Zhigang Jin

β-Lactams and macrolides are two cornerstone classes of antimicrobials in clinical practice. Traditionally, this combination was considered potentially antagonistic. However, accumulating evidence from basic and clinical research has begun to challenge this view and indicates that the two classes may exert complementary and synergistic effects in specific clinical contexts. This review first describes the mechanisms of action and resistance of both antibiotic classes, and then presents clinical evidence supporting the use of combination therapy. The greatest clinical benefit of combination therapy is observed in adults with severe community-acquired pneumonia (CAP). By contrast, results from non-severe CAP or pediatric populations have been inconsistent. We then systematically review potential synergistic mechanisms, including complementary antibacterial targets, macrolide penetration facilitated by β-lactam-induced cell-wall injury, suppression of bacterial repair and stress responses, biofilm disruption, immunomodulation, and quorum-sensing interference. We also classify the strength of evidence for each proposed mechanism. Finally, we compare the pharmacokinetic/pharmacodynamic (PK/PD) profiles of azithromycin, clarithromycin, and erythromycin and assess their potential impact on combination efficacy. We also discuss safety concerns, including adverse effects, drug interactions, and selection for resistance, along with strategies to address these issues. It should be emphasized that most mechanistic evidence derives from in vitro or animal studies, and only a minority comes from clinical research. The combination should be used with strict attention to indications, and its benefits should not be extrapolated indiscriminately to other conditions. We conclude that β-lactam–macrolide combination therapy demonstrates promising synergy in severe CAP and other specific infections. The multi-level mechanistic framework lends biological plausibility to the observed synergy, but biological synergy does not guarantee clinical benefit in all patients. Only when used in the right patients, at the right time, and with the right drug combination can this therapeutic strategy produce clinical benefit.

This study addresses the critical clinical challenge of precise identification and treatment of cancer cells by proposing a novel targeting strategy based on differences in plasma membrane viscosity, and accordingly developing a multicharged foldable fluorescent probe, CSP-BP-CSP. Through rational structural design featuring a rigid bipyridine bridge and four cationic pyridinium units, the probe achieves high-affinity membrane anchoring with minimal cellular internalization, thereby significantly improving the signal-to-noise ratio and enabling long-term tracking. CSP-BP-CSP sensitively responds to viscosity variations between cancerous and normal cell membranes, allowing high-contrast specific cancer cell recognition and prolonged membrane labeling. Upon membrane damage, the probe translocates into the nucleus, enabling real-time monitoring of apoptosis. In animal models, CSP-BP-CSP exhibits sustained tumor-specific accumulation and has been successfully applied to fluorescence-guided precise tumor resection. Furthermore, the probe was employed to evaluate the antitumor efficacy of deuterium-enriched water, demonstrating its potential for theranostic integration. This work not only provides a new design strategy for membrane-anchored probes but also offers a versatile molecular platform for precise cancer diagnosis, intraoperative navigation, and treatment monitoring.

Objectives Alzheimer's disease (AD) and mild cognitive impairment (MCI) represent significant health challenges, with identification of biomarkers from non-invasive biofluid critical for large-scale screening and effective intervention. Material and methods In this study, we performed a comprehensive analysis integrating non-targeted metabolomics and 16S rDNA sequencing of saliva samples from 3 age and sex-matched groups containing 18 AD patients, 15 MCI individuals and 19 healthy controls (HC). Results Salivary metabolites including histamine (biogenic amine), carveol (monoterpene), and 2-phosphoglycerate (glycolytic intermediate) were significantly altered in AD patients. In addition, L-glutamic acid (excitatory neurotransmitter) levels were notably reduced in MCI patients, suggesting its potential as a biomarker for MCI. Microbial analysis revealed a decrease in the abundance of Actinomyces and Stomatobaculum in AD patients. In contrast, MCI patients exhibited a reduction in Atopobium and Actinomyces, along with an increase in Gemella and Peptostreptococcus compared to HC. An integrated analysis of microbiota and metabolites uncovered significant correlations, such as a positive correlation between Lactobacillus crispatus and GABA in AD patients, and an association between Klebsiella pneumoniae and multiple metabolites in AD patients. Additionally, MCI patients exhibited a higher abundance of “potentially pathogenic” microbiota species, highlighting a distinct microbiome profile. Conclusions Our findings revealed distinct metabolic and microbiomic alterations across the groups. Clinical relevance These findings suggest that saliva may harbor valuable biomarkers for the early diagnosis of AD and MCI. Moreover, our results underscore the involvement of the “oral-brain axis” in the pathogenesis of neurodegenerative diseases, offering new insights into potential therapeutic targets.

Hierarchical chiral structures have wide applications in materials science and biomedicine. The synthesis of multilevel chiral structures with specific functions is a key issue. In this work, we have successfully designed and synthesized R/S-Co₄Zn₅L₁₀ (L = C₁₆H₁₅O₃N) quinary chiral helix, in which the chirality transfers from the chiral carbon atoms of ligands to octahedral stereochirality, then to a single helix, further to a supramolecular helical chain, and ultimately to the chiral crystal structure. R/S-Co₄Zn₅L₁₀ consists of two chiral building units, R/S-Zn₃L₂ and R/S-CoL₂. R/S-CoL₂ can also agglomerate into R/S-Co₄L₆. The evaluation of the biocompatibility and bioactivity for three pairs of enantiomers reveals that R-Co₄Zn₅L₁₀ and R-CoL₂ effectively restore dopaminergic neuron loss and improve dopamine-dependent locomotion deficits in nematodes. Additionally, these compounds inhibit α-synuclein aggregation during nematode development. These findings suggest that elaborately designed cobalt-based chiral structures have potential as novel therapeutic candidates for Parkinson's disease.

Foam cell formation is a key pathological event in atherosclerosis, which can be used as an early diagnosis and drug selection platform for atherosclerotic disease. Current methods are hindered by an inability to distinguish pathological lipid aggregates in foam cells from normal lipid droplets in healthy macrophages in a live-cell context. Herein, we developed and synthesized a membrane-impermeable, near-infrared fluorescent probe named FMNIR-DBO for high-fidelity imaging of foam cell formation. The membrane impermeability was achieved by incorporating a charged, rigid moiety into a near-infrared D-π-A fluorophore, thereby enabling long-term anchoring to the plasma membrane in live cells. This probe uniquely exploits the loss of plasma membrane integrity that occurs as macrophages transform to foam cells. Consequently, FMNIR-DBO remains extracellular to healthy cells but selectively enters foam cells to illuminate pathological lipid aggregates, thereby eliminating interference from normal lipid droplets. This strategy enables rapid, dynamic imaging of lipid accumulation in living foam cells within 6 h, a 75% reduction in time compared to conventional Oil Red O staining. Furthermore, FMNIR-DBO was used to evaluate the cellular-level effects of ethanol on foam cell formation, providing robust evidence to support its role in excess-alcohol-induced atherosclerotic disease progression.

Stable fluorescent labeling holds significant value in elucidating the roles of plasma membrane during various cellular processes. However, current plasma membrane probes primarily rely on noncovalent labeling strategies that often results in poor label stability over long-term observations. To address this limitation, we introduce an innovative electrostatic-directed covalent labeling strategy. Our findings demonstrate that this method enables ultralong-term tracking of plasma membrane dynamics through covalent labeling of pan-membrane proteins in live cells, addressing the growing demand for prolonged monitoring of plasma membranes during cellular processes requiring temporal resolution down to the hourly scale. The optimal probe, Sulfo-Cy5-Br, consists of a Cy5 fluorophore conjugated with two sulfonate groups and a central bromide atom. The reactive bromide group facilitates covalent attachment to proteins via nucleophilic substitution with amino or thiol groups in proteins, which ensures stable binding to plasma membrane proteins. The incorporation of two negatively charged sulfonate groups not only ensures excellent water solubility and cell impermeability during the labeling process but also enables electrostatic interaction between negatively charged probes and partially protonated amino groups on plasma membrane proteins. Moreover, the probe can detect plasma membrane damage by transferring its label, enabling real-time assessment of plasma membrane damage status during long-term cellular events. Notably, the labeling stability of the plasma membrane with Sulfo-Cy5-Br persists for up to 44 h, allowing continuous tracking of plasma membrane morphology and damage during prolonged cellular processes such as pyroptosis and necroptosis, which typically span several-to-tens hours.

Saliva, a non-invasive biofluid with a variety of biomolecules, has been increasingly recognized as a reliable specimen in the diagnostics of viral infections. Compared to the standard specimens represented by blood and nasopharyngeal swab, saliva is advantageous in non-invasive, simple collection, convenient storage and compatibility with self-testing and large-scale screening. Saliva is an all-round specimen for viral detection as the shedding of viral nucleic acid fragments, antigens and the secretion of virus-specific antibodies are present in saliva. Accordingly, saliva has been widely used to detect a variety of viruses, including saliva-borne, air-borne and blood-borne transmitted viruses. However, challenges also arise as diverse methods during collection, storage and processing of the saliva could lead to discordant results among different studies. It is now aware that the methodology of saliva sampling is critical to the detection of viral biomarkers in the accuracy, repeatability and consistence with the data retrieved from the standard specimens. Therefore, establishing a standardized procedure for saliva sampling is crucial. Here we focus on a dozen factors that may affect the results of salivary diagnostic of viral infections and suggest a set of standardized procedures for saliva sampling, aiming to minimize result variation and benefit the application of saliva in salivary diagnostics of viral infections.