126.95) in 1990 to 129.85 (129.72, 129.98) in 2019 with an AAPC of 0.08% (0.00%, 0.16%, P = 0.040), and the age-standardized prevalence rate significantly increased from 1477.54 (1477.03, 1478.06) to 1645.32 (1644.86, 1645.78) with an AAPC of 0.38% (0.35%, 0.40%, P < 0.001). In terms of type-specific CVDs, the age-standardized incidence and prevalence rate in rheumatic heart disease, prevalence rate in ischemic heart disease, and incidence rate in endocarditis increased from 1990 to 2019 (all P < 0.001). When stratified by sociodemographic index (SDI), the countries/territories with low and low-middle SDI had a higher burden of CVDs than the countries/territories with high and high-middle SDI. Women had a higher prevalence rate of CVDs than men, whereas men had a higher DALY and mortality rate than women. High systolic blood pressure, high body mass index, and low-density lipoprotein cholesterol were the main attributable risk factors for DALY of CVDs for all included countries and territories. Household air pollution from solid fuels was an additional attributable risk factor for DALY of CVDs in low and low-middle SDI countries compared with middle, high-middle, and high SDI countries. Compared with women, DALY for CVDs in men was more likely to be affected by almost all risk factors, especially for smoking. CONCLUSIONS: There is a substantial global burden of CVDs in youths and young adults in 2019. The burden of overall and type-specific CVDs varied by age, sex, SDI, region, and country. CVDs in young people are largely preventable, which deserve more attention in the targeted implementation of effective primary prevention strategies and expansion of young-people's responsive healthcare systems.

Handgrip strength is associated with risks of new-onset stroke and heart disease: results from 3 prospective cohorts.

BACKGROUND: Stroke and heart disease are two major contributors to the global disease burden. We aimed to evaluate and compare the roles of different handgrip strength (HGS) expressions in predicting stroke and heart disease in three nationally representative cohorts. METHODS: This longitudinal study used data from the Health and Retirement Study (HRS), the Survey of Health, Ageing, and Retirement in Europe (SHARE), and the China Health and Retirement Longitudinal Study (CHARLS). The Cox proportional hazard model was applied to analyze the relationship between HGS and stroke and heart disease, and Harrell's C index was used to assess the predictive abilities of different HGS expressions. RESULTS: A total of 4,407 participants suffered from stroke and 9,509 from heart disease during follow-up. Compared with the highest quartile, participants in the lowest quartile of dominant HGS, absolute HGS and relative HGS possessed a significantly higher risk of new-onset stroke in Europe, America, and China (all P < 0.05). After adding HGS to office-based risk factors, there were minimal or no differences in the increases of Harrell's C indexes among three HGS expressions. In contrast, the modest association between HGS and heart disease was only seen in SHARE and HRS, but not in CHARLS. CONCLUSION: Our findings support that HGS can be used as an independent predictor of stroke in middle-aged and older European, American and Chinese populations, and the predictive ability of HGS may not depend on how it is expressed. The relationship between HGS and heart disease calls for further validation.

Effect of renal function on the diagnostic performance of plasma biomarkers for Alzheimer's disease.

Background: Several blood-based biomarkers are promising to be used in the diagnosis of Alzheimer's disease (AD) including Aß42/40, p-tau181, and neurofilament light (NfL). The kidney is associated with the clearance of proteins. It is crucial to evaluate the effect of renal function on the diagnostic performance of these biomarkers before clinical implementation, which is important for the establishment of reference ranges and the interpretation of results. Methods: This study is a cross-sectional analysis based on ADNI cohort. Renal function was determined by the estimated glomerular filtration rate (eGFR). Plasma Aß42/40 was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Plasma p-tau181 and NfL were analyzed by Single Molecule array (Simoa) technique. [18F] florbetapir-PET (Aß-PET) was used as a reference standard to estimate the brain amyloid load. The cutoff of Aß-PET positivity was defined as ≥1.11. Linear regression models were used to investigate the associations of continuous eGFR with each plasma biomarker separately. The diagnostic accuracies of plasma biomarkers for positive brain amyloid across different renal function groups were analyzed by Receiver operating characteristic (ROC) curve. Youden-Index was used to determine the cutoff levels. Results: A total of 645 participants were included in this study. The levels and diagnostic performance of Aß42/40 were not affected by renal function. eGFR was only found negatively associated with p-tau181 levels in Aß-PET negetive sample (ß = -0.09, p = 0.039). eGFR was found negatively associated with NfL levels both in whole sample and Aß-PET stratified groups (ß = -0.27, p < 0.001 in whole sample; ß = -0.28, p = 0.004 in A-; ß = -0.27, p < 0.001 in A+). The diagnostic accuracies of p-tau181 and NfL were not affected by renal function. But the cutoff values of p-tau181 and NfL changed in participants with mild to moderate eGFR decline compared to participants with normal eGFR. Conclusion: Plasma Aß42/40 was a robust biomarker for AD which was not affected by renal function. Plasma p-tau181 and NfL levels were affected by renal function, specific reference values of them should be considered in populations with different renal function stages.

Amino acids downregulate SIRT4 to detoxify ammonia through the urea cycle.

Ammonia production via glutamate dehydrogenase is inhibited by SIRT4, a sirtuin that displays both amidase and non-amidase activities. The processes underlying the regulation of ammonia removal by amino acids remain unclear. Here, we report that SIRT4 acts as a decarbamylase that responds to amino acid sufficiency and regulates ammonia removal. Amino acids promote lysine 307 carbamylation (OTCCP-K307) of ornithine transcarbamylase (OTC), which activates OTC and the urea cycle. Proteomic and interactome screening identified OTC as a substrate of SIRT4. SIRT4 decarbamylates OTCCP-K307 and inactivates OTC in an NAD+-dependent manner. SIRT4 expression was transcriptionally upregulated by the amino acid insufficiency-activated GCN2-eIF2α-ATF4 axis. SIRT4 knockout in cultured cells caused higher OTCCP-K307 levels, activated OTC, elevated urea cycle intermediates and urea production via amino acid catabolism. Sirt4 ablation decreased male mouse blood ammonia levels and ameliorated CCl4-induced hepatic encephalopathy phenotypes. We reveal that SIRT4 safeguards cellular ammonia toxicity during amino acid catabolism.

Liverwort-Derived Metabolites Retard Endophyte Growth and Inspire Antifungal Application.

Liverwort secondary metabolites play an important role in the peaceful relationship between liverwort endophytic fungi and the host. This study identified potential antifungal agents based on interactions between host plants and endophytic fungi. Two endophytic fungi strains and 25 metabolites, including nine new compounds, were isolated from the Chinese liverwort Herbertus herpocladioides. Endophytic fungi were identified using internal transcribed spacer and whole-genome sequencing, and the compound structures were determined using comprehensive spectroscopic analysis coupled with electronic circular dichroism calculations. Among these compounds, compounds 10-13 exhibited potent antifungal activities. Compound 10, the most potent antifungal agent, disrupted fungal mitochondrial respiration by inhibiting the activity of mitochondrial complexes I and IV and resulted in the intracellular ATP content of endophytic fungi being significantly reduced. The in vivo results show that compound 10 protected fruits and animals from infection by phytopathogen Alternaria citriarbusti and human pathogen Candida albicans, respectively.

Highly Accessible Computational Prediction and In Vivo/In Vitro Experimental Validation: Novel Synthetic Phenyl Ketone Derivatives as Promising Agents against NAFLD via Modulating Oxidoreductase Activity.

Nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions with no pharmacological treatment approved. Several highly accessible computational tools were employed to predict the activities of twelve novel compounds prior to actual chemical synthesis. We began our work by designing two or three hydroxyl groups appended to the phenyl ketone core, followed by prediction of drug-likeness and targets. Most predicted targets for each compound overlapped with NAFLD targets (≥80%). Enrichment analysis showed that these compounds might regulate oxidoreductase activity. Then, these compounds were synthesized and confirmed by IR, MS, 1H, and 13C NMR. Their cell viability demonstrated that twelve compounds exhibited appreciable potencies against NAFLD (EC50 values ≤ 13.5 µM). Furthermore, the most potent compound 5f effectively prevented NAFLD progression as evidenced by the change in histological features. 5f significantly reduced total cholesterol and triglyceride levels in vitro/in vivo, and the effects of 5f were significantly stronger than those of the control drug. The proteomic data showed that oxidoreductase activity was the most significantly enriched, and this finding was consistent with docking results. In summary, this validated presynthesis prediction approach was cost-saving and worthy of popularization. The novel synthetic phenyl ketone derivative 5f holds great therapeutic potential by modulating oxidoreductase activity to counter NAFLD.

Urine metabolomics phenotyping and urinary biomarker exploratory in mild cognitive impairment and Alzheimer's disease.

Introduction: Alzheimer's disease is a prevalent disease with a heavy global burden and is suggested to be a metabolic disease in the brain in recent years. The metabolome is considered to be the most promising phenotype which reflects changes in genetic, transcript, and protein profiles as well as environmental effects. Aiming to obtain a comprehensive understanding and convenient diagnosis of MCI and AD from another perspective, researchers are working on AD metabolomics. Urine is more convenient which could reflect the change of disease at an earlier stage. Thus, we conducted a cross-sectional study to investigate novel diagnostic panels. Methods: We first enrolled participants from China-Japan Friendship Hospital from April 2022 to November 2022, collected urine samples and conducted an LC-MS/MS analysis. In parallel, clinical data were collected and clinical examinations were performed. After statistical and bioinformatics analyzes, significant risk factors and differential urinary metabolites were determined. We attempt to investigate diagnostic panels based on machine learning including LASSO and SVM. Results: Fifty-seven AD patients, 43 MCI patients and 62 CN subjects were enrolled. A total of 2,140 metabolites were identified among which 125 significantly differed between the AD and CN groups, including 46 upregulated ones and 79 downregulated ones. In parallel, there were 93 significant differential metabolites between the MCI and CN groups, including 23 upregulated ones and 70 downregulated ones. AD diagnostic panel (30 metabolites+ age + APOE) achieved an AUC of 0.9575 in the test set while MCI diagnostic panel (45 metabolites+ age + APOE) achieved an AUC of 0.7333 in the test set. Atropine, S-Methyl-L-cysteine-S-oxide, D-Mannose 6-phosphate (M6P), Spiculisporic Acid, N-Acetyl-L-methionine, 13,14-dihydro-15-keto-tetranor Prostaglandin D2, Pyridoxal 5'-Phosphate (PLP) and 17(S)-HpDHA were considered valuable for both AD and MCI diagnosis and defined as hub metabolites. Besides, diagnostic metabolites were weakly correlated with cognitive functions. Discussion: In conclusion, the procedure is convenient, non-invasive, and useful for diagnosis, which could assist physicians in differentiating AD and MCI from CN. Atropine, M6P and PLP were evidence-based hub metabolites in AD.

Inhibition of fungal pathogenicity by targeting the H2S-synthesizing enzyme cystathionine ß-synthase.

The global emergence of antifungal resistance threatens the limited arsenal of available treatments and emphasizes the urgent need for alternative antifungal agents. Targeting fungal pathogenic functions is an appealing alternative therapeutic strategy. Here, we show that cystathionine ß-synthase (CBS), compared with cystathionine γ-lyase, is the major enzyme that synthesizes hydrogen sulfide in the pathogenic fungus Candida albicans. Deletion of CBS leads to deficiencies in resistance to oxidative stress, retarded cell growth, defective hyphal growth, and increased ß-glucan exposure, which, together, reduce the pathogenicity of C. albicans. By high-throughput screening, we identified protolichesterinic acid, a natural molecule obtained from a lichen, as an inhibitor of CBS that neutralizes the virulence of C. albicans and exhibits therapeutic efficacy in a murine candidiasis model. These findings support the application of CBS as a potential therapeutic target to fight fungal infections.