Ectopic CD4+ T cells in choroid plexus mediate neuropsychiatric lupus symptoms in mice via interferon-γ induced microglia activation.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a disabling and potentially life-threatening complication of SLE. This study aims to investigate whether ectopic CD4+ T cells in the choroid plexus mediate NPSLE in mice. Intracerebroventricular (ICV) injection of anti-CD4 antibody effectively depleted CP-resident CD4+ T cells and alleviated NPSLE-like symptoms in MRL/lpr mice. Following ICV injection, the majority of isolated lupus CD4+ T cells from donor MRL/lpr mice predominantly stayed in the CP for at least 28 days in recipient C57BL/6 mice, while nearly all isolated CD4+ T cells from MRL/MpJ mice disappeared within 7 days. ICV injection of lupus CD4+ T cells resulted in NPSLE-like symptoms, including impaired behavioral performances, increased microglial activation, and abnormal microstructure changes. Flow cytometry analysis revealed that the majority of isolated lupus CD4+ T cells were positive for IFN-γ. Neutralizing intracerebral IFN-γ alleviated NPSLE-like symptoms in MRL/lpr mice. Moreover, ICV injection of anti-IFN-γ antibody or microglial depletion by PLX3397 benefited most NPSLE-like symptoms in lupus CD4+ T-treated mice, while ICV injection of IFN-γ mimicked most NPSLE-like symptoms. In conclusion, CP-resident lupus CD4+ T cells contribute to NPSLE-like symptoms in mice via Interferon-γ induced microglia activation. Depleting CP-resident lupus CD4+ T cells, interferon-γ, or activated microglia may be potential therapeutic targets for NPSLE.

Pharmacological and Behavioral Interventions for Fatigue in Parkinson's Disease: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: This study aims to evaluate pharmacological and behavioral interventions for the treatment of fatigue in Parkinson's disease (PD) patients. METHODS: We systematically searched PubMed, PsycINFO, Web of Science, EMBASE, CNKI, Wan fang, and VIP up to July 31, 2022. We used Revman 5.3 software for the meta-analysis. The outcomes included Fatigue Severity Scale (FSS) and Parkinson's Fatigue Scale (PFS). The mean difference (MD) and 95% confidence intervals (CI) were collected or calculated. RESULTS: Thirteen randomized controlled trials (RCTs) with a total of 1758 patients were included. The meta-analysis showed that current clinical treatments reduced FSS (MD: -1.60, 95% CI: -3.14 to -0.05) and PFS (MD: -0.61, 95% CI: -1.17 to -0.05) in patients with PD. Subgroup meta-analysis showed that: (1) neither pharmacological interventions nor behavioral interventions reduced FSS in PD patients; (2) dopaminergic drugs dose-dependently significantly reduced the PFS in patients with PD; (3) behavioral interventions have an almost significant effect (MD: -6.69, 95% CI: -13.71 to 0.33, P = 0.06, I2 = 74%) on alleviating PFS in PD patients; (4) vestibular rehabilitation training significantly reduced the PFS in patients with PD. CONCLUSIONS: Current clinical treatments alleviate fatigue in PD patients. Dopaminergic drugs may act a stronger effect than amphetamines. Behavioral interventions, especially vestibular rehabilitation training, may be a promising way for the treatment of fatigue in patients with PD though further evidence is still needed.

Efficacy and safety of granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in COVID-19 patients: a meta-analysis.

OBJECTIVE: This study aims to determine the efficacy and safety of granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in COVID-19 patients. METHODS: We searched Cochrane Library, PubMed, Embase, and ClinicalTrials.gov databases until July 27, 2022. Both randomized control trials (RCTs) and cohort studies were included and analyzed separately. The outcomes included mortality, incidence of invasive mechanical ventilation (IMV), ventilation improvement rate (need oxygen therapy to without oxygen therapy), secondary infection, and adverse events (AEs). The odds ratio (OR) with a 95% confidence interval (CI) was calculated by a random-effects meta-analysis model. RESULTS: Five RCTs and 2 cohort studies with 1726 COVID-19 patients were recruited (n = 866 in the GM-CSF antibody group and n = 891 in the control group). GM-CSF antibodies treatment reduced the incidence of IMV, which was supported by two cohort studies (OR 0.16; 95% CI 0.03, 0.74) and three RCTs (OR 0.62; 95% CI 0.41, 0.94). GM-CSF antibodies resulted in slight but not significant reductions in mortality (based on two cohort studies and five RCTs) and ventilation improvement (based on one cohort study and two RCTs). The sensitive analysis further showed the results of mortality and ventilation improvement rate became statistically significant when one included study was removed. Besides, GM-CSF antibodies did not increase the risks of the second infection (based on one cohort study and five RCTs) and AEs (based on five RCTs). CONCLUSION: GM-CSF antibody treatments may be an efficacious and well-tolerant way for the treatment of COVID-19. Further clinical evidence is still warranted.

Joint fluid interleukin-6 combined with the neutral polymorphonuclear leukocyte ratio (PMN%) as a diagnostic index for chronic periprosthesis infection after arthroplasty.

BACKGROUND: The diagnosis of periprosthetic joint infection (PJI) remains a challenge in clinical practice. Many novel serum and joint fluid biomarkers have important implications for the diagnosis of PJI. The presented study evaluated the value of joint fluid interleukin-6 (IL-6) combined with the neutral polymorphonuclear leukocyte (PMN%) ratio for chronic PJI diagnosis after arthroplasty. MATERIALS AND METHODS: Sixty patients with chronic PJI or aseptic failure who underwent hip or knee revision from January 2018 to January 2020 in our department were included in this retrospective study. According to the 2013 MSIS diagnostic criteria, the 60 patients were divided into a PJI group and a non-PJI group (30 patients per group). We collected the joint fluid before surgery and determined the level of IL-6 and the PMN% by ELISA, and the differences between the two groups were compared. The diagnostic efficacy of joint fluid IL-6 combined with PMN% in chronic PJI was analyzed using a receiver operating characteristic curve (ROC curve). RESULTS: The diagnosis of PJI using joint fluid IL-6 combined with PMN% presented an area under the curve of 0.983, which was more accurate than the areas under the curve for diagnosis using IL-6 and PMN% individually (0.901 and 0.914, respectively). The optimal threshold values for IL-6 and PMN% were 662.50 pg/ml and 51.09%, respectively. Their sensitivity and specificity were 96.67% and 93.33%, respectively. The accuracy of the diagnosis of PJI was 95.00%. CONCLUSIONS: Joint fluid IL-6 combined with PMN% can be used as an auxiliary method to detect chronic infection around the prosthesis after hip/knee arthroplasty. LEVEL OF EVIDENCE: Patients who underwent hip/knee revision at the First Hospital of Chongqing Medical University for periprosthetic infection or aseptic failure of the prosthesis after hip/knee arthroplasty from January 2018 to January 2020 were included. Trial registration This study was approved by the ethics committee of the First Hospital of Chongqing Medical University on September 26, 2018 (local ethics committee number: 20187101) and registered with the China Clinical Trials Registry (registration number: ChiCTR1800020440) with an approval date of December 29, 2018.

Time Course of Metabolic Alterations Associated with the Progression of Systemic Lupus Erythematosus in MRL/lpr Mice Based on GC/MS.

Exploring the dynamic changes of metabolites and metabolic pathways during the development of the disease can help to further understand the etiology and pathogenesis of systemic lupus erythematosus (SLE). In this study, serum metabolomics based on gas chromatography/mass spectrometry (GC/MS) was employed to investigate the metabolic alterations at different stages of SLE using lupus-prone mice (MRL/lpr) of 9, 11, and 13 weeks of age. Multivariate statistical analysis was performed to view the alterations of metabolic profiles between MRL/lpr mice and age-matched C57BL/6 mice, and t-test and fold change criteria were used to identify differential metabolites at each stage. 11 changed metabolites were found in MRL/lpr mice at 9 weeks of age, which were mainly involved in the tricarboxylic acid (TCA) cycle, glycolysis, and butanoate metabolism; with the increase of week age, the TCA cycle was still disturbed, and the biosynthesis of fatty acids was significantly upregulated since 11 weeks of age; in addition, urea, urate, and indole-3-lactate were increased at 13 weeks of age. We found a time course of metabolic alterations in MRL/lpr mice, which may be related to the progression of SLE. These findings could provide a reference for studying the mechanism of SLE and judging the pathological stage and severity of the disease. The MS data have been deposited in Mendeley (https://www.mendeley.com/).

Analysis of brain metabolites by gas chromatography-mass spectrometry reveals the risk-benefit concerns of prednisone in MRL/lpr lupus mice.

OBJECTIVE: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a common cause of disability in systemic lupus erythematosus (SLE). This study aims to investigate the metabolic changes in the hypothalamus and frontal cortex in lupus-prone MRL/lpr mice. METHODS: Metabolic changes were analyzed using gas chromatography-mass spectrometry (GC-MS). RESULTS: According to the principal component analysis (PCA), the metabolic profiles were different between the frontal cortex and hypothalamus, but they were comparable between MRL/lpr and MRL/MpJ mice (16 weeks of age). By OPLS-DA, eight cortical and six hypothalamic differential metabolites were identified in MRL/lpr as compared to MRL/MpJ mice. Among these differential metabolites, we found a decrease of N-acetyl-L-aspartate (NAA, a potential marker of neuronal integrity), an increase of pyruvate and a decrease of glutamate in the frontal cortex but not in the hypothalamus. Prednisone treatment (3 mg/kg from 8 weeks of age) relieved the decrease of NAA but further increased the accumulation of pyruvate in the frontal cortex, additionally affected eight enriched pathways in the hypothalamus, and led to significant imbalances between the excitation and inhibition in both the frontal cortex and hypothalamus. CONCLUSION: These results suggest that the frontal cortex may be more preferentially affected than the hypothalamus in SLE. Prednisone disrupted rather than relieved metabolic abnormalities in the brain, especially in the hypothalamus, indicating that the risk-benefit balance of prednisone for SLE or NPSLE remains to be further evaluated.

Correction to: Oral prednisolone versus non-steroidal anti-inflammatory drugs in the treatment of acute gout: a meta-analysis of randomized controlled trials.

The authors would like to inform you that Jie Yu and Haimei Lu contributed equally to this study and should be considered as co-first authors.

Limited preventive effect of prednisone on neuropsychiatric symptoms in murine systemic lupus erythematosus.

OBJECTIVE: To investigate whether glucocorticoids, the hallmark medication for systemic lupus erythematosus (SLE), could prevent the development of neuropsychiatric SLE (NPSLE). METHODS: The protective effects of prednisone on NPSLE were tested using the open field, object recognition/placement, forced swim, tail suspension, and sucrose preference tests in MRL/lpr mice. Auto-antibody titres and the weight of lymph nodes were also measured. RESULTS: MRL/lpr mice exhibited mild depression at the age of 8 weeks before progressing with spatial cognitive impairment and severe depression-like behaviour at the age of 16 weeks. Treating MRL/lpr mice with prednisone (5 mg/kg) from the age of 8 weeks decreased anti-cardiolipin and anti-N-methyl-D-aspartate (NMDA) receptor antibody titres in the brain, reduced the weight of lymph nodes, and prolonged the floating latency in the forced swim test. However, prednisone (3 or 5 mg/kg) had no preventive effect on the development of spatial cognitive impairment and other depression-like behaviours in MRL/lpr mice. The dose of prednisone had a positive correlation with the floating latency in the forced swim test, while it offered no effects on all other behavioural tests. CONCLUSION: Our results provide evidence that early treatment with prednisone had a limited effect on the development of neuropsychiatric symptoms in MRL/lpr mice. Further work is needed in other models beyond NPSLE in MRL/lpr mice before any definitive conclusions are made on the efficacy of prednisone in human NPSLE.

Oral prednisolone versus non-steroidal anti-inflammatory drugs in the treatment of acute gout: a meta-analysis of randomized controlled trials.

OBJECTIVES: To evaluate the efficacy and safety of oral prednisolone in the treatment of acute gout compared with non-steroidal anti-inflammatory drugs (NSAIDs). METHODS: A comprehensive search of databases in both Chinese and English was performed. Data from the selected studies were extracted and analyzed independently by two authors. RESULTS: Three double-blind, randomized, controlled trials were included in the final analysis, with a total of 584 patients. Regarding the efficacy, oral prednisolone (30-35 mg/day) was comparable with NSAIDs (naproxen at 500 mg/day or indomethacin at 50-100 mg/day) on the pain relief scale, both in activity (difference in means 0.259, 95% CI - 1.532 to 2.050, P = 0.777) and at rest (difference in means - 0.502, 95% CI - 4.961 to 3.956, P = 0.825) during the first 2-6 h. During the following 4 to 6 days, prednisolone acted with comparable efficacy either in activity (difference in means - 0.552, 95% CI - 1.364 to 0.260, P = 0.183) or at rest (difference in means - 0.164, 95% CI - 0.463 to 0.134, P = 0.281). Regarding safety, prednisolone did not increase the total adverse events (AEs) (risk ratios [RR] 0.765, 95% CI 0.473 to 1.238, P = 0.275) and reduced the withdrawal rate because of the AEs (RR 0.127, 95% CI 0.021-0.763, P = 0.024). Prednisolone decreased the risks of several AEs (including indigestion: RR 0.544, 95% CI 0.311-0.952, P = 0.033; nausea: RR 0.296, 95% CI 0.136-0.647, P = 0.002; and vomiting: RR 0.155, 95% CI 0.033-0.722, P = 0.018) but increased the risk of skin rashes (RR 4.049, 95% CI 1.241-13.158, P = 0.021). CONCLUSIONS: Oral prednisolone may be of similar efficacy and a slightly safer strategy for treatment of active, acute gout compared with NSAIDs. Further clinical studies are still warranted to investigate its long-term efficacy and safety.

Low-frequency stimulation of the external globus palladium produces anti-epileptogenic and anti-ictogenic actions in rats.

AIM: To investigate the anti-epileptic effects of deep brain stimulation targeting the external globus palladium (GPe) in rats. METHODS: For inducing amygdala kindling and deep brain stimulation, bipolar stainless-steel electrodes were implanted in SD rats into right basolateral amygdala and right GPe, respectively. The effects of deep brain stimulation were evaluated in the amygdala kindling model, maximal electroshock model (MES) and pentylenetetrazole (PTZ) model. Moreover, the background EEGs in the amygdala and GPe were recorded. RESULTS: Low-frequency stimulation (0.1 ms, 1 Hz, 15 min) at the GPe slowed the progression of seizure stages and shortened the after-discharge duration (ADD) during kindling acquisition. Furthermore, low-frequency stimulation significantly decreased the incidence of generalized seizures, suppressed the average stage, and shortened the cumulative ADD and generalized seizure duration in fully kindled rats. In addition, low-frequency stimulation significantly suppressed the average stage of MES-induced seizures and increased the latency to generalized seizures in the PTZ model. High-frequency stimulation (0.1 ms, 130 Hz, 5 min) at the GPe had no anti-epileptic effect and even aggravated epileptogenesis induced by amygdala kindling. EEG analysis showed that low-frequency stimulation at the GPe reversed the increase in delta power, whereas high-frequency stimulation at the GPe had no such effect. CONCLUSION: Low-frequency stimulation, but not high-frequency stimulation, at the GPe exerts therapeutic effect on temporal lobe epilepsy and tonic-colonic generalized seizures, which may be due to interference with delta rhythms. The results suggest that modulation of GPe activity using low-frequency stimulation or drugs may be a promising epilepsy treatment.

[Antiepileptic effect of low frequency stimulation in kindling rats].

OBJECTIVE: To investigate the antiepileptic effects of various stimulation modes of low-frequency stimulation(LFS) on the kindling rats. METHODS: Stimulating electrodes were implanted in the amygdala and current with constant intensity was applied to evoke kindling-induced seizures. The antiepileptic effect of LFS by open loop stimulation(before kindling), closed loop stimulation(immediately after kindling) and different forms of closed loop stimulation(whole stage after kindling and early stage after kindling) were investigated in amygdala kindled rats. RESULTS: The closed loop LFS of whole stage after kindling can significantly inhibited seizure stages(P<0.01) and reduced afterdischarge duration(P<0.05). The closed loop LFS of early stage after kindling can significantly suppress the seizure stages, mainly in stages 0-3(P<0.05 or P<0.01). The open loop low-frequency stimulation did not inhibit the seizure stage during kindling acquisition(P>0.05). CONCLUSION: The antiepileptic effect of low frequency stimulation may have a mode-dependent effect. It may be helpful for the deep brain stimulation as a promising approach applied to clinical antiepileptic therapy in the future.

[Antiepileptic effect of low-frequency electrical stimulation is waveform-dependent in hippocampal kindled mice].

OBJECTIVE: To investigate whether the waveform of electrical stimulus affects the antiepileptic effect of focal low-frequency stimulation (LFS). METHODS: The antiepileptic effects of the LFS in sine, monophase square and biphase square waves were investigated in hippocampal kindled mice, respectively. RESULTS: Compared to the control group, sine wave focal LFS (30 s) inhibited seizure stages (2.85 ± 0.27 vs 4.75 ± 0.12, P<0.05), lowered incidence of generalized seizures (53.6% vs 96.5%, P<0.01) and reduced afterdischarge durations [(16.2 2 ± 1.69)s vs (30.29 ± 1.12)s, P<0.01] in hippocampal kindled mice, while monophase or biphase square wave LFS (30 s) showed no antiepileptic effect. Monophase square LFS (15 min) inhibited seizure stages (3.58 ± 0.16, P<0.05) and incidence of generalized seizures (66.7%,P<0.01), but had weaker inhibitory effect on hippocampal afterdischarge durations than sine wave LFS. In addition, pre-treatment and 3 s but not 10 s post-treatment with sine wave LFS resulted in suppression of evoked seizures (P<0.05 or P<0.01). CONCLUSION: The antiepileptic effect of LFS is dependent on its waveform. Sine wave may be optimal for closed-loop LFS treatment of epilepsy.

Discrimination between 5-hydroxymethylcytosine and 5-methylcytosine in DNA by selective chemical labeling.

Detection of DNA damage has been greatly improved following the development of equipment and techniques, however, discrimination between 5-hydroxymethylcytosine (5-hmC) and 5-methylcytosine (5-mC) is still a thorny problem. In the present study, an approach to oxidize and selective label (Ox-Labeling) 5-hmC in native DNA has been reported, which conveniently distinguishes 5-hmC from 5-mC using simple and effective processes.

Angiopep-conjugated electro-responsive hydrogel nanoparticles: therapeutic potential for epilepsy.

A safe and effective therapy for epilepsy requires a drug delivery system that can penetrate the blood-brain barrier and subsequently release antiepileptic drugs rapidly to suppress neuronal discharges in a timely manner. We have developed electro-responsive hydrogel nanoparticles (ERHNPs) modified with angiopep-2 (ANG) to facilitate the delivery of the antiepileptic drug phenytoin sodium. The resulting ANG-ERHNPs had an average diameter of (102.3±16.8) nm and were electro-sensitive with regard to particle size and drug release in vitro. ANG-ERHNPs have the characteristics of penetrate the BBB easily, resulting in a higher distribution in the central system. The improved antiepileptic effects were investigated with the amygdala kindling model. The results demonstrate that the ANG-ERHNPs were able to transport antiepileptic drugs into the brain and release them under electroencephalograph epileptiform abnormalities to greatly improve the therapeutic index of existing drugs in clinical use.

Age-Dependent Phenomena of 6-Hz Corneal Kindling Model in Mice.

Although numerous studies have acknowledged disparities in epilepsy-related disease processes between young and aged animals, little is known about how epilepsy changes from young adulthood to middle age. This study investigates the impact of aging on 6-Hz corneal kindling in young-adult mice and middle-aged mice. We found that the kindling acquisition of the 6-Hz corneal kindling model was delayed in middle-aged mice when compared to young-adult mice. While the seizure stage and incidence of generalized seizures (GS) were similar between the two age groups, the duration of GS in the kindled middle-aged mice was shorter than that in the kindled young-adult mice. Besides, all kindled mice, regardless of age, were resistant to phenytoin sodium (PHT), valproate sodium (VPA), and lamotrigine (LGT), whereas middle-aged mice exhibited higher levetiracetam (LEV) resistance compared to young-adult mice. Both age groups of kindled mice displayed hyperactivity and impaired memory, which are common behavioral characteristics associated with epilepsy. Furthermore, middle-aged mice displayed more pronounced astrogliosis in the hippocampus. Additionally, the expression of Brain-Derived Neurotrophic Factor (BDNF) was lower in middle-aged mice than in young-adult mice prior to kindling. These data demonstrate that both the acquisition and expression of 6-Hz corneal kindling are attenuated in middle-aged mice, while hippocampal astrogliosis and pharmacological resistance are more pronounced in this age group. These results underscore the importance of considering age-related factors when utilizing the 6-Hz corneal kindling model in mice of varying age groups.

Brain Pathology in COVID-19: Clinical Manifestations and Potential Mechanisms.

Neurological manifestations of coronavirus disease 2019 (COVID-19) are less noticeable than the respiratory symptoms, but they may be associated with disability and mortality in COVID-19. Even though Omicron caused less severe disease than Delta, the incidence of neurological manifestations is similar. More than 30% of patients experienced "brain fog", delirium, stroke, and cognitive impairment, and over half of these patients presented abnormal neuroimaging outcomes. In this review, we summarize current advances in the clinical findings of neurological manifestations in COVID-19 patients and compare them with those in patients with influenza infection. We also illustrate the structure and cellular invasion mechanisms of SARS-CoV-2 and describe the pathway for central SARS-CoV-2 invasion. In addition, we discuss direct damage and other pathological conditions caused by SARS-CoV-2, such as an aberrant interferon response, cytokine storm, lymphopenia, and hypercoagulation, to provide treatment ideas. This review may offer new insights into preventing or treating brain damage in COVID-19.

Locus coeruleus tyrosine hydroxylase positive neurons mediated the peripheral and central therapeutic effects of transcutaneous auricular vagus nerve stimulation (taVNS) in MRL/lpr mice.

OBJECTIVE: This study aims to investigate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on the development of systemic lupus erythematosus (SLE) in MRL/lpr mice. METHODS: MRL/lpr mice were treated with taVNS for ten weeks. Locus coeruleus (LC) tyrosine hydroxylase positive (TH+) neurons were selectively lesioned by stereotactic injection of 6-hydroxydopamine (6-OHDA) or selectively activated by chemogenetic methods. Sympathetic denervation was conducted by intraperitoneal injection of 6-OHDA. RESULTS: TaVNS activated the TH + neurons in LC. TaVNS produced central therapeutic effects by reducing the number of hippocampal microglia, and increasing the number of surviving LC TH+ neurons in MRL/lpr mice. TaVNS also retarded the development of lymphadenectasis and splenomegaly, decreased the proportion of double-negative T (DNT) cells, and alleviated nephritis in MRL/lpr mice. The lesion of LC TH+ neurons eliminated both these central and peripheral therapeutic effects of taVNS, while chemogenetic activation of LC TH+ neurons mimicked most central and peripheral protective effects of taVNS in MRL/lpr mice. Furthermore, taVNS regulated the autonomic nervous system in MRL/lpr mice. CONCLUSION: This study provides direct evidence that taVNS can retard the development of peripheral and central symptoms of SLE, which is mediated by the LC TH+ neurons.

Leptin attenuates the osteogenic induction potential of BMP9 by increasing ß-catenin malonylation modification via Sirt5 down-regulation.

BMP9 has demonstrated significant osteogenic potential. In this study, we investigated the effect of Leptin on BMP9-induced osteogenic differentiation. Firstly, we found Leptin was decreased during BMP9-induced osteogenic differentiation and serum Leptin concentrations were increased in the ovariectomized (OVX) rats. Both in vitro and in vivo, exogenous expression of Leptin inhibited the process of osteogenic differentiation, whereas silencing Leptin enhanced. Exogenous Leptin could increase the malonylation of ß-catenin. However, BMP9 could increase the level of Sirt5 and subsequently decrease the malonylation of ß-catenin; the BMP9-induced osteogenic differentiation was inhibited by silencing Sirt5. These data suggested that Leptin can inhibit the BMP9-induced osteogenic differentiation, which may be mediated through reducing the activity of Wnt/ß-catenin signalling via down-regulating Sirt5 to increase the malonylation level of ß-catenin partly.

Prospects and challenges for the application of tissue engineering technologies in the treatment of bone infections.

Osteomyelitis is a devastating disease caused by microbial infection in deep bone tissue. Its high recurrence rate and impaired restoration of bone deficiencies are major challenges in treatment. Microbes have evolved numerous mechanisms to effectively evade host intrinsic and adaptive immune attacks to persistently localize in the host, such as drug-resistant bacteria, biofilms, persister cells, intracellular bacteria, and small colony variants (SCVs). Moreover, microbial-mediated dysregulation of the bone immune microenvironment impedes the bone regeneration process, leading to impaired bone defect repair. Despite advances in surgical strategies and drug applications for the treatment of bone infections within the last decade, challenges remain in clinical management. The development and application of tissue engineering materials have provided new strategies for the treatment of bone infections, but a comprehensive review of their research progress is lacking. This review discusses the critical pathogenic mechanisms of microbes in the skeletal system and their immunomodulatory effects on bone regeneration, and highlights the prospects and challenges for the application of tissue engineering technologies in the treatment of bone infections. It will inform the development and translation of antimicrobial and bone repair tissue engineering materials for the management of bone infections.

Lanthionine synthetase C-like protein 1 interacts with and inhibits cystathionine ß-synthase: a target for neuronal antioxidant defense.

The finding that eukaryotic lanthionine synthetase C-like protein 1 (LanCL1) is a glutathione-binding protein prompted us to investigate the potential relationship between LanCL1 and cystathionine ß-synthase (CBS). CBS is a trans-sulfuration enzyme critical for the reduced glutathione (GSH) synthesis and GSH-dependent defense against oxidative stress. In this study we found that LanCL1 bound to CBS in mouse cortex and HEK293 cells. Mapping studies revealed that the binding region in LanCL1 spans amino acids 158-169, and that in CBS contains N-terminal and C-terminal regulatory domains. Recombinant His-LanCL1 directly bound endogenous CBS from mouse cortical lysates and inhibited its activity. Overexpression of LanCL1 inhibited CBS activity in HEK293 cells. CBS activity is reported to be regulated by oxidative stress. Here we found that oxidative stress induced by H(2)O(2) or glutamate lowered the GSH/GSSG ratio, dissociated LanCL1 from CBS, and elevated CBS activity in primary rat cortical neurons. Decreasing the GSH/GSSG ratio by adding GSSG to cellular extracts also dissociated LanCL1 from CBS. Either lentiviral knockdown of LanCL1 or specific disruption of the LanCL1-CBS interaction using the peptide Tat-LanCL1(153-173) released CBS activity in neurons but occluded CBS activation in response to oxidative stress, indicating the major contribution of the LanCL1-CBS interaction to the regulation of CBS activity. Furthermore, LanCL1 knockdown or Tat-LanCL1(153-173) treatment reduced H(2)O(2) or glutamate-induced neuronal damage. This study implies potential therapeutic value in targeting the LanCL1-CBS interaction for neuronal oxidative stress-related diseases.