Phototherapy promotes anti-tumor immunity by inducing immunogenic cell death (ICD), However, the accompanying inflammatory responses also trigger immunosuppression, attenuating the efficacy of photo-immunotherapy. Herein, they co-assembled a cell-membrane targeting chimeric peptide C16-Cypate-RRKK-PEG8-COOH (CCP) and anti-inflammatory diclofenac (DA) to develop a nanodrug (CCP@DA) that both enhances the immune effect of phototherapy and weakens the inflammation-mediated immunosuppression. CCP@DA achieves cell membrane-targeting photodynamic and photothermal synergistic therapies to damage programmed death ligand 1 (PD-L1) and induce a strong ICD to activate anti-tumor response. Simultaneously, the released DA inhibits the cycoperoxidase-2 (COX-2)/prostaglandin E2 (PGE2) pathway in tumor cells to inhibit pro-tumor inflammation and further down-regulate PD-L1 expression to relieve the immunosuppressive microenvironment. CCP@DA significantly inhibited tumor growth and inflammation both in vitro and in vivo, while maintaining a potent anti-tumor immune response. Additionally, it exhibits excellent anti-metastatic capabilities and prolongs mouse survival time with a single dose and low levels of near-infrared (NIR) light exposure. This work provides a valuable strategy to control the therapy-induced inflammation for high-efficiency photoimmunotherapy.

The prevalence of drug-resistant bacteria presents a significant challenge to the antibiotic treatment of Helicobacter pylori (H. pylori), while traditional antimicrobial agents often suffer from shortcomings such as poor gastric retention, inadequate alleviation of inflammation, and significant adverse effects on the gut microbiota. Here, a selenized chitosan (CS-Se) modified bismuth-based metal-organic framework (Bi-MOF@CS-Se) nanodrug is reported that can target mucin through the charge interaction of the outer CS-Se layer to achieve mucosal adhesion and gastric retention. Additionally, the Bi-MOF@CS-Se can respond to gastric acid and pepsin degradation, and the exposed Bi-MOF exhibits excellent antibacterial properties against standard H. pylori as well as clinical antibiotic-resistant strains. Remarkably, the Bi-MOF@CS-Se effectively alleviates inflammation and excessive oxidative stress by regulating the expression of inflammatory factors and the production of reactive oxygen species (ROS), thereby exerting therapeutic effects against H. pylori infection. Importantly, this Bi-MOF@CS-Se nanodrug does not affect the homeostasis of gut microbiota, providing a promising strategy for efficient and safe treatment of H. pylori infection.

UNASSIGNED: Intervertebral disc degeneration (IDD) is closely related to heightened inflammation in the annulus fibrosis (AF) and nucleus pulposus (NP) cells in the intervertebral disc. An imbalanced matrix homeostasis has been shown to contribute to disc degeneration and associated discogenic low back pain. Metformin, a diabetes medication, has been noted to exhibit anti-inflammatory properties through upregulation of the AMPK pathway, leading to various anti-inflammatory-related responses in hepatocytes. However, it is still unclear how metformin influences disc cellular response to inflammatory stress and the corresponding mechanism. Hence, the objective of this study is to elucidate the effects of metformin on expression of key pro-inflammatory, catabolic, and anabolic factors within rat AF cells in response to inflammatory stimulation and mechanical tensile stress.
UNASSIGNED: Five Fischer 344 rats were sacrificed and their spines isolated. AF cells were cultured and plated in flexible silicone membrane-based six-well plates. Wells were split into eight groups and subjected to metformin, IL-1β, mechanical stretch, and combined treatments. Relative gene expressions of MMP-13, COX-2, iNOS, AGC, and Col1 were assessed with quantitative real-time polymerase chain reaction (qRT-PCR), and downstream prostaglandin E2 (PGE2) production was quantified with enzyme-linked immunosorbent assay (ELISA). NF-kB nuclear translocation was also quantified.
UNASSIGNED: Metformin in the presence of the combined stress treatments (M + IL/S) significantly increased Col1, COX-2, and MMP-13 gene expression, decreased PGE2 production compared to IL/S conditions alone. Metformin treatment of cultured rat annulus fibrosus cells significantly reduced the nuclear translocation of NF-κB after 4 h of IL-1β treatment from 43.1% in case of IL-1β treatment down to 26.2% in the case of metformin + IL-1β treatment.
UNASSIGNED: The lack of metformin-mediated suppression of inflammatory response in the nonstretch groups indicates that metformin may be enacting its effects through a stretch-dependent manner. These results suggest a foundation for pursuing further research into metformin\'s potential role as an anti-inflammatory agent for curtailing intervertebral disc degeneration.

BACKGROUND: The syndrome of constipation with other abdominal symptoms (\"proximal constipation\") in ulcerative colitis (UC) is commonly recognized by practitioners but is poorly described, with no recognized definition and little understanding with regard to prevalence and effect of therapies on disease outcomes. This study aimed to address these issues in a cross-sectional, consecutive series of patients with UC.
METHODS: A working definition of proximal constipation was established. Consecutive patients were recruited, and their disease activity, recent medications, and investigations plus abdominal symptoms were assessed at a study visit. Relevant clinical data were also extracted from medical records.
RESULTS: Of 125 patients with UC, (mean age 47, range 14-84 years, 61 male), 58 (46%) fulfilled the definition of proximal constipation. The main symptoms were reduced stool frequency (69%), hard stools (43%), abdominal pain (40%), excessive flatus (29%), straining (24%), and sensation of incomplete emptying (14%). Proximal constipation was associated with female gender (OR 3.45 [1.45-8.24]), left-sided (OR 2.84 [1.14-7.11]) and concurrently active disease (OR 5.56 [1.96-16.67]), but not age, disease duration or therapy. A total of 88% had an increase in anti-inflammatory therapy, with the use of laxatives or fiber supplements in 63% compared with 1.4% of those without proximal constipation.
CONCLUSIONS: Proximal constipation is common, and its risk increases in active and distal disease, especially in women. Validation of its definition and evaluation of therapeutic strategies are needed. A new term \"ulcerative colitis-associated constipation syndrome\" is proposed to more accurately depict its nature.

Macrophages contribute to tissue homeostasis and influence inflammatory responses by modulating their phenotype in response to the local environment. Understanding the molecular mechanisms governing this plasticity would open new avenues for the treatment for inflammatory disorders. We show that deletion of calcineurin (CN) or its inhibition with LxVP peptide in macrophages induces an anti-inflammatory population that confers resistance to arthritis and contact hypersensitivity. Transfer of CN-targeted macrophages or direct injection of LxVP-encoding lentivirus has anti-inflammatory effects in these models. Specific CN targeting in macrophages induces p38 MAPK activity by downregulating MKP-1 expression. However, pharmacological CN inhibition with cyclosporin A (CsA) or FK506 did not reproduce these effects and failed to induce p38 activity. The CN-inhibitory peptide VIVIT also failed to reproduce the effects of LxVP. p38 inhibition prevented the anti-inflammatory phenotype of CN-targeted macrophages, and mice with defective p38-activation were resistant to the anti-inflammatory effect of LxVP. Our results identify a key role for CN and p38 in the modulation of macrophage phenotype and suggest an alternative treatment for inflammation based on redirecting macrophages toward an anti-inflammatory status.