Long non­coding RNAs MALAT1, NEAT1 and DSCR4 can be serum biomarkers in predicting urosepsis occurrence and reflect disease severity.

Sepsis commonly occurs in patients with serious infections. It severely threatens the health of patients and has very high mortality rates. Urosepsis is a type of sepsis in which the serious infection originates from the urinary system. Early diagnosis of the occurrence and severity of urogenital sepsis is crucial for improving patient prognosis. Long noncoding RNAs (LncRNAs) play important roles in the occurrence of a number of diseases, including sepsis, and can be potential biomarkers that predict disease development. The present study aimed to discover potential LncRNAs that can predict the occurrence of urosepsis. RNA-sequence data from patients with sepsis from the GEO database was analyzed and LncRNAs associated with sepsis were identified. The expression of LncRNAs associated with sepsis was tested in clinical urosepsis samples. Finally, the value of these LncRNAs in predicting urosepsis was verified using clinical samples. From the GEO database a total of nine LncRNAs (MALAT1, NEAT1, RMRP, LncIRX5, LINC01742, DSCR4, C22ORF34, LINC00381, and LINC01102) were identified that had expression changes corresponding with the occurrence of sepsis. Specifically, MALAT1, NEAT1 and DSCR4 revealed differential expression in patients with urosepsis. Moreover, MALAT1, and DSCR4 were shown to be significant risk indicators for urosepsis, and NEAT1 was shown to reflect disease severity. Therefore, the present study indicated that the LncRNAs, MALAT1, NEAT1 and DSCR4 can reflect the occurrence and severity of urosepsis and may act as potential biomarkers.

Polarity-Driven Fluorescence Monitoring of Lipid Droplet Dynamics in Dry Eye Disease.

The emergence of lipid droplets (LDs) has been recognized as cellular markers of ocular surface hyperosmosis, which is recognized as a fundamental mechanism driving dry eye disease (DED), while their dynamics during DED progression and therapy remains unlocked. For this purpose, an LD-specific fluorescent probe P1 is presented in this work that exhibits highly selective and sensitive emission enhancement in response to a decreased ambient polarity (Δf) from 0.209 to 0.021. The hydrophobic nature of P1 enables specific staining of LDs, facilitating visualization of changes in polarity within these cellular structures. Utilizing P1, we observe a decrease in polarity accompanied by an increase in the size and number of LDs in hyperosmotic human corneal epithelial cells (HCECs). Furthermore, interplays between LDs and cellular organelles such as mitochondria and the Golgi apparatus are visualized, suggesting the underlying pathogenesis in DED. Notably, the variations of LDs are observed after the inhibition of ferroptosis or activation of autophagy in hyperosmotic HCECs, implying the great potential of LDs as indicators for the design and efficacy evaluation of DED drugs regarding ferroptosis or autophagy as targets. Finally, LDs are confirmed to be overproduced in corneal tissues from DED mice, and the application of clinical eye drops effectively impedes these changes. This detailed exploration underscores the significant roles of LDs as an indicator for the deep insight into DED advancement and therapy.

A cuttlefish ink nanoparticle-reinforced biopolymer hydrogel with robust adhesive and immunomodulatory features for treating oral ulcers in diabetes.

Oral ulcers can be managed using a variety of biomaterials that deliver drugs or cytokines. However, many patients experience minimal benefits from certain medical treatments because of poor compliance, short retention times in the oral cavity, and inadequate drug efficacy. Herein, we present a novel hydrogel patch (SCE2) composed of a biopolymer matrix (featuring ultraviolet-triggered adhesion properties) loaded with cuttlefish ink nanoparticles (possessing pro-healing functions). Applying a straightforward local method initiates the formation of a hydrogel barrier that adheres to mucosal injuries under the influence of ultraviolet light. SCE2 then demonstrates exceptional capabilities for near-infrared photothermal sterilization and neutralization of reactive oxygen species. These properties contribute to the elimination of bacteria and the management of the oxidation process, thus accelerating the healing phase's progression from inflammation to proliferation. In studies involving diabetic rats with oral ulcers, the SCE2 adhesive patch significantly quickens recovery by altering the inflamed state of the injured area, facilitating rapid re-epithelialization, and fostering angiogenesis. In conclusion, this light-sensitive hydrogel patch offers a promising path to expedited wound healing, potentially transforming treatment strategies for clinical oral ulcers.

Erratum: Author correction to 'Co-delivery of nigericin and decitabine using hexahistidine-metal nanocarriers for pyroptosis-induced immunotherapeutics' [Acta Pharm Sin B 12 (2022) 4458-4471].

[This corrects the article DOI: 10.1016/j.apsb.2022.11.002.].

Oxygen vacancy-rich nickel oxide nanoplatforms for enhanced photothermal and chemodynamic therapy combat methicillin-resistant Staphylococcus aureus.

Bacterial infections pose a global concern due to high fatality rates, particularly with the rise of drug-resistant bacteria and biofilm formation. There is an urgent need for innovative strategies to combat this issue. A study on chemodynamic therapy (CDT) using nanozymes in conjunction with photothermal therapy (PTT) has displayed potential in addressing drug-resistant bacterial infections. However, the effectiveness of this combined approach is limited by inadequate light absorption. This work suggests the NiOx nanoparticles enriched with oxygen vacancies enhance CDT and PTT to overcome this challenge. The presence of oxygen vacancies in NiOx can reduce the energy gap between its valence band and conduction band, facilitating oxygen adsorption. NiOx has exhibited notable antibacterial properties and complete eradication of biofilms in both laboratory and animal trials. In animal abscess models, NiOx demonstrated antibacterial and anti-inflammatory effects in the initial stages, while also promoting wound healing and tissue regeneration by influencing immune factors and encouraging collagen deposition and neovascularization. With positive biosafety and biocompatibility profiles, the oxygen vacancy-enhanced CDT and PTT therapy proposed in this article hold promise for effective sterilization, deep biofilm removal, and treatment of infections caused by drug-resistant bacteria. STATEMENT OF SIGNIFICANCE: This study constructs oxygen vacancies NiOx nanoparticles (NiOx NPs) to improve the efficacy of photothermal therapy and chemodynamic therapy. The presence of oxygen vacancies in NiOx NPs helps bridge the energy gap between its valence band and conduction band, facilitating oxygen adsorption and improving catalytic efficiency. In both in vivo and in vitro antibacterial experiments, NiOx NPs demonstrate effective antibacterial and anti-inflammatory properties. Furthermore, it aids in wound healing and tissue regeneration by modulating immune factors, collagen deposition, and angiogenesis. This approach presents a promising collaborative strategy for utilizing nickel-based defective nanomaterials in combating deep drug-resistant bacterial infections.

Single Atom-Dispersed Silver Incorporated in ZIF-8-Derived Porous Carbon for Enhanced Photothermal Activity and Antibacterial Activities.

Purpose: Recently, Single-atom-loaded carbon-based material is a new environmentally friendly and stable photothermal antibacterial nanomaterial. It is still a great challenge to achieve single-atom loading on carbon materials. Materials and Methods: Herein, We doped single-atom Ag into ZIF-8-derived porous carbon to obtain Ag-doped ZIF-8-derived porous carbon(AgSA-ZDPC). The as-prepared samples were characterized by XRD, XPS, FESEM, EDX, TEM, and HAADF-STEM which confirmed that the single-atom Ag successfully doped into the porous carbon. Further, the photothermal properties and antimicrobial activity of AgSA-ZDPC have been tested. Results: The results showed that the temperature increased by 30 °C after near-infrared light irradiation(1 W/cm2) for 5 min which was better than ZIF-8-derived porous carbon(ZDPC). It also exhibits excellent photothermal stability after the laser was switched on and off 5 times. When the AgSA-ZDPC concentration was greater than 50 µg/mL and the near-infrared irradiation was performed for 5 min, the growth inhibition of S. aureus and E. coli was almost 100%. Conclusion: This work provides a simple method for the preparation of single-atom Ag-doped microporous carbon which has potential antibacterial application.

Mitochondria Energy Metabolism Depression as Novel Adjuvant to Sensitize Radiotherapy and Inhibit Radiation Induced-Pulmonary Fibrosis.

Currently, the typical combination therapy of programmed death ligand-1 (PD-L1) antibodies with radiotherapy (RT) still exhibits impaired immunogenic antitumor response in clinical due to lessened DNA damage and acquired immune tolerance via the upregulation of some other immune checkpoint inhibitors. Apart from this, such combination therapy may raise the occurrence rate of radiation-induced lung fibrosis (RIPF) due to enhanced systemic inflammation, leading to the ultimate death of cancer patients (average survival time of about 3 years). Therefore, it is newly revealed that mitochondria energy metabolism regulation can be used as a novel effective PD-L1 and transforming growth factor-ß (TGF-ß) dual-downregulation method. Following this, IR-TAM is prepared by conjugating mitochondria-targeted heptamethine cyanine dye IR-68 with oxidative phosphorylation (OXPHOS) inhibitor Tamoxifen (TAM), which then self-assembled with albumin (Alb) to form IR-TAM@Alb nanoparticles. By doing this, tumor-targeting IR-TAM@Alb nanoparticle effectively reversed tumor hypoxia and depressed PD-L1 and TGF-ß expression to sensitize RT. Meanwhile, due to the capacity of heptamethine cyanine dye in targeting RIPF and the function of TAM in depressing TGF-ß, IR-TAM@Alb also ameliorated fibrosis development induced by RT.

Mitochondria-Targeted Nanoadjuvants Induced Multi-Functional Immune-Microenvironment Remodeling to Sensitize Tumor Radio-Immunotherapy.

It is newly revealed that collagen works as a physical barrier to tumor immune infiltration, oxygen perfusion, and immune depressor in solid tumors. Meanwhile, after radiotherapy (RT), the programmed death ligand-1 (PD-L1) overexpression and transforming growth factor-ß (TGF-ß) excessive secretion would accelerate DNA damage repair and trigger T cell exclusion to limit RT efficacy. However, existing drugs or nanoparticles can hardly address these obstacles of highly effective RT simultaneously, effectively, and easily. In this study, it is revealed that inducing mitochondria dysfunction by using oxidative phosphorylation inhibitors like Lonidamine (LND) can serve as a highly effective multi-immune pathway regulation strategy through PD-L1, collagen, and TGF-ß co-depression. Then, IR-LND is prepared by combining the mitochondria-targeted molecule IR-68 with LND, which then is loaded with liposomes (Lip) to create IR-LND@Lip nanoadjuvants. By doing this, IR-LND@Lip more effectively sensitizes RT by generating more DNA damage and transforming cold tumors into hot ones through immune activation by PD-L1, collagen, and TGF-ß co-inhibition. In conclusion, the combined treatment of RT and IR-LND@Lip ultimately almost completely suppressed the growth of bladder tumors and breast tumors.

Cascade Reactions Catalyzed by Gold Hybrid Nanoparticles Generate CO Gas Against Periodontitis in Diabetes.

The treatment of diabetic periodontitis poses a significant challenge due to the presence of local inflammation characterized by excessive glucose concentration, bacterial infection, and high oxidative stress. Herein, mesoporous silica nanoparticles (MSN) are embellished with gold nanoparticles (Au NPs) and loaded with manganese carbonyl to prepare a carbon monoxide (CO) enhanced multienzyme cooperative hybrid nanoplatform (MSN-Au@CO). The Glucose-like oxidase activity of Au NPs catalyzes the oxidation of glucose to hydrogen peroxide (H2O2) and gluconic acid，and then converts H2O2 to hydroxyl radicals (•OH) by peroxidase-like activity to destroy bacteria. Moreover, CO production in response to H2O2, together with Au NPs exhibited a synergistic anti-inflammatory effect in macrophages challenged by lipopolysaccharides. The underlying mechanism can be the induction of nuclear factor erythroid 2-related factor 2 to reduce reactive oxygen species, and inhibition of nuclear factor kappa-B signaling to diminish inflammatory response. Importantly, the antibacterial and anti-inflammation effects of MSN-Au@CO are validated in diabetic rats with ligature-induced periodontitis by showing decreased periodontal bone loss with good biocompatibility. To summarize, MSN-Au@CO is fabricate to utilize glucose-activated cascade reaction to eliminate bacteria, and synergize with gas therapy to regulate the immune microenvironment, offering a potential direction for the treatment of diabetic periodontitis.

An NIR-II-enhanced nanozyme to promote wound healing in methicillin-resistant Staphylococcus aureus infections.

Deep tissue bacterial infections, especially methicillin-resistant Staphylococcus aureus (MRSA) infections, pose challenges to clinical therapy due to their low debridement efficiency and relapsing. Molybdenum disulfide (MoS2) is used in the antibacterial field as a classic photothermal agent (NIR-I) with good biocompatibility. However, due to its limited NIR-I tissue penetration ability and single treatment mode, MoS2 has poor therapeutic effects on deep tissue infection. Herein, we prepared a defect-type hybrid 2H-MoS2 nanozyme (MoWS2) using hydrothermal method fabricate the MoWS2 composite, which is a new antibacterial strategy involving photothermal and enzyme catalysis, and further enhances the activity of the nanozyme through overheating. The regulation of 2H-MoS2 defects through tungsten ion doping endows MoWS2 with better near-infrared two-region absorption (NIR-II) and enzyme catalytic performance. Antibacterial activity experiments in vitro have shown that MoWS2 can achieve efficient bactericidal activity and biofilm clearance through hyperthermia and reactive oxygen species (ROS). Deep MRSA infection experiments have shown that MoWS2 rapidly removes bacteria from subcutaneous infected tissues through photothermal therapy (PTT) and chemodynamic therapy (CDT), accelerates the dissipation of abscesses, and promotes the healing of infected wounds. Additionally, the versatile treatment mode of MoWS2 was further confirmed through tissue sectioning and immunofluorescence staining analysis. Overall, these results provide a feasible approach for achieving efficient treatment of deep tissue infections through tungsten ion doping to regulate defective 2H-MoS2. STATEMENT OF SIGNIFICANCE: The photothermal effect of MoS2 nanosheets in the NIR-I (650-900 nm) window in anti-MRSA therapy is considered to be highly reliable and efficient in PTA. However, most of the developed PPT therapies or antimicrobial systems based on PTT therapies developed with 1T-MoS2 have in vivo sterilization temperatures of more than 55°C, which have the risk of damaging the normal tissues of the skin. In this study, we prepared W@MoS2 with a good photothermal effect (36.9%) in the NIR-II window and good peroxidase-like activity. The combined effect of PTT and CDT has a stronger bactericidal effect while avoiding high-temperature damage, which makes the W@MoS2 material more advantageous in terms of antimicrobial effect.

Activation of polyamine catabolism promotes glutamine metabolism and creates a targetable vulnerability in lung cancer.

Polyamines are a class of small polycationic alkylamines that play essential roles in both normal and cancer cell growth. Polyamine metabolism is frequently dysregulated and considered a therapeutic target in cancer. However, targeting polyamine metabolism as monotherapy often exhibits limited efficacy, and the underlying mechanisms are incompletely understood. Here we report that activation of polyamine catabolism promotes glutamine metabolism, leading to a targetable vulnerability in lung cancer. Genetic and pharmacological activation of spermidine/spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme of polyamine catabolism, enhances the conversion of glutamine to glutamate and subsequent glutathione (GSH) synthesis. This metabolic rewiring ameliorates oxidative stress to support lung cancer cell proliferation and survival. Simultaneous glutamine limitation and SAT1 activation result in ROS accumulation, growth inhibition, and cell death. Importantly, pharmacological inhibition of either one of glutamine transport, glutaminase, or GSH biosynthesis in combination with activation of polyamine catabolism synergistically suppresses lung cancer cell growth and xenograft tumor formation. Together, this study unveils a previously unappreciated functional interconnection between polyamine catabolism and glutamine metabolism and establishes cotargeting strategies as potential therapeutics in lung cancer.

Iron-Single-Atom Nanozyme with NIR Enhanced Catalytic Activities for Facilitating MRSA-Infected Wound Therapy.

Patients with methicillin-resistant Staphylococcus aureus (MRSA) infections may have higher death rates than those with non-drug-resistant infections. Nanozymes offer a promising approach to eliminating bacteria by producing reactive oxygen species. However, most of the conventional nanozyme technologies encounter significant challenges with respect to size, composition, and a naturally low number of active sites. The present study synthesizes a iron-single-atom structure (Fe-SAC) via nitrogen doped-carbon, a Fe-N5 catalyst (Fe-SAC) with a high metal loading (4.3 wt.%). This catalyst permits the development of nanozymes consisting of single-atom structures with active sites resembling enzymes, embedded within nanomaterials. Fe-SAC displays peroxidase-like activities upon exposure to H2O2. This structure facilitates the production of hydroxyl radicals, well-known for their strong bactericidal effects. Furthermore, the photothermal properties augment the bactericidal efficacy of Fe-SAC. The findings reveal that Fe-SAC disrupts the bacterial cell membranes and the biofilms, contributing to their antibacterial effects. The bactericidal properties of Fe-SAC are harnessed, which eradicates the MRSA infections in wounds and improves wound healing. Taken together, these findings suggest that single Fe atom nanozymes offer a novel perspective on the catalytic mechanism and design, holding immense potential as next-generation nanozymes.

Erratum: Author correction to "Cascade two-stage tumor re-oxygenation and immune re-sensitization mediated by self-assembled albumin-sorafenib nanoparticles for enhanced photodynamic immunotherapy" [Acta Pharm Sin B (2022) 4204-4223].

[This corrects the article DOI: 10.1016/j.apsb.2022.07.023.].

A Hybrid Nanoadjuvant Simultaneously Depresses PD-L1/TGF-ß1 and Activates cGAS-STING Pathway to Overcome Radio-Immunotherapy Resistance.

Currently, certain cancer patients exhibit resistance to radiotherapy due to reduced DNA damage under hypoxic conditions and acquired immune tolerance triggered by transforming growth factor-ß1 (TGF-ß1) and membrane-localized programmed death ligand-1 (PD-L1). Meanwhile, cytoplasm-distributed PD-L1 induces radiotherapy resistance through accelerating DNA damage repair (DDR). However, the disability of clinically used PD-L1 antibodies in inhibiting cytoplasm-distributed PD-L1 limits their effectiveness. Therefore, a nanoadjuvant is developed to sensitize cancer to radiotherapy via multi-level immunity activation through depressing PD-L1 and TGF-ß1 by triphenylphosphine-derived metformin, and activating the cGAS-STING pathway by generating Mn2+ from MnO2 and producing more dsDNA via reversing tumor hypoxia and impairing DDR. Thus, Tpp-Met@MnO2@Alb effectively enhances the efficiency of radiotherapy to inhibit the progression of irradiated local and abscopal tumors and tumor lung metastases, offering a long-term memory of antitumor immunity without discernible side effects. Overall, Tpp-Met@MnO2@Alb has the potential to be clinically applied for overcoming radio-immunotherapy resistance.

Mitochondrial Disruption Nanosystem Simultaneously Depressed Programmed Death Ligand-1 and Transforming Growth Factor-ß to Overcome Photodynamic Immunotherapy Resistance.

Currently, limited photosensitizers possess the capacity to reverse tumor hypoxia and reduce programmed death ligand-1 (PD-L1) and transforming growth factor-ß (TGF-ß) expression simultaneously, hindering the perfect photodynamic therapy (PDT) effect due to acquired immune resistance and the tumor hypoxic microenvironment. To tackle these challenges, in this research, we demonstrated that mitochondrial energy metabolism depression can be utilized as an innovative and efficient approach for reducing the expression of PD-L1 and TGF-ß simultaneously, which may offer a design strategy for a more ideal PDT nanosystem. Through proteomic analysis of 5637 cells, we revealed that tamoxifen (TMX) can incredibly regulate PD-L1 expression in tumor cells. Then, to selectively deliver clinically used mitochondrial energy metabolism depressant TMX to solid tumors as well as design an ideal PDT nanosystem, we synthesized MHI-TMX@ALB by combining a mitochondria-targeted heptamethine cyanine PDT-dye MHI with TMX through self-assembly with albumin (ALB). Interestingly enough, the MHI-TMX@ALB nanoparticle demonstrated effective reversion of tumor hypoxia and inhibition of PD-L1 protein expression at a lower dosage (7.5 times to TMX), which then enhanced the efficacy of photodynamic immunotherapy via enhancing T-cell infiltration. Apart from this, by leveraging the heptamethine dye's targeting capacity toward tumors and TMX's role in suppressing TGF-ß, MHI-TMX@ALB also more effectively mitigated 4T1 tumor lung metastasis development. All in all, the MHI-TMX@ALB nanoparticle could be used as a multifunctional economical PD-L1 and TGF-ß codepression immune-regulating strategy, broadening the potential clinical applications for a more ideal PDT nanosystem.

Recent progress, perspectives, and issues of engineered PD-L1 regulation nano-system to better cure tumor: A review.

Currently, immune checkpoint blockade (ICB) therapies that target the programmed cell death ligand-1 (PD-L1) have been used as revolutionary cancer treatments in the clinic. Apart from restoring the antitumor response of cytotoxic T cells by blocking the interaction between PD-L1 on tumor cells and programmed cell death-1 (PD-1) on T cells, PD-L1 proteins were also newly revealed to possess the capacity to accelerate DNA damage repair (DDR) and enhance tumor growth through multiple mechanisms, leading to the impaired efficacy of tumor therapies. Nevertheless, current free anti-PD-1/PD-L1 therapy still suffered from poor therapeutic outcomes in most solid tumors due to the non-selective tumor accumulation, ineludible severe cytotoxic effects, as well as the common occurrence of immune resistance. Recently, nanoparticles with efficient tumor-targeting capacity, tumor-responsive prosperity, and versatility for combination therapy were identified as new avenues for PD-L1 targeting cancer immunotherapies. In this review, we first summarized the multiple functions of PD-L1 protein in promoting tumor growth, accelerating DDR, as well as depressing immunotherapy efficacy. Following this, the effects and mechanisms of current clinically widespread tumor therapies on tumor PD-L1 expression were discussed. Then, we reviewed the recent advances in nanoparticles for anti-PD-L1 therapy via using PD-L1 antibodies, small interfering RNA (siRNA), microRNA (miRNA), clustered, regularly interspaced, short palindromic repeats (CRISPR), peptide, and small molecular drugs. At last, we discussed the challenges and perspectives to promote the clinical application of nanoparticles-based PD-L1-targeting therapy.

Facile General Injectable Gelatin/Metal/Tea Polyphenol Double Nanonetworks Remodel Wound Microenvironment and Accelerate Healing.

Treating the most widespread complication of diabetes: diabetic wounds poses a significant clinical obstacle due to the intricate nature of wound healing in individuals with diabetes. Here a novel approach is proposed using easily applicable injectable gelatin/metal/tea polyphenol double nanonetworks, which effectively remodel the wound microenvironment and accelerates the healing process. The gelatin(Gel) crosslink with metal ions (Zr4+ ) through the amino acids, imparting advantageous mechanical properties like self-healing, injectability, and adhesion. The nanonetwork's biological functions are further enhanced by incorporating the tea polyphenol metal nanonetwork through in situ doping of the epigallocatechin gallate (EGCG) with great antibacterial, self-healing, antioxidant, and anticancer capabilities. The in vitro and in vivo tests show that this double nanonetworks hydrogel exhibits faster cell migration and favorable anti-inflammatory and antioxidant properties and can greatly reshape the microenvironment of diabetic wounds and accelerate the wound healing rate. In addition, this hydrogel is completely degraded after subcutaneous injection for 7 days, with nondetectable cytotoxicity in H&E staining of major mice organs and the serum level of liver function indicators. Considering the above-mentioned merits of this hydrogel, it is believed that the injectable gelatin/metal/tea polyphenol double nanonetworks have broad biomedical potential, especially in diabetic wound repair and tissue engineering.

NQO-1 activatable NIR photosensitizer for visualization and selective killing of breast cancer cells.

The diagnosis and treatment of breast cancer is of immense importance in improving patient outcomes. The biological marker NAD(P)H:quinone oxidoreductase 1 was utilized to design BrCyS-Q, a near-infrared activatable photosensitizer for breast cancer. BrCyS-Q was successfully employed to diagnose breast cancer cells using fluorescence and photodynamic inhibition. The findings of this research may offer novel insights for the diagnosis and treatment of clinical breast cancer via photodynamic therapy.

Clinical efficacy of the mulligan maneuver for cervicogenic headache: a randomized controlled trial.

Cervicogenic headache is an often observed secondary headache in clinical settings, with patients who endure prolonged and persistent pain being particularly susceptible to mood changes. Currently, the Mulligan is one of the effective methods for CEH. However, there is a lack of evaluation about the strength and frequency of headaches, as well as the assessment of pain-induced emotions, in individuals with CEH using this particular procedure. Herein, we aimed to evaluate the effectiveness of the Mulligan maneuver from a multidimensional perspective of pain intensity and mood. A total of forty patients diagnosed with CEH who satisfied the specified inclusion criteria were recruited and allocated randomly into two groups: the control group and the treatment group, with each group consisting of twenty cases. The control group received health education, while the treatment group received the Mulligan maneuver once daily over a course of 10 treatment sessions.The clinical outcome of patients with CEH in two groups was assessed using the Visual Analog Scale (VAS), Hamilton Anxiety Scale (HAMA), and Hamilton Depression Scale (HAMD). Resting-state functional magnetic resonance imaging was employed to examine variations in brain function activities between the two CEH groups. Brain regions showing differences were identified as regions of interest and subsequently correlated with clinical behavioral measures using Pearson's correlation analysis. The differences in VAS, HAMA and HAMD between the two groups of CEH patients were also statistically significant. The brain regions that showed differences in the ReHo scores between the two groups of CEH patients included the left cerebellum, the frontal gyrus, and the middle temporal gyrus. There was a positive correlation between the left frontal gyrus and VAS, HAMA and HAMD. The left middle temporal gyrus had a negative correlation with VAS, HAMA, and HAMD and the left cerebellum had a positive correlation with VAS correlation. The Mulligan maneuver may improve pain levels and have a moderating effect on pain-related negative emotions by regulating the function of relevant brain regions in CEH patients.