Biomedical subjects

Dongdong Zhao

Publications and source records attributed to Dongdong Zhao.

8 recordsLinked to original sources

PubMed2026

Base editing for precision therapeutics.

Base editing (BE), the precise installation of single-nucleotide changes in DNA or RNA without inducing double-strand breaks, holds substantial therapeutic promise for correcting single-nucleotide variants, which constitute more than half of the known pathogenic genetic variants. Recent advances have improved base editor specificity, efficiency, and delivery, enabling clinically oriented procedures. Clinically, BE has shown early success or strong translational promise in sickle cell disease, β-thalassemia, leukemia (via CAR T and epitope engineering), hypercholesterolemia (PCSK9 and ANGPTL3), alpha-1-antitrypsin deficiency, and glycogen storage disease type Ia. Key remaining challenges include bystander editing within the activity window, residual off-target DNA and RNA editing, delivery constraints (payload size, tissue targeting, and redosing limits), immunogenicity, and the need for durable long-term safety evidence across relevant cell types and disease contexts. Continued technological refinements, careful preclinical validation, and rigorous clinical assessment will be essential to fully realize BE's transformative potential in precision medicine.

Humans↗

PubMed2026

Multi-omics reveals that burdock seed aglycone alleviates renal fibrosis by restoring mitochondrial oxidative phosphorylation function.

Renal fibrosis (RF), a common pathological process driving chronic kidney disease (CKD) progression to end-stage renal failure, is closely associated with oxidative phosphorylation (OXPHOS). Arctigenin (ATG), the main active component of burdock seed, exhibits anti-inflammatory and anti-fibrotic activities, but its mechanisms in RF treatment remain unclear. Here, we performed integrated transcriptomic and proteomic analyses to identify key targets and pathways of ATG in a unilateral ureteral obstruction-induced rat RF model. Multi-omics enrichment analysis revealed that NDUFS8 and NDUFS2 were the core targets of ATG, with the OXPHOS pathway as the central intersecting pathway. Our results suggest that ATG exerts anti-renal fibrosis effects by targeting the OXPHOS pathway to inhibit excessive reactive oxygen species production and oxidative stress. SIGNIFICANCE: Chronic kidney disease (CKD) continues to impose an escalating global health and socioeconomic burden, while renal fibrosis (RF), as the convergent pathological endpoint of virtually all progressive nephropathies, remains the principal determinant of irreversible renal failure and adverse clinical outcomes. Despite extensive efforts to develop antifibrotic therapies, effective clinical interventions remain elusive, largely due to the complex and multifactorial nature of RF pathogenesis. In this study, we employed an integrated multi-omics framework encompassing transcriptomics, proteomics, and metabolomics to systematically decipher the antifibrotic mechanism of arctigenin (ATG), a bioactive natural compound derived from traditional Chinese medicine. Our findings identify mitochondrial oxidative phosphorylation as the pivotal regulatory axis underlying the renoprotective effects of ATG and further establish key catalytic subunits of mitochondrial complex I as its direct molecular targets. Mechanistically, ATG not only restores complex I activity and reprograms mitochondrial energy metabolism but also preserves the intracellular stability and localization of these subunits, thereby preventing their aberrant release-mediated inflammatory activation and disrupting the self-perpetuating cycle linking metabolic dysfunction, inflammation, and fibrosis progression. Beyond revealing a previously unrecognized dual mechanism integrating metabolic and inflammatory regulation, this study provides compelling evidence that mitochondrial dysfunction is not merely a secondary consequence of tissue injury but a fundamental driver of fibrotic remodeling. Importantly, our work highlights the translational potential of natural product-based mitochondrial interventions for CKD treatment and supports a broader conceptual shift toward metabolism-centered therapeutic strategies for chronic fibrotic diseases. Given the central role of mitochondrial dysfunction across multiple organs, these findings may also have far-reaching implications for the treatment of systemic fibrosis-related disorders beyond the kidney.

Animals↗

PubMed2006

Abnormal intracellular calcium handling underlying T-wave alternans and its hysteresis.

AIMS: To investigate the mechanism underlying T-wave alternans (TWA) and its hysteresis under ischemia conditions. METHODS: Transmembrane action potential (AP) from endocardial, M, and epicardial cells and monophasic AP (MAP) from four epicardial sites were recorded in ventricular wedge preparation and in isolated intact rabbit heart, respectively. The AP/MAP duration (APD/ MAPD), effective refractory period (ERP), activation time, and APD/MAPD restitution were determined under control and ischemia conditions. The effects of ryanodine (0.01 and 1 micromol x l(-1)) on TWA, and the effects of low extracellular Ca2+ and 4-aminopyridine on its hysteresis were studied. RESULTS: Ischemia shortened the APD/MAPD and effective refractory period of all recording sites symmetrically, except the APD of M cells, which shortened markedly. In the ischemia group, TWA was induced within a cycle length (CL) range from 160 to 250 ms, which corresponded to a diastolic interval region of 0-70 ms. In this diastolic interval region, the repolarization restitution curve was the steepest (slope > 1.0). All TWA were accompanied by repolarization alternations. Low concentration ryanodine (0.01 micromol x l(-1)) facilitated TWA, high concentration (1 micromol x l(-1)) abolished it. Alternans of calcium transient were observed in myocytes purfused with ischemia solution during rapid stimulation. Ryanodine (0.1 micromol x l(-1)) abolished alternans of calcium transient, and ryanodine (0.01 micromol x l(-1)) facilitated them. After 60 min pacing at a CL of 200 ms, TWA persisted until the initial several beats at a CL of 300 ms at which a TWA was exceptional. The suppression of hysteresis by low extracellular Ca2+ and 4-aminopyridine indicated an underlying role of the intracellular Ca2+ overload and transient outward current (I(to)). CONCLUSION: TWA is principally due to repolarization alternans, which is secondary to steep APD/MAPD restitution, and relates to intracellular calcium cycling. Hysteresis relates to intracellular Ca2+ overload and I(to).

4-Aminopyridine↗

PubMed2006

Effects of metoprolol on sympathetic remodeling and electrical remodeling at infarcted border zone after myocardial infarction in rabbits.

BACKGROUND: The findings of sympathetic remodeling and its electrophysiological implications force us to rerecognize the drugs presently used. The aim of this study was to investigate the effects of metoprolol on sympathetic remodeling and electrical remodeling at the infarcted border zone (IBZ) after myocardial infarction (MI). METHODS: Forty rabbits were randomly assigned into two groups: MI group (n = 20), ligation of the anterior descending coronary; Metoprolol group (n = 20), ligation of the anterior descending coronary and administration of oral metoprolol 5 mg/kg/day. Eight weeks after surgery, transmural dispersion of repolarization (TDR) at baseline, TDR and difference of TDR (deltaTDR) during sympathetic nerve stimulation were measured at the IBZ. The distribution and densities of growth associated protein 43 and tyrosine hydroxylase positive nerves at the IBZ were detected with immunohistochemical techniques. RESULTS: The study was completed in the 36 surviving animals (18 rabbits in each group). The densities of growth associated protein 43 and tyrosine hydroxylase positive nerves in the Metoprolol group (2,550 +/- 554 and 1,779 +/- 458 microm2/mm2, respectively) were lower than in the MI group (3,217 +/- 589 and 2,616 +/- 528 microm2/mm2, respectively; both p < 0.01). TDR at baseline, TDR and deltaTDR during sympathetic nerve stimulation were shorter in the Metoprolol group than in the MI group (p < 0.01 for all). CONCLUSION: Metoprolol can inhibit sympathetic remodeling and electrical remodeling at the IBZ after MI. The association of metoprolol with improved electrical remodeling may be partly related to the inhibition of sympathetic remodeling.

Action Potentials↗

PubMed2006

Predictors of early recurrence and delayed cure after segmental pulmonary vein isolation for paroxysmal atrial fibrillation without structural heart disease.

BACKGROUND: Early recurrence of atrial fibrillation (ERAF) and delayed cure are commonly observed after atrial fibrillation (AF) ablation. The purpose of this study was to determine the predictors of ERAF and delayed cure after a single pulmonary vein isolation (PVI) performed in paroxysmal AF patients without structural heart disease. METHODS AND RESULTS: In 108 consecutive patients (93 men, 15 women; mean age 51 +/- 8 years) with paroxysmal AF and no structural heart disease, segmental PVI guided by a Lasso catheter was performed. Forty-one percent (44/108) AF patients had ERAF after a single PVI. Univariate analysis revealed that left atrial diameter (p = 0.004), age (p = 0.024) and P-wave dispersion (p = 0.045) were significantly related to ERAF. Logistic regression analysis revealed that left atrial enlargement was the only independent predictor of ERAF (odds ratio [OR] 1.17; 95% confidence interval [CI] 1.04-1.30, p = 0.006). Delayed cure occurred in 32% (14/44) patients with ERAF. P-wave dispersion (p = 0.001), left atrial diameter (p = 0.008) were significantly related to delayed cure. P-wave dispersion was the only independent predictive factor of delayed cure (OR 0.91; 95% CI 0.85-0.97, p = 0.004). CONCLUSIONS: Elderly patients with left atrial enlargement and a high dispersion of P wave are susceptible to ERAF after a single PVI. Left atrial enlargement is the only independent predictor of ERAF. Among patients with ERAF, those with less P-wave dispersion and less left atrial diameter have a higher probability of delayed cure. P-wave dispersion can independently predict delayed cure.

Adult↗

PubMed2006

Differences in the aging-associated trends of the monophasic action potential duration and effective refractory period of the right and left atria of the rat.

BACKGROUND: The incidence of atrial fibrillation (AF) increases with aging, but the aging-associated electrophysiological changes of atrial myocardium are poorly understood. METHODS AND RESULTS: Based on the hypothesis that aging of the atrium enhances AF susceptibility, 30 Wistar rats were divided into 3 age groups: adult, middle-aged, and aged (n=20 per group). Their hearts were isolated and perfused by Langendorff apparatus. Monophasic action potential duration at 90% repolarization (MAPD(90)) and effective refractory period (ERP) at the basic stimulation cycle length (BCL: 400 ms), and MAPD(90) at other different stimulation cycle lengths in each age group were measured. At the BCL, the MAPD (90) of the right atrial myocardium was prolonged from the adult to the aged group, that of the left atrial myocardium was prolonged from the adult to middle-aged group, and the MAPD(90) of the left atrial myocardium in the aged group were shorter than that in the adult and middle-aged groups. The ERP of the atrial myocardium showed the same age-associated trend as MAPD(90). As the stimulation frequency increased, the MAPD(90) of both the left and right atrial myocardium shortened correspondingly in the adult and middle-aged groups, but in the aged group the MAPD(90) of the right atrial myocardium shortened markedly more than that of the left atrial myocardium. CONCLUSIONS: There are different aging-associated electrophysiological changes in the right and left atrium, and the older heart is more vulnerable to developing the substrate for AF.

Action Potentials↗

PubMed2004

Endoscopic third ventriculostomy in the management of obstructive hydrocephalus: an outcome analysis.

OBJECT: The purpose of this paper is to elucidate the safety and efficacy of, and indications and outcome prognosis for endoscopic third ventriculostomy (ETV) in 58 patients with obstructive hydrocephalus. METHODS: Between September 1999 and April 2003, 58 ETVs were performed in 58 patients with obstructive hydrocephalus (36 male and 22 female patients) at the authors' institution. The ages of the patients ranged from 5 to 67 years (mean age 35 years) and the follow-up period ranged from 3 to 41 months (mean duration of follow up 24 months). Patients were divided into four subgroups based on the cause of the obstructive hydrocephalus: 21 with intracranial tumors; 11 with intracranial cysts; 18 with aqueductal stenosis: and eight with intracranial hemorrhage or infection. Both univariate and multivariate statistical analyses were performed to assess the prognostic relevance of the cause of the obstructive hydrocephalus, early postoperative clinical appearance, and neuroimaging findings in predicting the result of the ETV. The survival rate was 87% at the end of the 1st year and 84% at the end of the 2nd year post-ETV. One month after ETV an overall clinical improvement was observed in 45 (77.6%) of 58 patients. If we also consider the successful revision of ETV in two patients, a success rate of 78.3% (47 of 60 patients) was reached. The ETV was successful in 17 (81%) of 21 patients with intracranial tumors, nine (82%) of 11 with cystic lesions, 16 (88.9%) of 18 with aqueductal stenosis, and three (38%) of eight with intracranial hemorrhage or infection. A Kaplan-Meier analysis illustrates that the percentage of functioning ETVs stabilizes between 75 and 80% 1 year after the operation. In a comparison of results 1 year after ETV, the authors found that the aqueductal stenosis subgroup had the highest proportion of functioning ETV (89%). The proportions of the tumor and cyst subgroups were 84 and 82%, respectively, whereas the proportion was only 50% in the ventriculitis/intracranial hemorrhage subgroup (strata log-rank test: chi2 = 7.93, p = 0.0475). In the present study, ETV failed in eight patients (13.8%) and the time to failure after the procedure was a mean of 3.4 months (median 2 months, range 0-8 months). The logistic regression analysis confirmed an early postoperative improvement (within 2 weeks after ETV, significance [Sig] of log likelihood ratio [LLR] < 0.0001) and a patent stoma on cine phase-contrast magnetic resonance (MR) images (Sig of LLR = 0.0002) were significant prognostic factors for a successful ETV. The results demonstrated the multivariate model (B = -53.7309, standard error = 325.1732, Wald = 0.0273, Sig = 0.8688) could predict a correct result in terms of success or failure from ETV surgery in 89.66% of observed cases. The Pearson chi-square test demonstrated that little reliance could be placed on the finding of a reduced size of the lateral ventricle (chi2 = 5.305, p = 0.07) on neuroimaging studies within 2 weeks after ETV, but it became a significant predictive factor at 3 months (chi2 = 8.992, p = 0.011) and 6 months (chi2 = 10.586, p = 0.005) post-ETV. Major complications occurred in seven patients (12.1%), including intraoperative venous bleeding in three, arterial bleeding in one, and occlusion of the stoma in three patients. The overall mortality rate was 10.3% (six patients). One of these patients died of pulmonary infection and another of ventriculitis. Four additional patients died of progression of malignant tumor during the follow-up period. CONCLUSIONS: The results indicate that ETV is a most effective treatment in cases of obstructive hydrocephalus that is caused by aqueductal stenosis and space-occupying lesions. For patients with infections or intraventricular bleeding, ETV has considerable effects in selected cases with confirmed CSF dynamic studies. Early clinical and cine phase-contrast MR imaging findings after the operation play an important role in predicting patient outcomes after ETV. The predictive value of an alteration in ventricle size, especially during the early stage following ETV, is unsatisfactory. Seventy-five percent of ETV failures occur within 6 months after surgery. A repeated ventriculostomy should be considered to be a sufficient treatment option in cases in which stoma dysfunction is suspected.

Adolescent↗

PubMed2002

[Inhibitory effect of cationic liposome-mediated antisense c-myb oligonucleotide on the growth of glioma].

OBJECTIVE: To aim at demonstrating whether cationic liposome-mediated antisense c-myb oligonucleotide(LipoAON) can inhibit the growth of C6 glioma by intravenous injection. METHODS: Intracerebral C6 glioma cells were implanted into the left caudal nucleus of forty-eight male Wistar rats. There were four groups: LipoAON(n = 12), antisense c-myb oligonucleotide (AON; n = 12), cationic liposome (Lipo; n = 12), and normal saline (NS; n = 12). Six days after tumor implantation, the above-mentioned drugs were injected into the right femoral veins of the rats respectively. Two days later, the same drugs were injected into the left femoral veins. The appetite, motor and weight of every animal were closely observed during the whole experiment. Six rats of each group were respectively killed 4 days and 10 days after the end of administration. The weight change, pathologic examination and immunohistochemical analysis of c-myb expression of the tumor were completed. RESULTS: In LipoAON group, the growth of the tumors was significantly inhibited in a short time after treatment and c-myb expression was down-regulated. But in the AON group and Lipo group, the growth of the tumors was not inhibited and c-myb expression was not down-regulated, compared with that in NS group. The inhibitory effect of LipoAON on the tumors rapidly declined with time and c-myb expression was again up-regulated. CONCLUSION: 1. Cationic liposome (LipofectAMINE) as transfection vehicle makes c-myb easily penetrate BBTB and enter the tumor. The technique is simple, safe, highly effective for the transfection of c-mybAON; 2. LipoAON has marked inhibitory effect on the growth of C6 glioma. The AON technical method for inhibiting the expression of c-myb oncogene has a research perspective in the treatment of glioma; 3. The inhibitory effect of LipoAON on the growth of glioma declines with time. The question about how to make c-myb AON have highly effective, sustained and stable expression in the tumor still requires further research.

Animals↗