Mahidol University's Institutional Repository
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Recent Submissions
Conformational ligand-directed targeting of calcium-dependent receptors in acute trauma
(2025-01-01) Pasqualini R.; Markosian C.; Staquicini D.I.; Dobroff A.S.; Dodero-Rojas E.; Whitford P.C.; Barbu E.M.; Bronk J.K.; Cardó-Vila M.; Christianson D.R.; Dias-Neto E.; Driessen W.H.P.; Guzman-Rojas L.; Marchiò S.; Nunes D.N.; de Oliveira F.S.; Ozawa M.G.; Proneth B.; Rangel R.; Smith T.L.; Souza G.R.; Staquicini F.I.; Tang F.H.F.; Baze W.B.; Setubal J.C.; Burns J.W.; Dubick M.A.; Gelovani J.G.; Batchinsky A.I.; Mogford J.E.; Wade C.E.; Holcomb J.B.; Burley S.K.; Onuchic J.N.; Arap W.; Pasqualini R.; Mahidol University
Background: Trauma is a leading cause of mortality, but injury-specific molecular targets remain largely unknown. We hypothesized that distinctive yet unrecognized tissue targets accessible to circulating ligands might emerge during trauma, thereby underscoring a trauma-related proteome. Methods: We screened a peptide library to discover targets in a porcine model of major trauma: compound femur fracture with hemorrhagic shock. Bioinformatics yielded conserved motifs, and candidate receptors were affinity purified. In silico and in vitro approaches served to investigate possible associations between candidate receptors and calcium, a major component of skeletal muscle and bone. In vivo homing and molecular imaging (PET/MRI and SPECT/CT) studies of the most promising ligand peptide candidate were performed in the porcine model and were also confirmed in a corresponding rat model of major trauma. Optical methodologies and molecular dynamics simulations served to explore the molecular attributes of the ligand-receptor binding. Findings: Nearly all molecular targets of the selected ligand peptides were calcium-dependent proteins, which become accessible upon trauma. We validated specific binding of homing peptides to these receptors in injured tissues, including CLRGFPALVC:CASQ1, CSEIGVRAC:HSP27, and CRQRPASGC:CALR. Notably, we determined that ligand peptide CRQRPASGC targets an injury-specific calcium-facilitated conformation of calreticulin, enabling specific molecular imaging of trauma. Conclusions: We conceptually propose the term “traumome” for the functional receptor repertoire that becomes readily amenable for ligand-directed targeting upon major trauma. These preclinical findings pave the way toward clinic-ready targeted theragnostic approaches in the setting of trauma. Funding: Major funding was provided by the Defense Advanced Research Projects Agency (DARPA).
Clinical and Multimodal Imaging of Acute Outer Retinopathy: Expanding the Spectrum of Acute Annular Outer Retinopathy
(2025-01-01) Ramtohul P.; Cicinelli M.V.; Chen F.K.; Oh D.J.; Freilich B.D.; Singer M.A.; Hartley M.J.; Biswas J.; Boulanger E.; Bae K.; Lim H.Y.; Sujirakul T.; Gascon P.; Blinder K.J.; Fardeau C.; Pockar S.; Androudi S.; Nakashizuka H.; Kitagawa Y.; Shinojima A.; Miserocchi E.; Freund K.B.; Ramtohul P.; Mahidol University
Purpose: To describe the clinical features, multimodal imaging findings, natural history, and treatment outcomes of acute outer retinopathy (AOR), which represents an expanded spectrum of acute annular outer retinopathy. Design: Retrospective, observational, longitudinal, multicenter case series. Participants: Twenty-three patients (15 female; 8 male) with a mean age of 41.8 ± 18.6 years (range: 14–86 years) and a mean follow-up duration of 3.7 ± 1.5 years (range: 1–12 years). Methods: Clinical characteristics, multimodal imaging findings, laboratory evaluations, genetic testing, natural history, therapeutic management, and outcomes were reviewed and analyzed. Main Outcomes Measures: Specific multimodal imaging signatures of AOR were identified, including findings from ophthalmoscopy, fundus autofluorescence (FAF), fluorescein angiography, indocyanine green angiography (ICGA), and OCT. Humphrey visual field testing, full-field electroretinography (ERG), and multifocal ERG were analyzed. Baseline features and the natural course of the disease were delineated. Results: Thirty-eight eyes from 23 patients were analyzed. Presenting symptoms included photopsia (87%), blurred vision (57%), and scotoma (57%). On ophthalmoscopy, AOR was acutely characterized by yellow-grayish outer retinal lesions corresponding to hyperautofluorescent changes on FAF and the angular sign of Henle fiber layer hyperreflectivity (ASHH) on OCT. Fundus autofluorescence imaging revealed ring-like hyperautofluorescent lesions surrounding the optic disc in 18% of eyes. Additional lesion patterns on FAF included perivenular (53%), sectoral (16%), and spot-like distributions (13%). Fluorescein angiography and ICGA findings were mostly unremarkable. Lesion progression primarily occurred within the initial weeks after presentation and stabilized in size beyond this period in the majority of eyes. Over time, affected areas progressed to outer retinal atrophy with pigmentary changes. Foveal sparing was observed in 68% of the eyes. None of the therapeutic interventions appeared effective in halting the progression to complete outer retinal atrophy or preventing lesion enlargement. Conclusions: Acute outer retinopathy is characterized by early photoreceptor disruption, evidenced by ASHH on OCT, leading to rapid outer retinal atrophy and subsequent degeneration of the retinal pigment epithelium within the damaged zones. Although distinct patterns of lesion distribution were observed, their consistent features on multimodal imaging support their inclusion within a unified disease spectrum termed AOR. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Comparison of homologous and heterologous vaccination strategies for combating disease caused by Burkholderia pseudomallei
(2025-01-01) Biryukov S.S.; Cote C.K.; Klimko C.P.; Dankmeyer J.L.; Rill N.O.; Hunter M.; Davies M.L.; Hedrick Z.M.; Shoe J.L.; Schmidt L.K.; Orne C.E.; Qiu J.; Welkos S.L.; Burtnick M.N.; Brett P.J.; DeShazer D.; Biryukov S.S.; Mahidol University
Introduction: Melioidosis is a major cause of disease and mortality in endemic tropical regions, and the etiologic agent, Burkholderia pseudomallei, is being isolated increasingly from an expanded range of environmental and clinical sources in locations including the United States. The disease can have multi-faceted clinical presentations and requires a complex and protracted treatment regimen which is confounded by resistance of this microbe to numerous antibiotics. Thus, prophylactic countermeasures are needed; however, a vaccine has yet to be licensed for human use. Since B. pseudomallei is classified as a Tier 1 select agent, the development of a safe and effective vaccine is both a military and public health need. Our laboratories have focused on the development of vaccines composed of live attenuated strains and defined subunit antigens. Methods: In the current study, we evaluated homologous and heterologous combinations of candidate subunits and live vaccines in a murine aerosol model of melioidosis to determine the effects of vaccine composition and delivery scheme on protection in conjunction with immune responses and bacterial clearance. Results: Both strategies provided significant protection against lethal aerosol challenges, and the accumulated data support that a heterologous vaccination strategy employing capsular polysaccharide conjugate and Hcp1 subunits and a live but highly safe capsular polysaccharide-producing surrogate strain of B. thailandensis is an effective and potentially agile prophylactic strategy.
Elucidation of phenolic profile and bioactive potential of Aeginetia indica L.: A comparative study between newly discovered yellow and native purple flowers
(2025-08-01) Temviriyanukul P.; Thangsiri S.; Inthachat W.; On–Nom N.; Sahasakul Y.; Aursalung A.; Chupeerach C.; Suttisansanee U.; Temviriyanukul P.; Mahidol University
Aeginetia indica L. is a wild plant, with scant information on its food and medicinal applications. This research investigated the phenolics, antioxidant properties, in vitro medicinal activities, and genotoxicity of the newly discovered yellow and native purple flowers of A. indica collected from diverse locations in Thailand. Purple A. indica harvested from Ubon Ratchathani Province (PU) exhibited 1.3–1.4-fold higher total phenolic content (TPC) and 1.1–1.4-fold higher total flavonoid content (TFC) than purple A. indica collected from Sakon Nakhon Province (PS) and yellow A. indica collected from Sakon Nakhon Province (YS), with apigenin and naringenin predominantly detected in PU by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). The purple color of PU and PS led to 2.5–2.9-fold higher total anthocyanin content (TAC) than YS. Higher phenolic content in PU led to stronger antioxidant activities by 1.2–1.3- and 1.2–1.8-fold as determined by ferric ion reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) assays, respectively, while the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity was not significantly different from PS. PU and PS exhibited 1.1-fold lower scavenging capacities (50 % of total radicals or SC50) than YS, suggesting their higher antioxidant strength. Higher inhibitory activities of most key enzymes relevant to obesity (lipase, 1.6–3.3-fold higher), type II diabetes (α-amylase, 1.3–1.6-fold higher), and Alzheimer's disease (acetylcholinesterase (AChE, 1.6–3.0-fold higher) and butyrylcholinesterase (BChE, 1.1-fold higher)) were also observed in PU. Further investigation of the PU extract with orlistat (a commercially available anti-obesity drug) and donepezil (a commercially available anti-Alzheimer's disease drug) suggested synergistic effects of PU with both drugs. PU did not induce gene mutations as assayed by the bacterial reverse mutation test. The results suggested that PU could be further developed as a future functional food or health ingredient.
Rattus spp. as Reservoirs of Multidrug Resistance- and Biofilm-Forming Escherichia coli in Urban Community from Southern Thailand
(2025-07-01) Mitsuwan W.; Saengsawang P.; Thaikoed S.; Tanthanathipchai N.; Saedan P.; Chaisiri K.; Boonmar S.; Morita Y.; Mitsuwan W.; Mahidol University
Rats are rodents commonly found in Thailand that carry various zoonotic pathogens. Bacterial zoonosis can occur in a shared environment between humans and rats, especially in human communities and agricultural areas. Escherichia coli, particularly pathogenic and multidrug-resistant strains, is a significant public health concern that is transmitted by rats. This study aimed to investigate the antibiotic resistance (ABR) and biofilm formation of E. coli in caught rodents from Nakhon Si Thammarat province, Thailand. Captured rats were dissected to collect intestinal content for E. coli isolation. Two hundred and two confirmed E. coli were subjected for pathotype identification, antibiotic susceptibility testing, biofilm-forming ability (BFA), and the presence of related genes. Two E. coli isolates from intestinal content samples were atypical enteropathogenic (aEPEC). Predominantly, 52.97% of E. coli had azithromycin resistance, which was harbored by 35.64% of captured rats. Multidrug resistance (MDR) was found in 12.38% of E. coli isolates with 17 different MDR patterns. Remarkably, 96% of MDR isolates were resistant to azithromycin. Most E. coli harbored ereA (52%), followed by the blaTEM and aacC2 genes (6.44% each). Approximately 87% of isolated E. coli revealed moderate-to-high BFA. Predominantly, moderate-to-strong biofilm-forming E. coli harbored pgaA and pgaC genes. aEPEC, azithromycin resistance, MDR, and moderate-to-strong formation were the aspects of concern. Furthermore, the study of antibiotic-resistant E. coli in rats should be performed, particularly in terms of the transmission pathway, and the application of rats as bioindicators for ABR surveillance in Thailand should be established.