Biomedical subjects

Dan He

Publications and source records attributed to Dan He.

9 recordsLinked to original sources

PubMed2026

Adolescent depression as a systemic multimorbidity catalyst: integrated genetic and metabolic pathway analysis.

BACKGROUND: Although adolescent depression has been linked to individual chronic conditions, its broader role in shaping multimorbidity risk remains understudied. METHODS: A total of 87,562 UK Biobank participants were included, of whom 18,851 had documented adolescent depression. Cox proportional hazards models were applied to evaluate associations between adolescent depression and 24 chronic diseases, followed by stratified analyses by sex and age. Two-sample Mendelian randomization (MR) was then conducted to infer causality for diseases showing significant associations. Genomic colocalization analyses were performed using relevant GWAS data to identify shared causal variants. Mediation analyses were performed to detect possible mediating factors, including the frailty index, KDM biological age acceleration, allostatic load and 30 circulating biomarkers. RESULTS: Adolescent depression was associated with elevated risk for 12 chronic diseases, with strongest associations for hypothyroidism (HR = 1.29 [1.18-1.42]), diabetes (HR = 1.25 [1.13-1.38]) and chronic obstructive pulmonary disease (COPD) (HR = 1.74 [1.50-2.01]). Risks were notably higher among females and younger adults. MR confirmed likely causal relationships for hypothyroidism (OR = 1.45 [1.03-2.05]), diabetes (OR = 1.01 [1.01-1.02]) and COPD (OR = 1.04 [1.02-1.06]). Genomic colocalization revealed a shared genetic signal at the CDSN/PSORS1C1 locus between adolescent depression and hypothyroidism. Mediation analyses revealed disease-specific pathways: creatinine for hypothyroidism, testosterone for diabetes, KDM biological ageing for COPD and frailty index across all three conditions. CONCLUSIONS: Adolescent depression confers systemic vulnerability through genetic and metabolic mechanisms, with amplified risks in females and individuals aged ≤55 years. These findings support early, integrated interventions to mitigate long-term multimorbidity.

Humans↗

PubMed2026

Redox-activated chemistry for probing and perturbing the proteome: Lessons from protein redox switches.

Covalent drug discovery and chemical proteomics have historically relied on a nucleophilic logic, where electrophilic "warheads" react with nucleophilic amino acid side chains. While powerful, this paradigm probes only a single dimension of the protein's chemical surface. In contrast, biology leverages a second axis: redox potential. This is exemplified by the regulated redox proteome, where specific residues undergo reversible oxidation and reduction as functional post-translational modifications. Inspired by this natural machinery, researchers are developing redox-activated probes to label proteins at oxidizable residues and deploying similar chemistry to selectively perturb protein function. This review highlights recent advances in redox-activated covalent chemistry and explores its burgeoning potential for the development of next-generation targeted therapeutics.

Oxidation-Reduction↗

PubMed2005

A space-efficient algorithm for the constrained pairwise sequence alignment problem.

The constrained pairwise sequence alignment (CPSA) problem aims to align two given sequences by aligning their similar subsequences in the same region under the guidance of a given pattern (constraint). Let the lengths of the sequences be m, and n where n <or= m, and let r <or= n be the length of the given pattern. The optimum constrained pairwise alignment score can be computed using O(rn) space by a naive dynamic programming solution. If an optimal alignment path is desired then the space requirement of the naive dynamic programming algorithm is O(rnm). There is a divide-and-conquer algorithm that reduces the memory requirement of finding an optimal alignment for the CPSA problem to O(rn). In this paper, we present a space-efficient CPSA algorithm that returns an optimal alignment. Our analysis on real protein sequences suggests that our algorithm requires only O(n) space in practice. This algorithm is not only space efficient but also very fast. A generalization of the CPSA problem for multiple sequences is called the constrained multiple sequence alignment (CMSA) problem. Our CPSA algorithm also improves the space requirement of progressive CMSA algorithms that use solutions of CPSA problems.

Algorithms↗

PubMed2004

[Soluble expression of recombinant immunotoxin against human bladder carcinoma and its anti-tumor activity].

AIM: To construct soluble expression vector of the recombinant immunotoxin against human bladder carcinoma and express and purify the immunotoxin with high biological activity. METHODS: The gene fragment of the immunotoxin containing the genes encoding the humanized single-chain antibody against human bladder carcinoma and the truncated and modified form of Pseudomonas exotoxin(PE) named PE38/KDEL was digested from the plasmid pABDIT and inserted into the expression vector pTMFK containing the FkpA gene. The recombinant plasmid was used to transform the E.coli strain BL21(DE3)-Star and the immunotoxin was co-expressed with the FkpA which served as the folding assistant factor. The immunotoxin was purified through Ni-NTA agarose and anti-PEAb Sepharose 4B columns. The binding activity of the immunotoxin to the antigen on BIU-87 cells was detected by ELISA. The specific cytotoxic effect of the immunotoxin against BIU-87 cells was assessed by MTT colorimetry. RESULTS: The immunotoxin was over-expressed in soluble form in E.coli. The immunotoxin showed good binding activity to the membrane antigen on BIU-87 cells. The result of MTT assay demonstrated that purified recombinant immunotoxin could specifically kill BIU-87 cells. CONCLUSION: The immunotoxin was obtained with specific cytotoxicity to human bladder cancer cells, which lays the foundation for the further application of the immunotoxin in the target therapy of human bladder carcinoma.

ADP Ribose Transferases↗

PubMed2004

[Studies of the expression, purification, renaturation and biologic activity of an anti-CEA immunotoxin].

A recombinant immunotoxin named CEA/PE38/KDEL was constructed, which was composed of anti-CEA single-chain Fv and the truncated and modified form of Pseudomonas exotoxin (PE38/KDEL). The CEA/PE38/KDEL immunotoxin was expressed in the E. coli strain BL21 (DE3)-star as inclusion bodies. The denatured inclusion bodies were purified with Ni-NTA chelate agarose, then the constant gradient dialysis was used to perform the refolding of the CEA/PE38/KDEL immunotoxin. Results of FACS and MTT assay indicate that the refolded immunotoxins keep potent and specific cytotoxicity to tumor cells bearing CEA antigens.

ADP Ribose Transferases↗

PubMed2003

Analysis of BRAF and N-RAS mutations in metastatic melanoma tissues.

We examined mutations in BRAF exons 11 and 15 and N-RAS exons 2 and 3, in 77 metastatic melanoma cases and 11 melanoma cell lines. Significant differences in the mutation rates observed at different metastatic sites could not be detected. The most frequent mutation, the V599E amino acid substitution in BRAF exon 15, was observed in 31 of 77 (40%) tissues and 5 of 11 (45%) cell lines. Tandem base-pair substitutions encoding V599R and V599K amino acid changes were observed in two cases. Novel findings with respect to melanoma include a cell line possessing a 2 base-pair substitution in BRAF exon 11 and a case harboring mutations in both BRAF exon 11 and N-RAS exon 3. Our data show that BRAF mutation is common in melanoma metastases, regardless of their site, that mutations include both exons 11 and 15, and suggest that anti-RAS/RAF strategies may be effective in metastatic melanoma patients.

Exons↗

PubMed2003

Production of soluble and functional engineered antibodies in Escherichia coli improved by FkpA.

Overproduction of genetically engineered antibodies, such as single-chain antibodies (scAbs) in Escherichia coli often results in insoluble and inactive products known as inclusion bodies. We now report that fusion or co-expression of FkpA, the E. coli periplasmic peptidyl-prolyl-isomerase with chaperone activity, substantially improves soluble and functional expression of scAbs. Anti-human bladder carcinoma scAb (PG) and anti-human CD3 x anti-human ovarian carcinoma-bispecific scAb (BH1) were fused with FkpA on the pTMF-based plasmid and expressed in E. coli. More than half of the amount of each expressed fusion protein FkpA-PG or FkpA-BH1 was soluble. In addition, the fusion protein cellulose-binding domain from Cellulomonas fimi (CBD)-PG and anti-human CD3 x anti-human CD28 x anti-human ovarian carcinoma-trispecific scAb (TRI) fused to the pelB (a signal peptide from pectate lysase B of a Bacillus sp.) signal sequence were co-expressed with FkpA under the control of the T7 promoter. A substantial portion of the co-expressed CBD-PG or TRI was soluble. Furthermore, PG, BH1, and TRI were biologically active as judged by ELISA and in vitro cytotoxicity assay. These results suggest that overexpression of FkpA should be useful in expressing heterologous proteins in E. coli.

Antibodies↗

PubMed2003

[Compatible-solute-supported periplasmic expression of recombinant immunotoxins and the effects of glucose thereby].

Bacteria protect themselves against high external osmolality by uptake or synthesis of a limited number of so-called compatible solutes. Under such extreme conditions, combine factors can facilitate the foreign recombinant protein expression. In our experiment, we added additional NaCl and two compatible solutes (glycine betaine and sorbitol) into the medium. The recombinant immunotoxin BDI(scFv)-PE38 was expressed mainly in soluble form and can be purified by Ni2+-NTA agarose. We also found the time when the glucose was added into the medium greatly affected the expression level of the recombinant immunotoxin. This suggested that glucose played an important role in the expression system.

English Abstract↗

PubMed2002

Clostridium difficile toxin A triggers human colonocyte IL-8 release via mitochondrial oxygen radical generation.

BACKGROUND & AIMS: Clostridium difficile toxin A causes mitochondrial dysfunction resulting in generation of oxygen radicals and adenosine triphosphate (ATP) depletion. We investigated whether mitochondrial dysfunction is involved in nuclear factor kappaB (NF-kappaB) activation and interleukin (IL)-8 release from toxin A-exposed enterocytes. METHODS: NF-kappaB activation and IL-8 release in response to toxin A were correlated with reactive oxygen intermediate (ROI) generation and ATP production in HT-29 monolayers or HT-29 cells exposed to ethidium bromide (EB) to inhibit mitochondrial function. RESULTS: HT-29 cells exposed to EB showed damaged mitochondria and diminished resting levels of ATP. ROI production in EB-treated cells exposed to toxin A for 30 minutes was significantly reduced. Exposure of wild-type HT-29 cells to toxin A resulted in increased oxygen radical generation and IL-8 production (P < 0.01 vs. control) that was inhibited by antioxidant pretreatment. Degradation of IkappaB was observed within 30 minutes of toxin exposure, before ras homologue (Rho) glucosylation, and was followed by nuclear translocation of NF-kappaB. Toxin A did not increase IL-8 levels in EB-treated cells, whereas IL-8 release in response to IL-1beta was not affected. CONCLUSIONS: Our data support an early role for mitochondria-derived ROIs in stimulation of IL-8 release from colonocytes by toxin A. ROI generation is independent of Rho inactivation and involves nuclear translocation of NF-kappaB before release of IL-8.

Adenosine Triphosphate↗