Neflamapimod

1Centre for Human Drug Research (CHDR), Leiden, Netherlands 2Leiden University Medical Center, Leiden, Netherlands 3Leiden Academic Centre for Drug Research, Universiteit Leiden, Leiden, Netherlands 4Poolbeg Pharma Limited, London, United Kingdom 5Department of Experimental and Translational Medicine, University College London Research, London, United Kingdom Background and aim: POLB 001 is an oral p38 mitogen-activated protein kinase (MAPK) inhibitor in development for the prevention of cancer immunotherapy-induced cytokine release syndrome (CRS). It has previously been shown to be well tolerated and capable of decreasing ex vivo lipopolysaccharide (LPS)-induced tumour necrosis factor (TNF) secretion in a phase 1 first-in-human trial. This study aimed to evaluate the anti-inflammatory effects of POLB 001 following in vivo LPS administration in healthy volunteers. Methods: Participants received POLB 001 at doses of 30, 70, or 150 mg, or placebo, twice daily for seven consecutive days and were challenged locally with intradermal (ID) LPS on day 4 and systemically with intravenous (IV) LPS on day 6. Following ID LPS administration, skin perfusion and erythema were measured, and skin suction blisters were created to collect blister fluid containing infiltrating immune cells and extracellular fluid. Following IV LPS administration, circulating cytokine levels, leukocyte counts, leukocyte p38 MAPK phosphorylation levels, and vital signs were measured. Results: POLB 001 was well tolerated. It reduced the ID LPS-driven immune cell attraction and cytokine responses measured in blister fluid. The suppression of immune cell recruitment was most pronounced in neutrophils (72.4%–81.5%, p = 0.0091), classical monocytes (68.4%–73.6%, p = 0.0036), CD3+ T cells (56.4%–65.9%, p = 0.0047), and myeloid dendritic cells (59%–64.4%, p = 0.0174). The suppression of cytokine responses was most pronounced for TNF (35.3%–65.1%, p = 0.0099). Overall, POLB 001 did not substantially modulate the intradermal LPS-driven increase in local erythema and perfusion. POLB 001 significantly reduced the IV LPS-driven increase in interleukin (IL)-6, IL-8, and TNF (37.7%–80.7%, all p < 0.0003), p38 MAPK phosphorylation levels in target cells (16.7%–60.9%, all p < 0.0001), and heart rate increase (4–9.3 bpm, p < 0.0001). Conclusion: POLB 001 was safe and well-tolerated. Pharmacodynamic findings confirm that POLB 001 inhibits LPS-induced local and systemic inflammation in vivo through inhibition of p38 MAPK. Clinical trial registration: https://onderzoekmetmensen.nl/en/trial/51741, identifier NL81214.056.22. Mitogen-activated protein kinases (MAPKs) are components of signalling cascades that initiate inflammatory cellular responses when activated by extracellular stimuli (1). Several subgroups of MAPKs have been identified, including p38 MAPK. Triggers for p38 MAPK activation include lipopolysaccharide (LPS) and other bacterial products, ultraviolet irradiation, hypoxia, and inflammatory cytokines (1, 2). Activation of the p38 signalling pathway plays an important role in the production of various inflammatory mediators, such as tumour necrosis factor (TNF) (3, 4). Inhibition of the p38 MAPK signalling pathway results in reduced production of these inflammatory mediators. POLB 001 (previously known as Org 48775-0) is a potent and highly selective p38α/β MAPK inhibitor in development for cancer immunotherapy-induced cytokine release syndrome (CRS). POLB 001 has shown efficacy in several pharmacological disease models, including humanised mouse models of CRS (5). It was well tolerated under both fed and fasted conditions in a previous phase 1 trial in healthy male volunteers. In that first-in-human single ascending dose (SAD) study and a multiple ascending dosing (MAD) study, POLB 001 was administered as a single dose up to 600 mg and as multiple doses twice daily for six consecutive days, up to 150 mg. Using peripheral whole blood samples from treated participants, POLB 001 was shown to effectively decrease LPS-induced TNF release (6). While previous results demonstrate that POLB 001 decreases LPS-induced TNF release from circulating leukocytes ex vivo, the effects of POLB 001 on in vivo inflammatory responses were unknown. Ex vivo refers to the evaluation of drug activity in a test tube, with the immune trigger added to the biospecimen obtained from drug-exposed participants. In contrast, in vivo refers to the evaluation of drug activity in humans, where drug-treated participants were exposed to the immune trigger. The aim of this phase 1 study was to determine the inhibitory effects of POLB 001 on the inflammatory response following local and systemic inflammation in healthy volunteers, upon intradermal (ID) and intravenous (IV) LPS administration. A multimodal pharmacodynamic evaluation approach was employed, comprising clinical endpoints, imaging-based endpoints, local tissue response endpoints, and blood-based endpoints. This was a randomised, double-blind, placebo-controlled, parallel-group, MAD study in healthy volunteers. The study was executed at the Centre for Human Drug Research, the Netherlands, between August 2022 and December 2022. It adhered to ethical principles derived from international guidelines, including the Declaration of Helsinki, as well as all applicable ICH, GCP, and Dutch Medical Research Involving Human Subjects Act guidelines. The study protocol was registered in the EudraCT database (number 2022-001458-48). The protocol (registered at Toetsingonline, number NL81214.056.22) was approved by a medical ethics committee (Stichting Beoordeling Ethiek Biomedisch Onderzoek, Assen, the Netherlands) prior to the start of the clinical phase. All participants provided written informed consent before any study-related activities were performed. The study aimed to recruit 36 healthy volunteers. Volunteers were eligible if they were men, had Fitzpatrick skin type I–III, and were aged between 18 and 55 years. Male volunteers were excluded if any of the following criteria applied: previous participation in a systemic (IV or inhaled) LPS challenge study within a year before the first study day, a current or recurrent clinically significant skin condition at the intradermal LPS target areas (including tattoos), or a known immunodeficiency. Participants received oral doses of POLB 001 (30 mg—low dose, 70 mg—intermediate dose, 150 mg—high dose) or a matching placebo twice daily for seven consecutive days (days 1 to 7) (Figure 1). Participants were scheduled to take the study medication either at the study site or at home. Drug intake at home was monitored using an electronic Patient Reported Outcomes (ePRO) application. All participants received the ID challenge on day 4 and the IV LPS challenge on day 6 upon admission to the clinical unit. Safety monitoring was performed throughout the study course for all participants. Blood samples for PK serum analysis were collected predose and repeatedly on days 1, 4, and 6, and were analysed at the Ardena Bioanalytical Laboratory (Assen, the Netherlands). Figure 1. Overview of the study design. POLB 001 or a matching placebo was administered twice daily for seven consecutive days. On day 4, participants received four intradermal injections of LPS. The local response was evaluated at specified timepoints by using different imaging techniques and skin blister fluid analysis. On day 6, participants received a single dose of intravenous LPS, with pre- and posthydration. Endpoints included different blood assessments and vital signs. The asterisk indicates PK on day 1 only for the highest dose group. PK, pharmacokinetics; LPS, lipopolysaccharide; MSD, Meso Scale Discovery; CRP, C-reactive protein. Created with Biorender.com. Both the study medication and LPS (for both ID and IV administration) were formulated by the pharmacy at the Leiden University Medical Centre, Leiden, the Netherlands. POLB 001 was administered as an oral suspension of 30, 70, or 150 mg POLB 001 powder in 20 mL SyrSpend® Cherry SF PH4 Vehicle. For each dose level, a matching placebo was prepared. Participants were instructed to fast for 8 h prior to every morning dose and for 1 h prior to each evening dose. Purified LPS, prepared from Escherichia coli O113:H10:K negative (US Standard Reference Endotoxin), was used as a challenge agent. The LPS batch was manufactured in the United States (USA) by List Biological Laboratories (Campbell, California). Each participant received four ID LPS injections on the volar forearms, each consisting of 5 ng LPS in 0.05 mL of 0.9% sodium chloride (NaCl) solution (a total of 20 ng per participant). A different LPS injection site was used for each blister timepoint. Participants also received an IV infusion of glucose (2.5% w/v) and NaCl (0.45% w/v) solution, starting 2 h prior to LPS administration and continuing for 6 h afterward. IV LPS consisted of 1 ng/kg LPS in 10 mL of 0.9% NaCl solution, administered as a 2-min infusion (7). For the evaluation of ex vivo pharmacodynamic effects, LPS was added as an immune trigger to test tubes containing whole blood obtained from drug-exposed participants. Baseline whole blood samples were collected on days 1 and 6 prior to the IV LPS challenge. Blood was diluted (1:1) with RPMI 1640 supplemented with 25 mM HEPES and l-glutamine, and stimulated with LPS (2.5 ng/mL). Samples were incubated for 24 h at 37 °C (5% CO2), and the supernatant was stored. Secreted interleukin (IL)-1β, IL-6, IL-8, and TNF were analysed from the supernatant using a Meso Scale Discovery (MSD) multiplex immunoassay (Ardena, Assen, the Netherlands). The skin was imaged pre-LPS and at 3, 9, and 24 h afterward. Perfusion was evaluated using laser speckle contrast imaging (LSCI) (PeriCam PSI System, Perimed Jäfälla, Sweden), and erythema was assessed with multispectral imaging using Antera 3D (Miravex, Dublin, Ireland). The performance and analysis of these noninvasive measurements were standardised for all participants. After skin imaging was performed, 10 mm suction blisters were generated over the LPS-injected skin areas, as previously reported (8). Three suction blisters were created per participant: at 3, 9, and 24 h after the ID LPS injections. Blister fluid was collected in a plate containing 50 μL of 3% cold sodium citrate (Sigma‐Aldrich, St. Louis, MO, USA) in PBS (Gibco, Thermo Fischer Scientific, Waltham, MA, USA). Levels of IL-1β, IL-6, IL-8, and TNF in blister fluid were analysed by MSD (Ardena, Assen, the Netherlands). Leukocytes in blister fluid were immunophenotyped by flow cytometry (for antibodies, see Supplementary Table S1). The gating strategy for blister leukocytes was selected using a peripheral blood sample collected before LPS administration (see Supplementary Figure S1). Flow cytometry measurements were done in the MACSQuant Analyzer 16 (Miltenyi Biotec GmbH, Bergisch Gladbach, Germany), and data were analysed with Flowlogic 8.7 (Inivai Technologies, Mentone, VIC, Australia) at the Centre for Human Drug Research (CHDR) laboratory (Leiden, the Netherlands). Blood samples for p38 MAPK phosphorylation analyses were collected prior to IV LPS administration and at 1, 1.5, and 2 h afterward. Within 1 h of collection, sodium heparinised whole blood was fixed, and red blood cell lysis was performed simultaneously. Cells were permeabilised and stained with anti-CD14 (REA 599) and p38 MAPK antibody (RUO 36/p38 [pT180/pY182]) in the same test tube (see Supplementary Table S1). Live cells were gated from the forward scatter (FSC) vs. side scatter (SSC) leukocyte population, and doublets were removed by gating for FSC-Height (FSC-H) vs. FSC-Area (FSC-A) (Supplementary Figure S2). Monocytes were identified as CD14+. Phosphorylation levels of p38 MAPK in whole blood and in CD14+ cells were expressed as a percentage and median fluorescence intensity (MFI). Analysis was performed at the laboratory of CHDR (Leiden, the Netherlands). Vital sign measurements, including heart rate, blood pressure, and temperature, were measured to evaluate the clinical response to IV LPS. Blood was collected from each participant prior to IV LPS administration and 1–4 h (every hour), 6 h, and 9 h after IV LPS administration for analysis of circulating cytokine levels by MSD: IL-1β, IL-6, IL-8, IL-10, and TNF (Ardena, Assen, the Netherlands). Blood samples for leukocyte differential analysis were collected prior to the IV LPS administration and at 3, 6, and 24 h after LPS administration. Blood samples for C-reactive protein (CRP) analysis were collected prior to the IV LPS challenge and 6, 9, and 24 h after administration. All blood samples were analysed at the laboratory of the Leiden University Medical Center (“Klinische chemie en laboratoriumgeneeskunde” LUMC, Leiden, the Netherlands). A sample size of nine per treatment group was deemed sufficient based on historical data (8–10). This sample size provides at least 80% power to detect a 50% decrease in LPS-induced systemic and dermal responses using a two-sided significance level of 0.05. Repeatedly measured data were analysed with a mixed model analysis of covariance (ANCOVA) with treatment, time, and treatment-by-time as fixed factors, subject as a random factor, and the (average) baseline measurement as a covariate. Treatment effects were calculated for each parameter over the time period from baseline up to 24 h, except for p38 MAPK phosphorylation (up to 2 h postdose), ex vivo analysis (baseline day 1 vs. day 6 pre-IV LPS), and circulating cytokines (up to 9 h postdose). The following comparisons were calculated for both the ID and IV LPS challenges (analysed separately): POLB 001 at 30 mg vs. pooled placebo, POLB 001 at 70 mg vs. pooled placebo, and POLB 001 at 150 mg vs. pooled placebo. Comparisons were reported with estimated differences, 95% confidence intervals (CI), and p-values. All calculations were performed using SAS for Windows V9.4 (SAS Institute Inc., Cary, NC, USA). Sixty-three participants were screened for this study. Of these, 41 participants, including reserve participants, were enrolled. Thirty-six participants were treated in three cohorts of 12 participants each (nine active vs. three placebo). All 36 participants were men, and 94.4% were White. The mean ± SD age was 28.6 years ± 10.1 years. Further baseline characteristics are presented in Table 1. Table 1. Baseline demographic characteristics. Administration of POLB 001 for seven consecutive days was well tolerated. No severe adverse events (SAEs) occurred following dosing. No meaningful relationships between POLB 001 dose and the incidence of adverse events (AEs) were observed. No clinically relevant changes in ECG parameters, blood chemistry, or haematology—apart from CRP and leukocyte differential levels described as PD endpoints and an increase in liver enzymes in one participant—were observed. A full list of AEs can be found in Supplementary Table S2. Headache was the most commonly reported AE overall and in the POLB 001 treatment groups. Dizziness, fatigue, and chills were additional commonly reported AEs in all treatment groups. Only three participants who received POLB 001 reported events considered probably related to the study drug. Most AEs were possibly or unrelated to POLB 001 and could be related to the LPS challenges. POLB 001 showed dose-proportional PK for Cmax and exposure over 12 h (AUC12 h), in line with the previous study (6). LPS-induced IL-1β, IL-6, IL-8, and TNF release ex vivo was decreased by POLB 001 in the day 6 samples compared to baseline. Percentages of inhibition by POLB 001 ranged from 38.8% to 42.2% for IL-1β, 32.1% to 52.2% for IL-6, 52.1% to 54.7% for IL-8, and 53% to 59.8% for TNF (Supplementary Figure S3). After administration of ID LPS, a gradual increase in skin erythema and perfusion was observed up to 24 h (Figure 2). POLB 001 at 30 mg slightly but significantly decreased LPS-driven erythema compared to placebo (change: − 0.6782 Antera® skin colour a* units [redness; p < 0.05]). However, the POLB 001 at 70 and 150 mg dose groups showed no significant effect compared to placebo (change: − 0.5495 and 0.0068 Antera® skin colour a* units with p = 0.1040 and p = 0.9831, respectively). Consistent with this, POLB 001 did not significantly reduce the LPS-driven increase in skin perfusion compared to placebo. Figure 2. Quantification of the inflammatory skin response following the intradermal LPS challenge by (A) multispectral imaging (erythema) and (B) laser speckle contrast imaging (LSCI; perfusion). In (A), POLB 001–30 mg vs. placebo showed p < 0.05, whereas other contrasts showed p > 0.05. In (B), POLB 001 vs. placebo, all p > 0.05. Data are expressed as means with SD. AU, arbitrary units; ID, intradermal; LPS, lipopolysaccharide. In the absence of POLB 001, ID LPS administration led to an increase in neutrophils and classical monocytes, peaking at 9 h, and an increase in myeloid dendritic cells (mDCs), plasmacytoid DCs (pDCs), CD3+ T cells, CD4+ T cells, CD8+ T cells, nonclassical monocytes, intermediate monocytes, B cells, natural killer (NK) cells, and total immune cells, peaking at 24 h in blister fluid (Figure 3, Supplementary Figure S4). For cytokines, a rapid response of IL-8 and TNF was observed, peaking at 3 h, whereas a more delayed response was observed for IL-1β and IL-6, peaking at 9 h (Figure 4). Figure 3. Overview of skin blister fluid analysis by flow cytometry following intradermal LPS administration: (A) CD3+ T cells, (B) CD4+ T cells, (C) CD8+ T cells, (D) mDCs, (E) classical monocytes, and (F) neutrophils. In (A, B), POLB 001 vs. placebo, all p < 0.01. In (C), POLB at 30 mg vs. placebo showed p > 0.05, whereas POLB 001 at 70 and 150 mg vs. placebo showed p < 0.01. In (D), POLB 001 vs. placebo, all p < 0.05. In (E), POLB 001 vs. placebo, all p < 0.01. In (F), POLB 001 vs. placebo, all p < 0.05. Data are expressed as means with SD. ID, intradermal; LPS, lipopolysaccharide; mDCs, myeloid dendritic cells; SD, standard deviation. Figure 4. Overview of cytokine responses in skin blister fluid following intradermal LPS administration: (A) IL-1β response, (B) TNF response, (C) IL-8 response, and (D) IL-6 response. In (A), POLB 150 mg vs. placebo showed p < 0.02, whereas other contrasts showed p > 0.05. In (B), POLB 150 mg vs. placebo showed p < 0.02, whereas other contrasts showed p > 0.05. In (C), POLB 001 vs. placebo, all p > 0.05. In (D), due to too many values above the ULOQ, the requirement for analysis was not met. Data are expressed as means with SD. ID, intradermal; LPS, lipopolysaccharide; TNF, tumour necrosis factor; IL, interleukin. Treatment with POLB 001 resulted in a decrease in the number of CD3+ T cells, CD4+ T cells, mDCs, classical monocytes, neutrophils, and total immune cells in blister fluid compared with placebo treatment (Figures 3A, B, D–F, Supplementary Figure S4A). This inhibition was dose-dependent for CD3+ T cells, classical monocytes, and total immune cells, with percentages of suppression ranging from 56.4% to 65.9% (all dose groups p < 0.01 vs. placebo) for CD3+ T cells, 68.4% to 73.6% (all dose groups p < 0.01 vs. placebo) for classical monocytes, and 65.5% to 70.9% (all dose groups p < 0.01 vs. placebo) for total immune cells. For mDCs, CD4+ T cells, and neutrophils, percentages of inhibition compared with placebo were comparable across the three dose levels: 59.0% to 64.4% for mDCs (all dose groups p < 0.05 vs. placebo), 62.8% to 66.2% for CD4+ T cells (all dose groups p < 0.01 vs. placebo), and 72.4% to 81.5% for neutrophils (all dose groups p < 0.05 vs. placebo). Additionally, CD8+ T cells and NK cells were reduced by POLB 001 treatment (Figure 3C, Supplementary Figure S4B), with significant inhibition observed for POLB 001 at 70 and 150 mg compared to placebo (64.1% and 66.6% for CD8+ T cells, 61.9% and 63.0% for NK cells, respectively; all dose groups p < 0.01 vs. placebo). For pDCs, nonclassical monocytes, intermediate monocytes, and B cells, there were too many zero values to allow formal analysis, mainly due to (i) a biologically delayed response to ID LPS by particular cell types, (ii) overall low cell counts, and/or (iii) substantially decreased infiltration induced by POLB 001. However, graphical presentations of nonclassical monocytes, intermediate monocytes, and B cells showed an apparent inhibitory effect of POLB 001 compared to placebo, which appeared to be dose-dependent for nonclassical and intermediate monocytes (Supplementary Figures S4C–E). Graphical presentation of pDCs also showed an apparent inhibitory effect with the two highest dose groups (POLB 001 at 70 and 150 mg) at 24 h compared to the placebo group (Supplementary Figure S4F). POLB 001 at 150 mg significantly decreased LPS-driven IL-1β (47.3%, p < 0.02 vs. placebo) and TNF (65.1%, p < 0.001 vs. placebo) responses in blister fluid compared to placebo (Figures 4A, B). No significant effect of POLB 001 compared to placebo was observed for IL-8 (Figure 4C). For IL-6, the requirements for analysis were not met due to too many values above the upper limit of quantification (ULOQ), mostly in the placebo group (Figure 4D). IV LPS administration resulted in the phosphorylation of p38 MAPK in whole blood and CD14+ monocytes, peaking at 1 h in the placebo group (Figure 5 for CD14+ monocytes; whole blood data not shown). Figure 5. Overview of p38 MAPK phosphorylation in CD14+ monocytes expressed as (A) MFI and (B) percentage. In (A), POLB 001 vs. placebo, all p < 0.02. In (B), POLB 001 vs. placebo, all p < 0.05. Data are expressed as means with SD. IV, intravenous; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MFI, mean fluorescence intensity. The level of p38 MAPK phosphorylation in whole blood upon IV LPS challenge was significantly lower in all participants receiving POLB 001, with an inhibition range of 16.7%–28.1% (all dose groups p < 0.01 vs. placebo), although no clear dose response was observed. LPS-induced p38 MAPK phosphorylation in CD14+ monocytes was significantly and dose-dependently decreased by POLB 001, with an inhibition range of 32.0%–60.9% (all dose groups p < 0.02 vs. placebo) compared to the placebo group. Heart rate (HR) increased in all participants as expected following IV LPS, peaking at 3–4 h post-LPS (Figure 6A). The increase in HR was 4.0–9.3 beats per minute (bpm) lower in participants receiving POLB 001 compared to placebo (p < 0.05 for POLB 001 at 30 mg vs. placebo and p < 0.001 for the two highest dose groups vs. placebo). Maximal inhibition was reached for POLB 001 at 70 mg. An increase in body temperature following IV LPS was also observed in all participants (Figure 6B), whereas minimal mean changes in blood pressure were noted (Figures 6C, D). POLB 001 had no statistically significant effect on LPS-driven changes in body temperature or blood pressure. Figure 6. Overview of vital sign measurements during the IV LPS challenge: (A) heart rate, (B) temperature, (C) systolic blood pressure, and (D) diastolic blood pressure. In (A), POLB 001 vs. placebo, all p < 0.05. In (B–D), POLB 001 vs. placebo, all p > 0.05. Data are expressed as means with SD. IV, intravenous; LPS, lipopolysaccharide; bpm, beats per minute; °C, degrees Celsius. In the placebo group, IV LPS caused a rapid increase in IL-6, IL-8, TNF, IL-10, and IL-1β in plasma, peaking 1–4 h after administration (Figures 7A–E). An increase in CRP levels was also observed, peaking at 24 h (Figure 7F). Figure 7. Overview of the cytokine and CRP response in plasma during the IV LPS challenge: (A) IL-6, (B) IL-8, (C) TNF, (D) IL-10, (E) IL-1β, and (F) CRP. In (A–C), POLB 001 vs. placebo, all p < 0.05. In (D), POLB 001 at 30 mg vs. placebo showed p > 0.05, whereas POLB 001 at 70 and 150 mg vs. placebo showed p < 0.001. In (E), due to levels below the LLOQ, the requirements for analysis were not met. In (F), POLB 001–30 at mg vs. placebo showed p > 0.05, whereas POLB 001 at 70 and 150 mg vs. placebo showed p < 0.05. Data are expressed as means with SD. IV, intravenous; LPS, lipopolysaccharide; TNF, tumour necrosis factor; IL, interleukin; CRP, C-reactive protein. Treatment with POLB 001 resulted in a significant, dose-dependent reduction in the LPS-driven IL-6 response, with an inhibition range of 37.7%–63.5% compared with placebo (all dose groups p < 0.05 vs. placebo). A significant reduction in the LPS-driven increase in IL-8 and TNF in plasma was observed in all POLB 001 treatment groups compared with the placebo group (all dose groups p < 0.05 vs. placebo). Maximal inhibition appeared to be reached at a dose of 70 mg, with 80.7% for IL-8 and 73.5% for TNF. For IL-10, a significant inhibition was observed for POLB 001 at 70 mg (62.4%) and 150 mg (62.7%) compared with placebo (both p < 0.001 vs. placebo). IL-1β levels in plasma were below the LLOQ, and the data distribution was not normal or log-normal; therefore, the requirements for analysis were not met. POLB 001 treatment dose-dependently decreased the LPS-driven CRP response, reaching statistical significance for the intermediate dose group, with a decrease of 33.1%, and for the highest dose group, with a decrease of 33.3%, compared with the placebo group (p < 0.05 vs. placebo). Administration of IV LPS resulted in a transient increase in neutrophils and a biphasic response in monocytes (an initial decrease at 3 h followed by an increase at 6 h), as observed in placebo participants (Supplementary Figure S5). Moreover, a mild decrease in lymphocytes, eosinophils, and basophils was observed following IV LPS administration (data not shown). The LPS-driven drop in monocytes was suppressed by POLB 001 in all treatment groups compared to the placebo group (30.9%–52.4%, all dose groups p < 0.05 vs. placebo). This effect was not dose-dependent. Neutrophils following IV LPS administration were significantly higher in the intermediate POLB 001 dose group compared to the placebo group (22.5%, p < 0.05). For eosinophils, basophils, and lymphocytes, no significant effect of POLB 001 compared with placebo was observed. The main goal of this randomised controlled trial was to evaluate the effect of POLB 001 on local and systemic inflammatory responses following in vivo LPS administration in healthy volunteers. In addition, the safety, tolerability, and PK of POLB 001 were assessed. The doses of POLB 001 administered in this study matched those tested in the previous MAD study (30, 70, and 150 mg twice daily). POLB 001 was well tolerated, and no treatment-related SAEs or death occurred. The safety profile observed in this study was similar to that reported in the phase 1 study (6), with headache, chills, and dizziness being the most commonly reported AEs. No trends in AEs were observed for POLB 001. As other p38 MAPK inhibitors have been associated with liver enzyme elevations, special attention was paid to increases in liver enzymes, particularly Alanine aminotransferase (ALAT). One participant who received the highest dose of POLB 001 had out-of-range ALAT levels, which resolved by day 21. POLB 001 decreased ex vivo TNF secretion, consistent with previously published results (6). Blood samples for ex vivo analysis in this study were collected at baseline and on day 6, before administration of the next POLB 001 dose. Compared to the same timepoint (before the next dose was taken) in the previous study, the percentages of inhibition were similar (± 50%–60%). Administration of ID and IV LPS in vivo resulted in consistent, well-detectable inflammatory responses, as expected and in line with previous studies (7, 8, 10, 11). POLB 001 had no meaningful effects on skin erythema or local perfusion after ID LPS administration. However, POLB 001 significantly decreased the attraction of CD3+ T cells, classical monocytes, mDCs, T-helper cells, and neutrophils in blister fluid at all dose levels tested. Local LPS-induced increases in IL-1β and TNF were suppressed by the highest dose of POLB 001. Furthermore, the effect of POLB 001 on systemic inflammatory responses was evaluated using an IV LPS challenge. LPS-driven p38 MAPK phosphorylation in CD14+ monocytes was lower in all POLB 001 treatment groups compared with the placebo group, showing a clear dose-dependent effect. Additionally, POLB 001 treatment resulted in lower levels of circulating cytokines (IL-6, IL-8, IL-10, and TNF) and reduced CRP levels following the IV LPS challenge. The p38 MAPK inhibitors RWJ-67657 and BIRB 796 BS were evaluated in healthy volunteers following an IV LPS dose of 4 ng/kg (1, 12–14). Consistent with our study, both inhibitors suppressed the LPS-induced increase of TNF, IL-6, and IL-8. In addition, both reduced the LPS-induced increase in temperature, and RWJ-67657 also reduced the LPS-induced increase in blood pressure and modulated leukocyte functions. Greater fluctuations in vital signs were observed in these studies compared with our study, which can be attributed to the fourfold higher LPS dose. PF-03715455, PH-797804, and AZD7624 were also shown to inhibit plasma cytokines and neutrophilic airway inflammation following an inhaled LPS challenge in healthy volunteers (15, 16). Over 20 other p38 MAPK inhibitors have been developed and evaluated in clinical trials across different patient populations. Several have shown (early) evidence of clinical utility, including neflamapimod, pexmetinib, and PH-797804. Neflamapimod demonstrated multiple positive effects in patients with mild Alzheimer’s disease (AD) and in patients with dementia with Lewy bodies and will be further investigated in phase 2b clinical trials for both indications (17, 18). In combination with nivolumab and/or ipilimumab, pexmetinib elicited disease control in a number of PD-(L)1-refractory patients with advanced solid tumours in a phase 1b study (19). PH-797804 demonstrated improvements in lung function and dyspnoea in a phase II study in patients with moderate to severe chronic obstructive pulmonary disease (COPD) (20). Other p38 MAPK inhibitors, such as dilmapimod, ralimetinib, losmapimod, BMS-582949, VX-702, pamapimod, and LY3007113, were evaluated in patients at risk for acute respiratory distress syndrome (ARDS), patients with neuropathic pain, (advanced) cancer, arterial inflammation, or rheumatoid arthritis (RA), but were less successful, or their clinical development was not progressed (21–33). POLB 001 is in clinical development for the prevention of cancer-immunotherapy-induced CRS. CRS is a common adverse event following CAR T-cell therapies and bispecific antibody therapies. It is characterised by fever, tachypnoea, headache, tachycardia, hypotension, rash, and/or hypoxia caused by the release of cytokines. CRS can progress rapidly, with potentially life-threatening effects, and requires close observation, management, and early intervention. The significant risk of CRS is one of several systemic barriers to wider access to CAR T-cell and T-cell-engaging bispecific antibodies, increasing the cost of treatment and limiting access by requiring a period of inpatient care or close monitoring following treatment. Existing treatment options have been investigated in a prophylactic setting but are less effective at preventing grade ≥ 2 CRS, which requires prompt intervention. In conclusion, POLB 001 was shown to be safe and effective in decreasing local and systemic LPS-induced inflammation in healthy male volunteers. Moreover, this study provides a solid basis for continuing investigations of POLB 001 in patients with inflammatory conditions. Raw data from the current study are available from the corresponding author upon reasonable request. The studies involving humans were approved by Stichting Beoordeling Ethiek Biomedisch Onderzoek, Assen, the Netherlands. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Dd: Writing – original draft. MJ: Writing – original draft. DP: Writing – review & editing. Lv: Writing – review & editing. EK: Writing – review & editing. MO: Writing – review & editing. JS: Writing – review & editing. PM: Writing – review & editing. LT: Writing – review & editing. AB: Writing – review & editing. LM: Writing – review & editing. KM: Writing – review & editing. MS: Writing – review & editing. DG: Writing – review & editing. NK: Writing – review & editing. MM: Writing – original draft. The author(s) declared that financial support was received for this work and/or its publication. This study was funded by Poolbeg Pharma Limited. POLB 001 was provided by Poolbeg Pharma limited. Authors JS, PM, LT, AB, LM, KM, and MS were employed by company Poolbeg Pharma Limited. DG received funds for scientific advice by Poolbeg Pharma Limited. The remaining author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author MM declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. The author(s) declared that generative AI was not used in the creation of this manuscript. Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2025.1684307/full#supplementary-material Supplementary Figure 1 | Gating strategy of immunophenotyping of blister cells. Expression of cell counts of the different cell subsets present in blister cell fluid are defined in a gating strategy for a whole blood sample (Bsgating). Events were gated in FSC vs. SSC dot plot and debris were excluded. Cells were gated on FSC-Area (A) vs. FSC-Height (H) dot plot to eliminate doublets. To define cell populations, first, live (PI-) CD45+ cells are gated. From the leukocyte gate, T cells are identified as CD3+ (total), and further subdivided into CD4+ (T helper, Th) and CD8+ (T cytotoxic, Tc). Next, total HLA-DR+ cells are gated. From HLA-DR+ gating, B cells are CD19+. From the CD19- downstream gate monocyte subsets are further characterised as: CD14+CD16- (classical), CD14+CD16+ (intermediate) and CD14-CD16+ (non-classical). From the HLA-DR+, CD14- CD16- cells, dendritic cells are defined as CD11c+ for myeloid DCs (mDCs) and CD123+ for plasmacytoid DCs (pDCs). Neutrophils are identified as SSChi, CD16+, CD66b+. Natural killer (NK) cells are identified from total leukocytes as CD56+. FSC, forward scatter; SSC, side scatter. Supplementary Figure 2 | Gating strategy for determining phosphorylation levels of p38 MAPK in ex-vivo LPS challenged whole blood. Events were gated in FSC vs. SSC dot plot and debris were excluded. Cells were gated on FSC-Area (A) vs. FSC-Height (H) dot plot to eliminate doublets. To define cell populations, first, live cells (DAPI, VioBlue -) are gated. From the leukocyte gate, monocytes are identified as CD14+. Phosphorylation levels of p38 MAPK in all cells - whole blood (live cell gating) and monocytes (CD14+) are expressed as percentage (%) and median fluorescence intensity (MFI) of p38 MAPK (PE). Supplementary Figure 3 | Ex vivo cytokine release measured in Day 6 samples compared to baseline for all treatment groups: (A) IL-1β, (B) IL-6, (C) IL-8, and (D) TNF. TNF, tumour necrosis factor; IL, interleukin. Supplementary Figure 4 | Overview of skin blister fluid analysis by flow cytometry following intradermal LPS administration: (A) Total immune cells, (B) NK cells, (C) non-classical monocytes, (D) intermediate monocytes, (E) B cells, and (F) pDCs. Data are expressed as means with SD. ID, intradermal; LPS, lipopolysaccharide; NK, natural killer; pDCs, plasmacytoid dendritic cells. Supplementary Figure 5 | Circulating leukocyte subset levels during the IV LPS challenge: (A) neutrophils and (B) monocytes. Data are expressed as means with SD. IV, intravenous; LPS, lipopolysaccharide. Supplementary Table 1 | Antibodies used for immunophenotyping of blister cells and to measure phosphorylation levels of p38 MAPK. Supplementary Table 2 | Treatment-emergent adverse events by preferred term by treatment group (including adverse events reported during the intradermal and intravenous LPS challenge). 1. Branger J, van den Blink B, Weijer S, Madwed J, Bos CL, Gupta A, et al. 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(2018) 36:629–37. doi: 10.1007/s10637-017-0532-2 PubMed Abstract | Crossref Full Text | Google Scholar Keywords: Cytokine release syndrome (CRS), in vivo, inflammation, LPS, p38 MAPK Citation: de Bruin DT, Jansen MAA, Pereira DR, van Schijndel L, Klaassen ES, Otto ME, Skillington J, Maguire P, Tremble L, Bell A, Maher L, Mihara K, Sumeray M, Gilroy DW, Klarenbeek NB and Moerland M (2026) POLB 001, a p38 MAPK inhibitor, decreases local and systemic inflammatory responses following in vivo LPS administration in healthy volunteers: a randomised, double-blind, placebo-controlled study. Front. Immunol. 16:1684307. doi: 10.3389/fimmu.2025.1684307 Received: 12 August 2025; Accepted: 30 December 2025; Revised: 15 December 2025;Published: 23 January 2026. Edited by: Reviewed by: Copyright © 2026 de Bruin, Jansen, Pereira, van Schijndel, Klaassen, Otto, Skillington, Maguire, Tremble, Bell, Maher, Mihara, Sumeray, Gilroy, Klarenbeek and Moerland. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Matthijs Moerland, mmoerland@chdr.nl

如果没有对研究结果进行彻底的分析和讨论，对未来病患的治疗也没有产生积极影响，那单纯的文献积累也没有任何意义。 ————Nikolaus L Renner《AO创伤骨科治疗关键点——从失败中学习》 📅 每周推送日程表 周一｜椎间盘 · 脊柱侧弯 · Piezo · Spp1 周二｜疼痛 · 电生理 · 脊髓电刺激 · 肠道菌群 周三｜脊髓损伤 · 脂代谢 周四｜骨坏死 · 骨缺损修复 · 骨质疏松 周五｜关节炎 · 软骨退变 周六｜生物医学工程（超声 · 3D打印） 周日｜Journal Club · 读刊笔记 本文由AI生成，请务必自主阅读信源进行理性判断。 foam cell OR foamy macrophage OR lipid droplets**Influence of PLIN5 and lipid composition on lipid droplet contact sites with other organelles • 中文标题：PLIN5和脂质组成对脂滴与其他细胞器接触位点的影响 • 作者：Mahsa Mohammadian, Shima Asfia, Ralf Seemann • 期刊名称：Biochem Biophys Rep • 影响因子：2.2 • 期刊分区：2区 • 论文总结：该研究探讨了脂滴蛋白PLIN5以及脂质组成在调节脂滴与其它细胞器之间膜接触位点中的作用。研究表明，PLIN5不仅影响脂滴的形成和稳定性，还通过调控脂滴表面的脂质成分，进而影响其与其他细胞器（如内质网、线粒体等）的相互作用。这一发现揭示了PLIN5在细胞脂质代谢和膜动力学中的关键角色，为理解脂滴相关代谢疾病提供了新的分子机制。 • DOI链接：http://dx.doi.org/10.1016/j.bbrep.2025.102402Targeting lipogenesis promotes the synergistic effect of the selective HDAC6 inhibitor ITF3756 with bortezomib in colon cancer cells • 中文标题：靶向脂肪生成促进选择性HDAC6抑制剂ITF3756与硼替佐米在结肠癌细胞中的协同作用 • 作者：Marzia Franzò, Chiara Zichittella, …, Sonia Emanuele • 期刊名称：Front Pharmacol • 影响因子：4.8 • 期刊分区：2区 • 论文总结：该研究探讨了选择性HDAC6抑制剂ITF3756与蛋白酶体抑制剂硼替佐米（BTZ）联用在结肠癌细胞中的抗肿瘤效果。研究表明，ITF3756可降低HCT116和HT29细胞活力并促进脂肪生成。当与BTZ联合使用时，在亚毒性剂量下表现出协同促凋亡效应，同时激活mTOR、SREBP和PPARγ通路，增强脂质合成。进一步发现，脂肪生成是癌细胞的一种防御机制，使用DGAT-1/2抑制剂或沉默SREBP-1可阻断脂质生成并显著增强药物组合的疗效，尤其是在HCT116细胞中。研究提示，靶向抑制脂质代谢可作为提升HDAC6抑制剂联合治疗效果的有效策略。 • DOI链接：http://dx.doi.org/10.3389/fphar.2025.1706770TMEM106A mediates atherosclerosis progression through macrophage-centered immune responses and chemokine signaling • 中文标题：TMEM106A通过以巨噬细胞为中心的免疫反应和趋化因子信号通路介导动脉粥样硬化进展 • 作者：Menglong Gao, Xingbang Liu, …, Zhenhua Li • 期刊名称：Front Immunol • 影响因子：5.9 • 期刊分区：2区 • 论文总结：该研究聚焦于跨膜蛋白TMEM106A在动脉粥样硬化（AS）中的作用。通过分析多个公共转录组数据集，发现TMEM106A在AS样本中显著上调，并具有良好的诊断效能（AUC为0.80-0.95）。单细胞RNA测序显示其主要富集于巨噬细胞中。功能研究表明，TMEM106A促进巨噬细胞浸润、泡沫细胞形成、氧化应激和炎症反应，并通过调控趋化因子信号通路中的PLCB2发挥作用；沉默TMEM106A可缓解这些促动脉粥样硬化效应。体内实验（ApoE-/-小鼠模型）和体外实验（RAW264.7细胞系）均验证了其在AS进展中的关键角色。结果表明，TMEM106A可能是AS的一个潜在生物标志物和治疗靶点。 • DOI链接：http://dx.doi.org/10.3389/fimmu.2025.1681645Genistein Ameliorates Rifampicin-Undermined Hepatic Cholesterol Efflux via the CH25H-LXRα-ABCA Pathway • 中文标题：金雀异黄素通过CH25H-LXRα-ABCA通路改善利福平损害的肝脏胆固醇外排 • 作者：Wei Jiang, Ding Zhang, …, Decheng Wang • 期刊名称：J Agric Food Chem • 影响因子：6.2 • 期刊分区：2区 • 论文总结：该研究揭示了抗结核药物利福平（RFP）导致肝损伤的机制，即通过抑制CH25H-LXRα-ABCA信号轴减少肝脏胆固醇外排，从而引发脂质沉积和脂肪变性。研究发现，植物来源的异黄酮类化合物金雀异黄素（GEN）能够上调CH25H表达，恢复胆固醇外排功能，显著缓解RFP引起的肝毒性。此外，分子对接和细胞热迁移实验表明，RFP可直接结合并降低CH25H蛋白的稳定性，而GEN能逆转这一作用。本研究为临床上减轻RFP长期使用所致肝损伤提供了潜在治疗策略。 • DOI链接：http://dx.doi.org/10.1021/acs.jafc.5c08641Nanometer-Precision Tracking of Adipocyte Dynamics via Single Lipid Droplet Whispering-Gallery Optical Resonances • 中文标题：通过单个脂滴 whispering-gallery 光学共振实现脂肪细胞动态的纳米级精度追踪 • 作者：Rok Podlipec, Ana Krišelj, …, Matjaž Humar • 期刊名称：ACS Sens • 影响因子：9.1 • 期刊分区：2区 • 论文总结：本文介绍了一种基于脂滴（LDs）内 whispering-gallery 模式（WGM）光学共振的新型生物光子学技术，用于在活体原代脂肪细胞中实现纳米级精度的实时动态监测。研究利用连续波激光在低于生物损伤阈值的功率下激发LDs中的WGM共振，实现了对脂滴尺寸变化和形变的分钟级高时空分辨率观测，远超传统显微镜的极限。该方法能够解析脂肪细胞间的异质性、监测对forskolin和异丙肾上腺素的脂解反应，并在常规检测手段之前识别细胞活力下降的早期迹象。这项概念验证研究表明，LDs内的WGM共振可作为研究单细胞代谢的强大平台，为肥胖及相关代谢疾病在细胞和组织层面的高通量分析奠定了基础。 • DOI链接：http://dx.doi.org/10.1021/acssensors.5c03272Kinetically Controlled Self-Assembly of a Lipophilic Fluorophore with Phenylalanine-Based Diamides in Artificial Lipid Droplets • 中文标题：基于苯丙氨酸二酰胺的疏水性荧光团在人工脂滴中的动力学控制自组装 • 作者：Miku Naruse, Soichiro Ogi, …, Shigehiro Yamaguchi • 期刊名称：Small • 影响因子：12.1 • 期刊分区：2区 • 论文总结：该研究属于化学生物学与纳米材料领域，亮点在于设计了一种带有苯丙氨酸衍生二酰胺单元的疏水性供体-受体型荧光分子，实现了在中性脂质三油酸甘油酯（模拟脂滴环境）中的可控超分子聚合。通过引入成核种子策略，成功加速了分子从动力学捕获的单体状态向纤维状聚集体的转变，并利用荧光成像证明可在人工脂滴中调控聚集体的尺寸。这一方法为在细胞脂滴内调控小分子自组装及功能提供了新思路。 • DOI链接：http://dx.doi.org/10.1002/smll.202513411Novel dual-responsive near-infrared fluorescent bio-probe for visualizing lipid droplet accumulation in living cell and non-alcoholic fatty liver mouse models • 中文标题：一种新型双响应近红外荧光生物探针，用于可视化活细胞和非酒精性脂肪肝小鼠模型中的脂滴积累 • 作者：Ya-Tong Liu, Yu-Yang Wang, …, Zhiyong Xing • 期刊名称：Spectrochim Acta A Mol Biomol Spectrosc • 影响因子：4.3 • 期刊分区：2区 • 论文总结：本文介绍了一种新型双响应近红外荧光生物探针，用于在活细胞和非酒精性脂肪肝（NAFLD）小鼠模型中实时可视化脂滴（lipid droplet, LD）的积累。该探针具有良好的选择性和灵敏度，能够在近红外区域发出荧光，有利于深层组织成像并减少背景干扰。研究验证了其在细胞水平和动物模型中的高效成像能力，为脂代谢相关疾病的机制研究和药物开发提供了有力工具。亮点包括双响应机制设计、近红外发射特性以及在NAFLD模型中的成功应用。 • DOI链接：http://dx.doi.org/10.1016/j.saa.2025.127388A non-ionic phenothiazine-derived type I photosensitizer. • 中文标题：一种非离子型吩噻嗪衍生物I型光敏剂 • 作者：Zhe Liu, Na Li, …, Jianliang Shen • 期刊名称：Spectrochim Acta A Mol Biomol Spectrosc • 影响因子：4.6 • 期刊分区：2区 • 论文总结：该研究报道了一种基于非离子型吩噻嗪（PTZ）的I型光敏剂PTZ-1，其在500 nm光照下能高效生成羟基自由基（•OH）和超氧阴离子（O₂•⁻），几乎不产生单线态氧，表现出典型的I型光动力行为。该分子具有小的S₁-Tₙ能隙和强自旋轨道耦合，有利于快速系间窜越和活性氧（ROS）生成。PTZ-1对4T1癌细胞表现出高光毒性（IC50 = 0.63 μM）且暗毒性低，并在低氧条件（2% O₂）下仍保持强效，显示出低氧依赖性。共聚焦成像表明其靶向脂滴，并在光照后引发大量ROS产生，进而通过凋亡途径诱导癌细胞死亡，未观察到铁死亡。该工作展示了PTZ-1在脂滴靶向、缺氧耐受的光动力癌症治疗中的潜力。 • DOI链接：http://dx.doi.org/10.1016/j.saa.2025.127387Tumor-secreted factors induce aberrant accumulation of vitamin A-enriched lipid droplets in the liver. • 中文标题：肿瘤分泌因子诱导肝脏中富含维生素A的脂滴异常积聚 • 作者：Xiangjie Huang, Wenyu Zhou, …, Hyeon Lee • 期刊名称：Commun Biol • 影响因子：5.1 • 期刊分区：2区 • 论文总结：本研究利用高光谱受激拉曼散射（hSRS）显微镜技术，发现远处肿瘤可通过分泌因子引发肝脏中富含维生素A的脂滴异常积聚，表现为不饱和度升高和维生素A酯代谢异常。研究进一步证实，抑制肿瘤的分泌途径可逆转这些代谢改变，并鉴定出肿瘤来源细胞外囊泡中的FABP5蛋白为关键调控因子。该成果揭示了癌症作为一种系统性疾病，可通过系统性脂质代谢重塑和维生素A失调促进转移进展和影响治疗反应的新机制，为癌症的全身性代谢干预提供了潜在靶点。 • DOI链接：http://dx.doi.org/10.1038/s42003-025-09404-xFABP4-mediated lipid droplet accumulation drives epithelial-mesenchymal transition and aggravates alveolar epithelial barrier disruption. • 中文标题：FABP4介导的脂滴积累驱动上皮-间质转化，并加剧肺泡上皮屏障破坏。 • 作者：Zihao Shen, Yuanpu Qi, …, Peng Lu • 期刊名称：Clin Transl Med • 影响因子：6.8 • 期刊分区：2区 • 论文总结：该研究聚焦于体外循环（CPB）后常见的急性呼吸窘迫综合征（ARDS），探讨脂肪酸结合蛋白4（FABP4）在肺缺血/再灌注损伤（LIRI）中的作用。研究发现，LIRI可诱导肺泡上皮细胞自分泌FABP4信号，进而通过激活p38 MAPK-ULK1通路抑制脂质自噬，导致脂滴（LDs）异常积累。这种脂质代谢重编程促进了上皮-间质转化（EMT）并破坏肺泡上皮屏障（AEB）完整性。靶向FABP4或抑制脂滴积聚可有效缓解EMT和屏障损伤，提示其作为治疗CPB相关ARDS的潜在策略。 • DOI链接：https://doi.org/10.1002/ctm2.70563Uncovering the Bidirectional Molecular Pathway: How Shugan Wendan Decoction Treats Concurrent Depression and Atherosclerosis. • 中文标题：揭示双向分子通路：疏肝温胆汤如何治疗并发抑郁症和动脉粥样硬化 • 作者：Peiying Huang, Weihang Peng, …, Bojun Chen • 期刊名称：J Ethnopharmacol • 影响因子：5.4 • 期刊分区：2区 • 论文总结：本研究探讨了舒肝温胆汤（SGWDD）在治疗抑郁症与动脉粥样硬化共病中的作用机制。通过慢性不可预测轻度应激（CUMS）联合高脂饮食（HFD）动物模型及THP-1泡沫细胞模型，发现CASP1和MMP9是连接两种疾病的双向调控核心。研究表明，抑郁症可通过“脂质和动脉粥样硬化通路”加剧动脉粥样硬化进展，而动脉粥样硬化则通过扰乱“色氨酸代谢通路”增加抑郁易感性。SGWDD能同时改善两种病症，其机制在于抑制CASP1和MMP9的表达，进而调节下游炎症因子（如IL-1β、IL-18）和代谢酶（如IDO、CYP7A1），具有多靶点协同治疗潜力。 • DOI链接：https://doi.org/10.1016/j.jep.2025.121096Drug Development. • 中文标题：药物研发 • 作者：Jasmine Phenix, Sarah Zünd, …, Lisa Munter • 期刊名称：Alzheimers Dement • 影响因子：11.1 • 期刊分区：2区 • 论文总结：该研究聚焦于阿尔茨海默病（AD）相关的星形胶质细胞中脂滴（LD）的形成机制。研究发现，携带ApoE ε4基因型的星形胶质细胞比ApoE ε3具有更高的脂滴数量。通过筛选2321种FDA批准的药物，研究人员鉴定出三种可特异性减少ApoE ε4星形胶质细胞中脂滴的化合物：环索奈德（ciclesonide）、VX745和伊格列净（ipragliflozine）。其中，环索奈德表现出剂量依赖性的脂滴减少效果，并通过转录组分析发现其影响细胞外基质组织相关基因的表达。这一结果揭示了ApoE亚型在脂代谢中的差异，为理解AD发病机制提供了新视角，并提示靶向脂滴形成的潜在治疗策略。 • DOI链接：http://dx.doi.org/10.1002/alz70859_102039A PET-Driven Strategy for Ultrasensitive Mapping of Lipid Microenvironment Heterogeneity in Dual Organelles during Metabolic Stress and Atherosclerosis. • 中文标题：一种基于PET的策略，用于超灵敏地绘制代谢应激和动脉粥样硬化期间双细胞器中脂质微环境异质性图谱 • 作者：Kun-Peng Xie, Hong Zhang, …, Kun Li • 期刊名称：J Am Chem Soc • 影响因子：15.6 • 期刊分区：2区 • 论文总结：该研究属于化学生物学与代谢疾病领域，亮点在于开发了一种新型喹啉稠合硅罗丹醇荧光探针DMA-SiRd，通过引入光诱导电子转移（PET）效应显著增强了对极性的敏感性。该探针具备双通道、无串扰成像能力，可同时实现对脂滴和线粒体的超灵敏成像，并结合荧光寿命成像显微镜（FLIM）技术定量分析细胞器内脂质微环境的动态变化。研究发现，在动脉粥样硬化斑块中存在明显的脂质分布异质性，而治疗干预可恢复其均一性；此外，利用双光子FLIM成功追踪了动脉粥样硬化小鼠脑血管中的低极性脂质斑块。这项工作为功能性荧光探针的设计提供了新思路，并为代谢紊乱相关疾病的机制研究提供了有力工具。 • DOI链接：https://doi.org/10.1021/jacs.5c17549Paeonol Inhibits Cell Growth by Inducing Ferroptosis in Human Glioma Cells. • 中文标题：芍药酚通过诱导人胶质瘤细胞铁死亡抑制细胞生长 • 作者：Xin Li, Xue-Qi Liao, …, Jin-Que Luo • 期刊名称：Pharmacol Res Perspect • 影响因子：2.3 • 期刊分区：2区 • 论文总结：本文研究了传统中药成分芍药酚（PAE）在人胶质瘤治疗中的潜在作用。研究表明，PAE能够通过诱导铁死亡（ferroptosis）这一铁依赖性的细胞死亡方式，显著抑制胶质瘤细胞的增殖、迁移和侵袭。其机制涉及消耗脂滴（LDs）、增加脂质过氧化物（LPO）和活性氧（ROS）水平，并引发不依赖caspase的细胞死亡。该效应可被铁死亡抑制剂（如ferrostatin-1和α-tocopherol）逆转，证实其作用通路特异性。因此，PAE具有双重抗肿瘤功能，既诱导铁死亡又抑制转移，为克服替莫唑胺耐药性提供了新的治疗策略。 • DOI链接：http://dx.doi.org/10.1002/prp2.70213HDAC6 deficiency exacerbates atherosclerosis via STAT3-K685 acetylation-mediated CD36/SR-A upregulation in macrophages. • 中文标题：HDAC6 缺陷通过 STAT3-K685 乙酰化介导的巨噬细胞 CD36/SR-A 上调加剧动脉粥样硬化 • 作者：Wenqing Wang, Yue Jiang, …, Bin Wang • 期刊名称：Cell Death Dis • 影响因子：9.6 • 期刊分区：2区 • 论文总结：本研究聚焦于动脉粥样硬化（AS）的分子机制，发现组蛋白去乙酰化酶6（HDAC6）在AS患者单核细胞中表达显著下调。体外和体内实验表明，HDAC6缺陷会促进巨噬细胞泡沫细胞形成，并加剧ApoE⁻/⁻小鼠的动脉粥样硬化进展。机制上，HDAC6通过调控STAT3在K685位点的乙酰化水平，抑制CD36和SR-A的表达，从而减少巨噬细胞对胆固醇的摄取。该研究揭示了HDAC6-STAT3-CD36/SR-A信号轴在脂质代谢和AS发展中的关键作用，提出HDAC6是一个潜在的治疗靶点。 • DOI链接：https://doi.org/10.1038/s41419-025-08344-yPiezo-type mechanosensitive ion channel component 1: a mechano-bioenergetic transducer in the tumour microenvironment. • 中文标题：压电型机械敏感离子通道组分1：肿瘤微环境中的机械-生物能量转换器 • 作者：Jialu Ma, Yuankang Feng, …, Yong Wang • 期刊名称：Ann Med • 影响因子：4.3 • 期刊分区：2区 • 论文总结：本文综述了Piezo1作为一种关键的机械敏感离子通道在肿瘤微环境（TME）中的作用。Piezo1能将机械刺激转化为调控肿瘤细胞增殖、迁移和侵袭的生化信号，广泛表达于TME的多种细胞类型中，其高表达与不良临床预后相关。文章系统阐述了Piezo1在内皮细胞和免疫细胞中的激活如何促进肿瘤血管生成和免疫逃逸，并强调其作为癌症治疗潜在靶点的重要性。此外，还总结了Piezo1靶向药物的研究进展及提高组织特异性、减少脱靶效应的策略。 • DOI链接：http://dx.doi.org/10.1080/07853890.2025.2603022Ginsenoside compound K exerts osteoprotective effects by suppressing osteoclastogenesis and promoting preosteoclast PDGF-BB-induced angiogenesis via targeting CSF1R. • 中文标题：人参皂苷化合物K通过靶向CSF1R抑制破骨细胞生成并促进破骨细胞前体PDGF-BB诱导的血管生成，从而发挥骨保护作用。 • 作者：Hyeri Park, Jun You, …, Gi Kim • 期刊名称：Biochem Pharmacol • 影响因子：5.6 • 期刊分区：2区 • 论文总结：该研究聚焦于骨质疏松治疗领域，发现人参皂苷化合物K（CK）作为三七皂苷的主要活性成分，具有显著的骨保护作用。其亮点在于揭示了CK通过直接靶向CSF1R，抑制PI3K/AKT/NFκB信号通路，从而抑制破骨细胞生成；同时促进前破骨细胞释放PDGF-BB，增强H型血管形成，改善骨微环境。这一双重机制为开发基于天然产物的抗骨质疏松药物提供了新的理论依据和潜在靶点。 • DOI链接：https://doi.org/10.1016/j.bcp.2025.117661Developing Topics • 中文标题：发展主题 • 作者：Chao-Yuan Ye • 期刊名称：Alzheimers Dement • 影响因子：11.1 • 期刊分区：2区 • 论文总结：该研究聚焦于阿尔茨海默病（AD）中的两个关键病理特征：微管相关蛋白tau的病理性积累和溶酶体功能障碍。通过在tau蛋白过表达的细胞模型（包括HEK293、N2a细胞和原代神经元）以及P301S tau小鼠模型中进行系统分析，研究人员利用蛋白质组学、Western blotting、溶酶体荧光成像、超显微成像和功能成像等多种技术手段，揭示了tau过表达对溶酶体结构与功能的显著影响。研究发现，tau过表达导致溶酶体体积增大、数量减少、分布更集中于核周区域、酸化能力下降以及蛋白水解活性减弱。此外，在P301S小鼠海马神经元中，含有未被降解物质的残余体型溶酶体（RLs）显著增多，提示溶酶体清除功能受损。蛋白质组数据还显示微管系统破坏及溶酶体转运蛋白缺陷。这些结果共同表明tau过表达引发溶酶体应激反应，进一步阐明了tau在AD神经退行性变中的作用机制。 • DOI链接：http://dx.doi.org/10.1002/alz70861_108034Basic Science and Pathogenesis • 中文标题：基础科学与发病机制 • 作者：Carmen Molina, Wen See, …, Alison Goate • 期刊名称：Alzheimers Dement • 影响因子：11.1 • 期刊分区：2区 • 论文总结：该研究聚焦于阿尔茨海默病（AD）中的免疫代谢机制，发现LACTB和LACTB2基因表达降低对AD具有保护作用。LACTB是一种线粒体丝氨酸蛋白酶，影响线粒体生物能量学和脂质代谢，其表达水平与AD风险相关的代谢物琥珀酰肉碱相关。通过构建LACTB/B2敲低/敲除的巨噬细胞和诱导多能干细胞分化的小胶质细胞（iMGLs），研究发现LACTB缺失会增强氧化磷酸化、干扰素反应，并改变脂质代谢，表现为神经酰胺增加和脂滴积累减少。异种移植实验显示，LACTB敲除的人源小胶质细胞可轻微减轻5xFAD小鼠的淀粉样蛋白病理并促进小胶质细胞活化。由于LACTB编码一种酶且其低表达具有保护效应，同时琥珀酰肉碱可作为潜在生物标志物，因此LACTB被视为一个有前景的AD治疗靶点。 • DOI链接：http://dx.doi.org/10.1002/alz70855_099086Basic Science and Pathogenesis • 中文标题：基础科学与发病机制 • 作者：Younji Nam, Brooke DeRosa, …, Margaret Pericak-Vance • 期刊名称：Alzheimers Dement • 影响因子：11.1 • 期刊分区：2区 • 论文总结：该研究聚焦于非裔美国人中ABCA7基因的44碱基对缺失（p.Arg578Alafs）在阿尔茨海默病（AD）中的作用。研究表明，该缺失导致产生一种稳定的、定位于细胞膜的截短蛋白，进而扰乱神经元内的脂质代谢。通过使用同源iPSC衍生的神经元和HepG2细胞模型发现，该缺失显著增加脂滴积累，并导致磷酸胆碱和磷酸乙醇胺水平上升超过1.2倍，这些分子已知可调节脂滴的大小与动态变化。转录组分析显示ABCA7表达水平普遍较低，但缺失不影响其转录水平。研究提示该遗传变异可能通过改变脂质稳态促进AD发生，而探索某些个体对该变异具有抵抗性的机制，可能为所有人群提供新的治疗靶点。 • DOI链接：https://doi.org/10.1002/alz70855Microautophagy mediated by lysosomal membrane proteins: insights from LAMP2B-dependent microlipophagy. • 中文标题：溶酶体膜蛋白介导的微自噬：来自 LAMP2B 依赖性微脂自噬的启示 • 作者：Ryohei Sakai, Tomohiro Kabuta • 期刊名称：Autophagy • 影响因子：14.3 • 期刊分区：2区 • 论文总结：本文研究了溶酶体膜蛋白LAMP2B在哺乳动物细胞中介导微自噬，特别是微脂自噬的作用机制。研究表明，LAMP2B通过其胞质区结合脂滴表面的磷脂酸，促进溶酶体对脂滴的直接摄取，该过程依赖ESCRT复合物且独立于巨自噬。研究发现LAMP2B过表达可增强脂滴降解，并在小鼠模型中显著抵抗高脂饮食诱导的肥胖及相关代谢紊乱。文章还提出一个模型，认为不同LAMP2亚型可能通过其胞质区域识别特定底物，从而介导选择性微自噬或类似过程。这项工作揭示了微自噬的分子机制及其在脂代谢和潜在治疗中的重要意义。 • DOI链接：https://doi.org/10.1080/15548627.2025.2609920Cholesterol-mediated inflammation activation in alveolar macrophages. • 中文标题：胆固醇介导的肺泡巨噬细胞炎症激活 • 作者：Elena Lopez-Rodriguez • 期刊名称：BMC Biol • 影响因子：4.5 • 期刊分区：2区 • 论文总结：该研究探讨了胆固醇代谢异常在肺泡巨噬细胞中引发炎症小体激活的机制。尽管胆固醇介导的炎症在心血管疾病中的循环巨噬细胞中已有广泛研究，但其在肺部疾病中的作用尚不清楚。研究发现，无论是可溶性胆固醇还是结晶胆固醇，均可被肺泡巨噬细胞摄取并导致胞内脂滴积累和泡沫细胞形成。然而，只有胆固醇晶体能够触发NLRP3炎症小体的组装与活化，并促进IL-18的释放，这一过程在未激活的肺泡巨噬细胞中表现为无菌性炎症反应。通过体外化学抑制和NLRP3缺陷小鼠模型验证了NLRP3的关键作用。结果表明，胆固醇晶体特异性地诱导肺泡巨噬细胞的炎症反应，揭示了其在肺部炎症性疾病中的潜在病理机制，为理解肺部脂质相关免疫反应提供了新视角。 • DOI链接：https://doi.org/10.1186/s12915-025-02494-3Mitochondrial remodeling and metabolic reprogramming drive long-term salinity adaptation in Tetrahymena thermophila. • 中文标题：线粒体重塑和代谢重编程驱动四膜虫的长期盐度适应 • 作者：Fengsong Liu • 期刊名称：mSystems • 影响因子：4.6 • 期刊分区：2区 • 论文总结：本研究通过实验进化和多组学整合方法，揭示了淡水纤毛虫四膜虫（Tetrahymena thermophila）在长期盐胁迫下的适应机制。研究发现，盐适应谱系在生长延迟与渗透耐受性之间存在权衡。转录组和蛋白质组分析显示：DNA复制、谷胱甘肽代谢和内质网蛋白加工通路被协同上调；脂质分解代谢受抑制并伴随脂滴积累；线粒体通过扩大与内质网的接触来维持ATP生成。此外，该适应过程容忍由复制应激引起的基因组不稳定性，并通过氧化损伤的区室化逃避免疫防御。研究表明，线粒体重塑和代谢重编程在微生物应对盐度胁迫中起关键作用，为理解原生生物在变化生态系统中的适应阈值提供了重要见解。 • DOI链接：https://doi.org/10.1128/msystems.01549-25CRISPR/Cas9-mediated LmSerpin5 knockout causes midgut dysplasia and leads to embryonic lethality in Locusta migratoria. • 中文标题：利用 CRISPR/Cas9 介导的 LmSerpin5 基因敲除导致飞蝗中肠发育不良并最终导致胚胎致死。 • 作者：Lixia Ma, Baiqi Wu, …, Tingting Zhang • 期刊名称：J Insect Physiol • 影响因子：2.3 • 期刊分区：2区 • 论文总结：本研究属于昆虫生理学与分子遗传学领域，通过CRISPR/Cas9技术敲除飞蝗中的LmSerpin5基因，揭示其在发育和先天免疫中的关键作用。亮点在于首次系统阐明了LmSerpin5对胚胎存活和中肠结构完整性的双重调控功能。关键结论包括：LmSerpin5纯合突变导致完全胚胎致死；突变体出现中肠微绒毛减少、结构缺陷及炎症反应；分子机制上，LmSerpin5缺失引起Toll信号通路下游基因（如LmMyd88、LmPelle和LmTube）在中肠特异性上调，表明该基因通过抑制Toll通路过度激活来维持体内平衡。 • DOI链接：https://doi.org/10.1016/j.jinsphys.2025.104925Chronic intermittent hypoxia increases Parkinson's disease susceptibility via PPARα-mediated lipid droplet-mitochondrial dysfunction. • 中文标题：慢性间歇性缺氧通过PPARα介导的脂滴-线粒体功能障碍增加帕金森病易感性。 • 作者：Ming-Rui Zhai, Jie Pan, …, Yue-Hua Liu • 期刊名称：Theranostics • 影响因子：13.3 • 期刊分区：2区 • 论文总结：本研究探讨了慢性间歇性低氧（CIH）在帕金森病（PD）发病机制中的作用。研究发现，CIH显著加剧亚毒性PD模型中黑质纹状体多巴胺能神经元的退行性变和运动功能障碍。机制上，CIH通过PPARα依赖性途径破坏Mfn2-Plin5蛋白连接，损害脂滴（LD）与线粒体之间的相互作用，导致LD周转受阻及DA神经元内病理性脂滴积累。进一步研究表明，通过药物干预恢复LD-线粒体偶联（如促进LD分解、抑制线粒体分裂或重建锚定连接）可有效缓解神经退行性变。该研究揭示了CIH相关PD病理中一条新的LD-线粒体调控轴，为治疗CIH加速的神经退行性疾病提供了潜在靶点。 • DOI链接：http://dx.doi.org/10.7150/thno.122944Spinal cord injuryFerroptosis-associated transcriptional factors in neurological diseases: molecular mechanisms and therapeutic prospects • 中文标题：铁死亡相关转录因子在神经系统疾病中的作用：分子机制与治疗前景 • 作者：Tianchen Jiang, Waner Ma, …, Xiaoyuan Mao • 期刊名称：Exp Mol Med • 影响因子：12.9 • 期刊分区：2区 • 论文总结：本文综述了铁死亡（ferroptosis）相关转录因子在阿尔茨海默病、帕金森病、癫痫、中风、脑外伤和脊髓损伤等神经系统疾病中的分子机制及治疗潜力。铁死亡是一种依赖铁的脂质过氧化积累引起的调节性细胞死亡形式，在多种神经退行性疾病中发挥关键作用。转录因子（TFs）通过调控铁代谢、抗氧化防御和脂质过氧化过程，参与铁死亡的遗传调控。文章重点介绍了Nrf2等关键转录因子的作用，并指出Nrf2激活剂RTA-408已进入针对阿尔茨海默病患者的II期临床试验，验证其安全性和有效性。此外，未来基于PROTAC技术及基因疗法的研究有望为神经系统疾病的治疗提供新策略。 • DOI链接：http://dx.doi.org/10.1038/s12276-025-01611-0Ependymal Yes-Associated Protein Promotes the Neural Regeneration Through Enhancing the Ependymal Cell-Derived Perilesional Glial Borders in Mice After Spinal Cord Injury. • 中文标题：室管膜Yes相关蛋白通过增强脊髓损伤小鼠室管膜细胞衍生的病灶周围胶质边界来促进神经再生 • 作者：Jiashu Lian, Xiaowu Lin, …, Honglin Teng • 期刊名称：Acta Physiol (Oxf) • 影响因子：5.6 • 期刊分区：2区 • 论文总结：该研究聚焦于脊髓损伤（SCI）后的神经再生机制，发现室管膜细胞中的Yes相关蛋白（YAP）在SCI后被激活，并通过调控细胞增殖、分化及神经营养因子分泌，在形成病灶周围胶质边界中发挥关键作用。YAP缺失会加剧神经元丢失，抑制胶质边界形成和功能恢复。机制研究表明，YAP通过P300-CRNDE-Wnt/β-catenin信号通路促进室管膜细胞向星形胶质细胞和少突胶质细胞分化，从而促进神经修复。该通路为脊髓损伤治疗提供了新的潜在靶点。 • DOI链接：http://dx.doi.org/10.1111/apha.70147A Conjugation Delivery System of Macrophages and Platelet Pharmacytes Promotes Regeneration After Spinal Cord Injury. • 中文标题：巨噬细胞和血小板药房的结合递送系统促进脊髓损伤后的再生 • 作者：Haoli Wang, Hao Hu, …, Qingqing Wang • 期刊名称：Adv Sci (Weinh) • 影响因子：15.8 • 期刊分区：2区 • 论文总结：该研究聚焦于脊髓损伤后巨噬细胞吞噬功能缺陷导致的线粒体功能障碍问题。研究发现，无核血小板中的线粒体具有较强的抗应激能力，并可在细胞应激条件下将线粒体转移至巨噬细胞，从而恢复其吞噬功能。为此，研究人员开发了一种名为M-P-NPs@PPARγ的递送系统，通过将负载PPARγ过表达阳离子聚合物的血小板与巨噬细胞结合，实现线粒体和基因的协同递送。该系统可显著提升巨噬细胞的ATP生成能力并维持脂质稳态，在脊髓损伤模型中成功逆转了吞噬功能障碍，促进了神经再生、髓鞘形成以及运动功能的恢复。本研究为治疗中枢神经系统损伤提供了一种通过调控能量与脂质代谢来恢复巨噬细胞功能的新策略。 • DOI链接：http://dx.doi.org/10.1002/advs.202513474Effective Connectivity Alterations of Directed Brain Network in Pediatric Patients With Spinal Cord Injury. • 中文标题：儿童脊髓损伤患者定向脑网络的有效连接性改变 • 作者：Yu Wang, Beining Yang, …, Nan Chen • 期刊名称：CNS Neurosci Ther • 影响因子：4.8 • 期刊分区：2区 • 论文总结：本研究利用静息态功能磁共振成像和动态因果模型（DCM），探讨了儿童脊髓损伤（SCI）患者脑网络有效连接的改变。研究发现，默认模式网络（DMN）与显著性网络（SAN）之间的连接显著减弱，后扣带回皮层（PCC）作为关键上游调节节点，对多个脑区表现出增强的抑制性影响。亚组分析显示，完全性SCI患者相较于不完全性SCI患者，在DMN到SAN通路中表现出更强的兴奋性驱动，但反向通路的抑制作用也增强，提示双向调节失衡与损伤严重程度密切相关。该研究揭示了SCI后大脑重组的机制，并提出PCC可能是神经调控干预的潜在靶点。 • DOI链接：http://dx.doi.org/10.1002/cns.70720Integration of angiogenesis and programmed cell death mechanisms unveils potential diagnostic and therapeutic targets in spinal cord injury. • 中文标题：血管生成和程序性细胞死亡机制的整合揭示了脊髓损伤潜在的诊断和治疗靶点 • 作者：Feng Lu, Zifeng Mai, …, Maolin Zhong • 期刊名称：J Transl Med • 影响因子：7.5 • 期刊分区：2区 • 论文总结：该研究通过整合血管生成与程序性细胞死亡（如凋亡、焦亡和铁死亡）的相关机制，系统分析了脊髓损伤（SCI）后的病理过程。研究识别出多个关键基因和信号通路，这些分子可能作为脊髓损伤的潜在诊断标志物或治疗靶点。结果表明，调控血管生成与程序性细胞死亡之间的平衡可能有助于改善脊髓损伤后的神经功能恢复，为未来开发精准治疗策略提供了理论依据。 • DOI链接：http://dx.doi.org/10.1186/s12967-025-07405-2Fabrication and evaluation of Edaravone-loaded chitosan/polyvinyl alcohol electrospun nanofibers scaffold for spinal cord injury repair. • 中文标题：制备和评价载有依达拉奉的壳聚糖/聚乙烯醇静电纺丝纳米纤维支架用于脊髓损伤修复 • 作者：Munira Momin, Namrata Vadak, …, Lokesh Bhatt • 期刊名称：Int J Biol Macromol • 影响因子：8.5 • 期刊分区：2区 • 论文总结：本研究开发了一种负载依达拉奉的壳聚糖/聚乙烯醇静电纺丝纳米纤维支架（EDANF），用于脊髓损伤（SCI）的修复。该支架具有均匀的纳米结构（平均直径266 nm），能模拟神经组织细胞外基质，支持轴突再生。EDANF表现出良好的药物释放特性：24小时内快速释放35%，28天内累积释放达94.02%。体外实验显示其无细胞毒性、无溶血性且无刺激性，并具备促进伤口愈合的能力。在脊髓损伤大鼠模型中，EDANF显著改善了神经功能恢复，减少组织空洞化，增强神经元保留，并降低炎症与氧化应激水平。研究表明，EDANF是一种安全有效的脊髓修复平台，在神经再生领域具有临床应用潜力。 • DOI链接：https://doi.org/10.1016/j.ijbiomac.2025.149866Functionalized nanozyme delivery of a KCC2-activator conjugate for the promotion of functional recovery after acute spinal cord injury. • 中文标题：利用功能化纳米酶递送KCC2激活剂缀合物促进急性脊髓损伤后的功能恢复 • 作者：Haosen Zhao, Sen Lin, …, Xifan Mei • 期刊名称：Mater Today Bio • 影响因子：10.2 • 期刊分区：2区 • 论文总结：本研究聚焦于急性脊髓损伤（SCI）的治疗挑战，发现KCC2在SCI后表达异常，但其激动剂因难以穿透中枢神经系统而受限。为此，研究人员开发了一种活性氧（ROS）响应型聚合物囊泡纳米载体（QZIF-polymersomes），用于靶向递送强效KCC2激活剂槲皮素。该系统可在损伤部位响应ROS释放药物，不仅保护残存脊髓组织，还通过促进线粒体生物合成和上调氧化磷酸化相关基因（如COXI、UCP2、TFAM）来增强神经元能量代谢，并显著促进损伤区域的髓鞘再生。结果表明，该递送系统可有效改善神经保护与代谢支持，推动SCI后的功能恢复，具有重要的转化潜力。 • DOI链接：http://dx.doi.org/10.1016/j.mtbio.2025.102624An intelligent nanoliposome alleviates disc degeneration and discogenic pain by inhibiting neurovascular ingrowth via a "Soil-conditioning, seed-modulating, and weeds-suppressing" strategy. • 中文标题：一种智能纳米脂质体通过“土壤改良、种子调控和杂草抑制”策略抑制神经血管长入，从而缓解椎间盘退变和椎间盘源性疼痛。 • 作者：Fudong Li, Yangyang Shi, …, Jiangang Shi • 期刊名称：Bioact Mater • 影响因子：20.3 • 期刊分区：2区 • 论文总结：本文研究领域为生物材料与椎间盘退行性疾病的治疗。亮点在于开发了一种仿生智能纳米脂质体（NM-LPTK/RSV-MnCDs），能够靶向退变椎间盘微环境并实现药物的按需释放。该纳米平台通过清除活性氧（ROS）来改善恶劣的微环境（“土壤”），同时递送白藜芦醇（RSV）以调节髓核细胞功能（“种子”），从而协同抑制病理性神经血管长入（“杂草”）。在体外和两种小鼠模型中均表现出显著疗效，可减轻椎间盘退变、抑制神经血管异常生长并缓解疼痛行为。机制研究表明其作用依赖于抑制Hippo-YAP信号通路，恢复氧化还原平衡并阻止组织异常重塑。该研究为退行性椎间盘疾病及其相关神经性疼痛提供了精准治疗的新范式。 • DOI链接：https://doi.org/10.1016/j.bioactmat.2025.11.048Schisandrol B inhibits osteoclastogenesis and mitigates estrogen deficiency-induced bone loss by targeting TRAF6-NOX1 pathway. • 中文标题：五味子醇B通过靶向TRAF6-NOX1通路抑制破骨细胞生成，从而减轻雌激素缺乏引起的骨丢失。 • 作者：Ashraf Gorgey, Refka Khalil, …, Robert Adler • 期刊名称：Phytomedicine • 影响因子：8.3 • 期刊分区：2区 • 论文总结：该研究属于骨代谢与天然药物领域，亮点在于揭示了中药成分五味子醇B（SolB）在防治绝经后骨质疏松症中的潜在作用机制。研究表明，SolB通过靶向TRAF6和NOX1蛋白，抑制RANKL诱导的TRAF6-NF-κB和MAPK信号通路激活，减少细胞内活性氧（ROS）水平和Ca2+内流，进而下调NFATc1表达，抑制破骨细胞生成和骨吸收功能。在卵巢切除（OVX）小鼠模型中，SolB显著减轻骨量丢失，显示出良好的骨保护作用。因此，SolB有望成为一种治疗骨质疏松症的天然候选药物。 • DOI链接：https://doi.org/10.1016/j.phymed.2025.157669Removal or inhibition of transglutaminase 2 decreases cellular stress, supporting tissue preservation, and recovery after SCI. • 中文标题：去除或抑制转谷氨酰胺酶2可降低细胞应激，有助于脊髓损伤后的组织保存和恢复。 • 作者：Mousumi Ghosh, Omar Elwardany, …, Damien Pearse • 期刊名称：Acta Neuropathol Commun • 影响因子：5.7 • 期刊分区：2区 • 论文总结：该研究属于神经病理学与脊髓损伤修复领域。文章亮点在于揭示了转谷氨酰胺酶2（transglutaminase 2, TG2）在脊髓损伤（SCI）后对细胞应激和组织退变的关键作用。通过去除或抑制TG2，研究人员发现能够显著降低细胞应激反应，减轻组织损伤，促进神经功能恢复。这一发现表明TG2是一个潜在的治疗靶点，为开发针对脊髓损伤的新型神经保护策略提供了理论依据。 • DOI链接：https://doi.org/10.1186/s40478-025-02135-4Correction: Therapeutic effects of rapamycin and surgical decompression in a rabbit spinal cord injury model. • 中文标题：更正：雷帕霉素和手术减压在兔脊髓损伤模型中的治疗效果 • 作者：Xin Zhang, Chuan Qin, …, Jianjun Li • 期刊名称：Cell Death Dis • 影响因子：9.6 • 期刊分区：2区 • 论文总结：该文献是对先前研究的更正，主要涉及雷帕霉素和手术减压在兔脊髓损伤模型中的治疗效果。原研究可能探讨了雷帕霉素（一种mTOR抑制剂）的神经保护作用以及手术减压对脊髓功能恢复的影响。本更正可能修正了实验数据、统计分析或方法描述中的错误，以确保研究结果的准确性和可重复性。研究领域属于神经科学与创伤医学，亮点在于结合药物干预与外科手段治疗脊髓损伤，关键结论应围绕两种疗法的联合或独立疗效展开。 • DOI链接：https://doi.org/10.1038/s41419-025-08267-8Material-based neuroimaging and biomarker detection for central nervous system disorder. • 中文标题：基于材料的中枢神经系统疾病神经影像学和生物标志物检测 • 作者：Liqun Yu, Yanjing Zhu, …, Rongrong Zhu • 期刊名称：Mater Today Bio • 影响因子：10.2 • 期刊分区：2区 • 论文总结：本文综述了纳米材料在中枢神经系统（CNS）疾病诊断中的最新进展，涵盖磁共振成像、正电子发射断层扫描以及光声成像、近红外成像和表面增强拉曼散射等新兴多模态成像技术。同时介绍了用于检测脑脊液、血液中Aβ、tau蛋白、α-突触核蛋白、神经丝轻链和microRNA等生物标志物的纳米颗粒生物传感器。文章强调通过结合人工智能与高通量优化策略，可提升血脑屏障穿透能力、靶向精度及个体化诊疗水平。未来临床转化需依赖严格的安全性评估、标准化性能指标和大规模多中心试验验证。这些材料驱动的技术有望推动CNS疾病的精准诊断与治疗监测。 • DOI链接：http://dx.doi.org/10.1016/j.mtbio.2025.102615The Relationship Between Age and Recovery After Spinal Cord Injury: A Longitudinal Cohort Study. • 中文标题：年龄与脊髓损伤后康复的关系：一项纵向队列研究 • 作者：Catherine Jutzeler • 期刊名称：Neurology • 影响因子：8.5 • 期刊分区：2区 • 论文总结：本研究基于欧洲多中心脊髓损伤研究数据，探讨了年龄对脊髓损伤（SCI）患者神经功能和功能恢复的影响。研究纳入2171名患者，发现高龄并不影响神经学恢复（如总运动评分TMS），但显著影响功能独立性和行走能力的恢复。每增加10岁，SCIM评分改善减少4.3分，且步行相关指标（如6分钟步行测试）均随年龄增长而下降。感觉功能恢复未受显著影响。研究识别出70岁为功能恢复明显下降的年龄临界点，提示在临床试验设计和个体化康复策略中应特别关注70岁以上患者。 • DOI链接：http://dx.doi.org/10.1212/WNL.0000000000214516 🩺 BoneWrights & Nephews：为了分享而建立的公众号 这里不仅有 日更的主题文献周报，还有定期更新的 临床知识、习题分析与经验分享，以及来自 骨科、康复科医生的生活日常与思考。 🌟 欢迎关注、留言与分享让更多同行加入我们的学习与交流。