The emergence of multidrug‐resistant bacteria poses a significant challenge in the treatment of osteomyelitis, rendering traditional antibiotic treatment strategies inadequate in terms of achieving a complete cure. In recent years, triggerable biomaterial‐based, antibiotic‐free osteomyelitis treatment strategies have rapidly evolved, demonstrating excellent bactericidal effects. Triggerable biomaterials‐based osteomyelitis theranostics encompass physical signal response strategies and host immune modulation approaches. These strategies can be effective against drug‐resistant bacteria, circumventing the gradual acquisition of resistance that often accompanies traditional antibiotic treatment. Additionally, the inherent physical properties of the triggerable biomaterials facilitate the precise imaging of osteomyelitis. There is no doubt that triggerable biomaterial‐mediated, antibiotic‐free therapies are emerging as a trend, which is critically important in combating multidrug‐resistant bacteria‐induced osteomyelitis. In this review, we summarize the latest advances in osteomyelitis treatment strategies from both pathogen‐directed and host‐directed perspectives. The design regimens and specific action mechanisms of triggerable biomaterial‐based nanoplatforms are also clarified. Finally, we outline the challenges faced by various antibiotic‐free therapies and provide an outlook on the prospects for synergistic interactions.

Most antirheumatic drugs with high toxicity exhibit a narrow therapeutic window due to their nonspecific distribution in the body, leading to undesirable side effects and reduced patient compliance. To in response to these challenges, prodrug-based nanoparticulate drug delivery systems (PNDDS), which combines prodrug strategy and nanotechnology into a single system, resulting their many advantages, including stability for prodrug structure, the higher drug loading capacity of the system, improving the target activity and bioavailability, and reducing their untoward effects. PNDDS have gained attention as a method for relieving arthralgia syndrome of rheumatoid arthritis in recent years. This article systematically reviews prodrug-based nanocarriers for rheumatism treatment, including Nano systems based on prodrug-encapsulated nanomedicines and conjugate-based nanomedicines. It provides a new direction for the clinical treatment of rheumatoid arthritis.

Simotinib hydrochloride (SIM6802), which is a new epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), is often prescribed for cancer patients with comorbidities and has serious adverse effects on gastrointestinal physiology. The drug-drug interactions (DDIs) between simotinib and other drugs in combination and the underlying mechanism of its gastrointestinal toxicity remain unclear. We hypothesized that the DDIs and the gastrointestinal toxicity of simotinib were related to its effects on the permeability of the intestine. To determine the intestinal absorption capacity, pharmacokinetic studies and an in situ loop assay were used. The intestinal permeability was measured by a Caco-2 Transwell model. Real time PCR and Western blots were applied to detecting the expression changes of cell junction genes. Our research demonstrated that simotinib upregulated the absorption of cefaclor, valaciclovir and acyclovir. The increase of non-selective absorption was caused by the low expression of cell junction gene afadin-6 and the increase in paracellular permeability in intestinal epithelial cells after simotinib treatment. These findings revealed that simotinib upregulated intestinal absorption by increasing the paracellular permeability of intestinal epithelial cells. Our research provides theoretical bases for better formulation of EGFR-TKIs to alleviate adverse gastrointestinal effects and also provides guidance for clinical administration of simotinib.

Background and Aims: Hepatocyte keratin polypeptides 8/18 (K8/K18) are unique among intermediate filaments proteins (IFs) in that their mutation predisposes to, rather than causes, human disease. Mice that overexpress human K18 R90C manifest disrupted hepatocyte keratin filaments with hyperphosphorylated keratins and predisposition to Fas‐induced liver injury. We hypothesized that high‐throughput screening will identify compounds that protect the liver from mutation‐triggered predisposition to injury. Approach and Results: Using A549 cells transduced with a lentivirus K18 construct and high‐throughput screening, we identified the SRC‐family tyrosine kinases inhibitor, PP2, as a compound that reverses keratin filament disruption and protects from apoptotic cell death caused by K18 R90C mutation at this highly conserved arginine. PP2 also ameliorated Fas‐induced apoptosis and liver injury in male but not female K18 R90C mice. The PP2 male selectivity is due to its lower turnover in male versus female livers. Knockdown of SRC but not another kinase target of PP2, protein tyrosine kinase 6, in A549 cells abrogated the hepatoprotective effect of PP2. Phosphoproteomic analysis and validation showed that the protective effect of PP2 associates with Ser/Thr but not Tyr keratin hypophosphorylation, and differs from the sex‐independent effect of the Ser/Thr kinase inhibitor PKC412. Inhibition of RAF kinase, a downstream target of SRC, by vemurafenib had a similar protective effect to PP2 in A549 cells and male K18 R90C mice. Conclusions: PP2 protects, in a male‐selective manner, keratin mutation‐induced mouse liver injury by inhibiting SRC‐triggered downstream Ser/Thr phosphorylation of K8/K18, which is phenocopied by RAF kinase inhibitor vemurafenib. The PP2/vemurafenib‐associated findings, and their unique mechanisms of action, further support the potential role of select kinase inhibition as therapeutic opportunities for keratin and other IF‐associated human diseases.

Exposure of isolated mouse livers, primary cultured hepatocytes, or mice to hypoosmosis/hyponatremia conditions induces significant mitochondrial shape alterations accompanied by preferential release of the mitochondrial matrix protein CPS1, a urea cycle enzyme. In contrast, the intermembrane space protein, cytochrome c, and two other matrix proteins, including the urea cycle enzyme ornithine transcarbamylase, remain preferentially retained in mitochondria. Therefore, hepatocyte CPS1 manifests unique mitochondrial stress response compartmentalization and is a sensitive sensor of mitochondrial hypoosmotic/hyponatremic injury.

Keratin (K) and other intermediate filament (IF) protein mutations at conserved arginines disrupt keratin filaments into aggregates and cause human epidermolysis bullosa simplex (EBS; K14-R125C) or predispose to mouse liver injury (K18-R90C). The challenge for more than 70 IF-associated diseases is the lack of clinically utilized IF-targeted therapies. We used high-throughput drug screening to identify compounds that normalized mutation-triggered keratin filament disruption. Parthenolide, a plant sesquiterpene lactone, dramatically reversed keratin filament disruption and protected cells and mice expressing K18-R90C from apoptosis. K18-R90C became hyperacetylated compared with K18-WT and treatment with parthenolide normalized K18 acetylation. Parthenolide upregulated the NAD-dependent SIRT2, and increased SIRT2-keratin association. SIRT2 knockdown or pharmacologic inhibition blocked the parthenolide effect, while site-specific Lys-to-Arg mutation of keratin acetylation sites normalized K18-R90C filaments. Treatment of K18-R90C–expressing cells and mice with nicotinamide mononucleotide had a parthenolide-like protective effect. In 2 human K18 variants that associate with human fatal drug-induced liver injury, parthenolide protected K18-D89H– but not K8-K393R–induced filament disruption and cell death. Importantly, parthenolide normalized K14-R125C–mediated filament disruption in keratinocytes and inhibited dispase-triggered keratinocyte sheet fragmentation and Fas-mediated apoptosis. Therefore, keratin acetylation may provide a novel therapeutic target for some keratin-associated diseases.