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Inflammatory environments provide vital biochemical stimuli (i.e., oxidative stress, pH, and enzymes) for triggered drug delivery in a controlled manner. Inflammation alters the local pH within the affected tissues. As a result, pH-sensitive nanomaterials can be used to effectively target drugs to the site of inflammation. Herein, we designed pH-sensitive nanoparticles in which resveratrol (an anti-inflammatory and antioxidant compound (RES)) and urocanic acid (UA) were complexed with a pH-sensitive moiety using an emulsion method. These RES-UA NPs were characterized by transmission electron microscopy, dynamic light scattering, zeta potential, and FT-IR spectroscopy. The anti-inflammatory and antioxidant activities of the RES-UA NPs were assessed in RAW 264.7 macrophages. The NPs were circular in shape and ranged in size from 106 to 180 nm. The RES-UA NPs suppressed the mRNA expression of the pro-inflammatory molecules inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages in a concentration-dependent manner. Incubation of LPS-stimulated macrophages with RES-UA NPs reduced the generation of reactive oxygen species (ROS) in a concentration-dependent manner. These results suggest that pH-responsive RES-UA NPs can be used to decrease ROS generation and inflammation.

We conducted a nationwide population-based cohort study to identify the risk factors associated with failure of total ankle arthroplasty (TAA). We included 2,914 subjects who underwent primary TAA between January 1, 2010, and December 31, 2016, utilizing the database of the Korean National Health Insurance Service. Failure of TAA was defined as revision TAA or arthrodesis procedures. An increased risk of TAA failure was observed in the < 65 age group versus the ≥ 75 age group [adjusted hazard ratios (aHR) 2.273, 95% confidence interval (CI) 1.223–4.226 in the 60–64 age group; aHR 2.697, 95% CI 1.405–5.178 in the 55–59 age group; aHR 2.281, 95% CI 1.145–4.543 in the 50–54 age group; aHR 2.851, 95% CI 1.311–6.203 in the < 50 age group]. Conversely, the ≥ 65 age group displayed no increase in the risk of TAA failure. The risk of TAA failure was increased in the severely obese group with body mass index (BMI) of ≥ 30 kg/m 2 versus the normal BMI group (aHR 1.632; 95% CI 1.036–2.570). This population-based longitudinal study demonstrated that age < 65 years and BMI of ≥ 30 kg/m 2 were associated with increased risk of TAA failure.

Although the use of topical skin adhesives has increased as an alternative to conventional skin closure methods, studies on the incidence and risk factors of allergic contact dermatitis (ACD) to topical skin adhesives have been limited. The purpose of this study was to investigate the incidence and risk factors of ACD after the use of 2-octyl cyanoacrylate and n-butyl cyanoacrylate topical skin adhesives. We retrospectively reviewed 1145 patients (739 patients with 2-octyl cyanoacrylate and 406 patients with n-butyl cyanoacrylate) who underwent skin closure with topical skin adhesives. Variables suspected to correlate with ACD were retrieved from medical records and analyzed to determine risk factors. The incidence of ACD from the use of 2-octyl cyanoacrylate and n-butyl cyanoacrylate topical skin adhesives was 2.7% and 2.2%, respectively. There was no statistically significant difference in the incidence between the two ingredients. In logistic regression analysis, none of the variables were found to increase the risk of ACD in both 2-octyl cyanoacrylate and n-butyl cyanoacrylate topical skin adhesives. As ACD occurs without risk factors in 2–3% of patients who used 2-octyl cyanoacrylate or n-butyl cyanoacrylate topical skin adhesives, clinicians and patients should be aware of these facts before using topical skin adhesives.

Cold-active lipolytic enzymes enable low-temperature biocatalysis, but remain underexplored in Antarctic actinomycetes. Here, we report the discovery and first-step characterization of a CALB-like cold-active lipolytic enzyme (PanLip) from Pseudonocardia antarctica. Sequence and structure analyses revealed a canonical α/β-hydrolase fold with a conserved Ser–Asp–His triad and short helical elements around the pocket reminiscent of CALB’s α5/α10 lid. Mature PanLip was expressed primarily as inclusion bodies in E. coli; an N-terminally truncation (PanLipΔN) improved solubility and PanLipΔN was purified by Ni–NTA. Far-UV CD confirmed a folded α/β architecture. PanLipΔN favored short-chain substrates (p-NPA, kcat/KM = 2.4 × 105 M−1·s−1) but also showed measurable hydrolytic activity toward natural triglycerides, consistently with a lipase-family esterase. The enzyme showed an activity optimum near 25 °C and pH 8.0. The enzyme tolerated low salt (maximal at 0.1 M NaCl), mild glycerol, and selected organic solvents (notably n-hexane), but was inhibited by high salt, Triton X-100, and SDS. AlphaFold predicted high local confidence for the catalytic core; DALI placed PanLip closest to fungal lipases (AFLB/CALB). Temperature-series MD and CABS-flex indicated enhanced surface breathing and flexible segments adjacent to the active site—including a region topologically matching CALB α10—supporting a flexibility-assisted access mechanism at low temperature. Structure-based MSAs did not support a cold adaptation role for the reported VDLPGRS motif. Taken together, these findings position PanLip as a promising cold-active catalyst with CALB-like access control and potential for low-temperature biocatalysis.

The expression of aminoglycoside-modifying enzymes represents a survival strategy of antibiotic-resistant bacteria. Aminoglycoside 2′- N -acetyltransferase [AAC(2′)] neutralizes aminoglycoside drugs by acetylation of their 2′ amino groups in an acetyl coenzyme A (CoA)-dependent manner. To understand the structural features and molecular mechanism underlying AAC(2′) activity, we overexpressed, purified, and crystallized AAC(2′) from Mycolicibacterium smegmatis [AAC(2′)-Id] and determined the crystal structures of its apo-form and ternary complexes with CoA and four different aminoglycosides (gentamicin, sisomicin, neomycin, and paromomycin). These AAC(2′)-Id structures unraveled the binding modes of different aminoglycosides, explaining the broad substrate specificity of the enzyme. Comparative structural analysis showed that the α4-helix and β8–β9 loop region undergo major conformational changes upon CoA and substrate binding. Additionally, structural comparison between the present paromomycin-bound AAC(2′)-Id structure and the previously reported paromomycin-bound AAC(6′)-Ib and 30S ribosome structures revealed the structural features of paromomycin that are responsible for its antibiotic activity and AAC binding. Taken together, these results provide useful information for designing AAC(2′) inhibitors and for the chemical modification of aminoglycosides.

Escherichia coli diacylglycerol kinase (DAGK) represents a family of integral membrane enzymes that is unrelated to all other phosphotransferases. We have determined the three-dimensional structure of the DAGK homotrimer with the use of solution nuclear magnetic resonance. The third transmembrane helix from each subunit is domain-swapped with the first and second transmembrane segments from an adjacent subunit. Each of DAGK's three active sites resembles a portico. The cornice of the portico appears to be the determinant of DAGK's lipid substrate specificity and overhangs the site of phosphoryl transfer near the water-membrane interface. Mutations to cysteine that caused severe misfolding were located in or near the active site, indicating a high degree of overlap between sites responsible for folding and for catalysis.

Calcium carbonate (CaCO3)-based materials have received notable attention for biomedical applications owing to their safety and beneficial characteristics, such as pH sensitivity, carbon dioxide (CO2) gas generation, and antacid properties. Herein, to additionally incorporate antioxidant and anti-inflammatory functions, we prepared tannylated CaCO3 (TA-CaCO3) materials using a simple reaction between tannic acid (TA), calcium (Ca2+), and carbonate (CO32−) ions. TA-CaCO3 synthesized at a molar ratio of 1:75 (TA:calcium chloride (CaCl2)/sodium carbonate (Na2CO3)) showed 3–6 μm particles, comprising small nanoparticles in a size range of 17–41 nm. The TA-CaCO3 materials could efficiently neutralize the acid solution and scavenge free radicals. In addition, these materials could significantly reduce the mRNA levels of pro-inflammatory factors and intracellular reactive oxygen species, and protect chondrocytes from toxic hydrogen peroxide conditions. Thus, in addition to their antacid property, the prepared TA-CaCO3 materials exert excellent antioxidant and anti-inflammatory effects through the introduction of TA molecules. Therefore, TA-CaCO3 materials can potentially be used to treat inflammatory cells or diseases.

Tendon rupture induces an inflammatory response characterized by release of pro-inflammatory cytokines and impaired tendon performance. This study sought to investigate the therapeutic effects of simvastatin-loaded porous microspheres (SIM/PMSs) on inflamed tenocytes in vitro and collagenase-induced Achilles tendinitis in vivo. The treatment of SIM/PMSs in lipopolysaccharide (LPS)-treated tenocytes reduced the mRNA expressions of pro-inflammatory cytokines (Matrix metalloproteinase-3 (MMP-3), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)). In addition, the local injection of SIM/PMSs into the tendons of collagenase-induced Achilles tendinitis rat models suppressed pro-inflammatory cytokines (MMP-3, COX-2, IL-6, TNF-α, and MMP-13). This local treatment also upregulated anti-inflammatory cytokines (IL-4, IL-10, and IL-13). Furthermore, treatment with SIM/PMSs also improved the alignment of collagen fibrils and effectively prevented collagen disruption in a dose-dependent manner. Therefore, SIM/PMSs treatment resulted in an incremental increase in the collagen content, stiffness, and tensile strength in tendons. This study suggests that SIM/PMSs have great potential for tendon healing and restoration in Achilles tendinitis.

Glycol chitosan (GC) and its derivatives have been extensively investigated as safe and effective drug delivery carriers because of their unique physiochemical and biological properties. The reactive functional groups such as the amine and hydroxyl groups on the GC backbone allow for easy chemical modification with various chemical compounds (e.g., hydrophobic molecules, crosslinkers, and acid-sensitive and labile molecules), and the versatility in chemical modifications enables production of a wide range of GC-based drug carriers. This review summarizes the versatile chemical modification methods that can be used to design GC-based drug carriers and describes their recent applications in disease therapy.

IntroductionTo date, only few studies have been performed on the accuracy of manual angle manipulation during orthopedic surgery. This cadaver study was aimed at quantitatively assessing the accuracy of manual angle manipulation performed by orthopedic surgeons according to their surgical experience and comparing it with manipulation performed with the assistance of a digital goniometer.Materials and methodsSix lower-leg specimens of fresh-frozen human cadavers were subjected to angle manipulation performed via Kirschner wire (K-wire) insertion. K-wires were inserted manually and with the assistance of a digital goniometer at target angles of 0°, 30°, and 60° by three operators who had different levels of experience in orthopedic surgery. The accuracy of the insertion angles at the target angles was evaluated using computed tomography.ResultsThe mean angle error in the manual angle manipulation was 8.8° (standard deviation [SD] 6.0). When the target angles were set to 0°, 30°, and 60°, the identified angle errors were 6.1° (SD 4.3), 8.8° (SD 6.6), and 11.7° (SD 5.6), respectively, and each value did not show any significant difference among the operators. With the assistance of a digital goniometer, the mean (SD) angle error was significantly improved to 2.1° (1.1°) (p < 0.001). The amount of improvement in accuracy significantly increased as the target angle increased (p = 0.01).ConclusionThis cadaver study quantified the inaccuracy of manual angle manipulation in orthopedic surgery and showed that these inaccuracies ​​can be improved using an assistive device. These results support the need to develop a device that can compensate manual angle manipulation in orthopedic surgery.