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PubMed2025

Identification of Potential Therapeutic Agents for Type I Interferonopathy Using iPSC-Based Disease Modeling.

PURPOSE: Type I interferonopathy encompasses disorders marked by systemic inflammation and neurological involvement, arising from genetic mutations that result in the upregulation of type I IFN signaling through various mechanisms. Currently, therapeutic options are limited, and no standard therapy exists. This study aims to develop a strategy for identifying new therapeutic targets for type I interferonopathy using induced pluripotent stem cells (iPSCs). METHODS: The IFIH1 R779H variant was introduced into iPSCs through genome editing. RNA sequencing of iPSC-derived dendritic cells (DCs) was performed, and differentially expressed genes (DEGs) were identified. IFN-α secretion, reactive oxygen species (ROS), and mitochondrial oxygen consumption rate (OCR) were analyzed in iPSC-derived DCs. An in silico prediction of compounds binding to the OAS-like domain was conducted. Candidate compounds were evaluated for their ability to inhibit IFN secretion from IFIH1 R779H-mutated iPSC-derived DCs. RESULTS: Transcriptome analysis indicated upregulation of the IFN-related and metabolic pathways. IFIH1 R779H-mutated iPSC-derived DCs exhibited increased OCR and ROS generation, and blocking mitochondrial metabolism significantly reduced excessive IFN-α secretion. Among the DEGs, PML was upregulated, and targeting this gene with arsenic trioxide (ATO), a PML antagonist, suppressed IFN-α secretion from IFIH1 R779H-mutated iPSC-derived DCs. Additionally, bisantrene, phthalylsulfathiazole and ganaplacide were predicted to bind to the RNA binding groove of OAS-like domain of human OASL in silico, effectively inhibiting IFN-α secretion from IFIH1 R779H-mutated DCs. CONCLUSION: Our iPSC-based disease modeling and drug investigation approach provides a robust platform for validating the efficacy and toxicity of candidate therapeutic agents for rare and intractable human diseases such as type I interferonopathy.

Humans↗
PubMed1976

myo-Inositol metabolism during lactation and development in the rat. The prevention of lactation-induced fatty liver by dietary myo-inositol.

Effects of dietary myo-inositol deprivation were examined during prenatal and postnatal development and during lactation in the rat. The deficient diet contained no detectable myo-inositol while the supplemented diet contained 0.5% (w/w) myo-inositol while the supplemented diet ct contained 0.5% (w/w) myo-inositol at the expense of sucrose. Both diets contained 25% casein, adequate amounts of all known vitamins, choline, and essential fatty acids as well as 0.5% (w/w) phthalylsulfathiazole to depress myo-inositol contribution to the diet by microorganisms. Pregnant rats of the Holtzman strain were fed the respective diets during gestation and lactation, and pups were fed the corresponding diet after weaning until 3 months of age. There were no significant differen-es in body weight between experimental groups. Supplementation of the diet with myo-inositol significanly increased the levels of myo-inositol in plasma, liver, kidney, and intestine of pups at all ages examined, and significantly increased the levels of myo-inositol in the milk and mammary tissue during lactation. During lactation, the myo-inositol deprived dams developed severe fatty livers (31% w/w) characterized by diminished phosphatidyl-inositol (50%) and total phospholipid phosphorus (57%) levels as compared with controls. After weaning, the liver lipid content of the myo-inositol deprived dams returned to normal (4.5%). The data suggest that a possible threshold level of free myo-inositol (approximately 0.15 mumoles/g lipid-free tissue) was required to prevent fatty liver in lactating dams under these dietary conditions. Effects of the deficient diet on fertility were also examined. Based on sperm count and production of offspring, there were no differnences between the experimental and control males. Females of both groups showed equal ability to produce offspring.

Amniotic Fluid↗
PubMed1978

A randomized prospective evaluation of orally administered antibiotics in operations on the colon.

In this randomized, prospective study of 91 patients undergoing operations on the colon, we found that neomycin, neomycin-phthalylsulfathiazole and neomycin-erythromycin base all provided adequate intestinal antisepsis. Wound infection rates for all groups were also similar and close to the national average for operations on the colon. A detailed analysis of the wound infections in our series revealed that 60 per cent of these infections were from organisms different from those found on the colonic mucosa. This evidence indicates the possible advantage of parenteral antibiotic therapy to achieve adequate tissue levels of antibiotics not presently possible with orally administered agents.

Administration, Oral↗
PubMed1979

[A prophylactic regimen for infections in colorectal surgery (author's transl)].

Without special prophylaxis, surgery of the colon and rectum is likely to result in postoperative complications due to infection at a percentage of 30 to 50. Prophylaxis against infections in colonic operations covers preoperative influence on general body defence, a subtle operating technique and special preparation of the intestine, the latter including adequate bulkage - free diet, a special preparation of the intestine and preoperative administration of antibiotics. Preparation by means of phthalylsulfathiazol has shown no effects. A preparation programme is suggested for 3 to 8 days preoperatively.

Adolescent↗
PubMed1978

The role of antibacterial preparation of the intestine in the reduction of primary wound sepsis after operations on the colon and rectum.

A consecutive series of 320 patients undergoing operations on the colon and rectum, under the care of one surgeon, was studied to determine the influence of oral antibacterial preparation of the intestine on the incidence of postoperative wound sepsis. Thirty patients were excluded from the analysis, and the rates of major wound sepsis in the remaining 290 patients were 21.7 per cent when no antibacterial preparation was used; 18.6 per cent when the intestine was prepared with phthalylsulfathiazole and neomycin, and 1.6 per cent when the intestine was prepared with phthalysulfathiazole, neomycin and tetracycline. Other important determinants of the rate of wound sepsis were obesity and the use of cephaloridine prophylaxis. Results of bacteriologic studies showed the effectiveness of triple antimicrobial preparation of intestine against gram-negative aerobes and Bacteriodes species.

Anti-Bacterial Agents↗
PubMed1983

[Antibacterial prevention of suppurative complications after operations on the large intestine].

The data on comparative study of complications after operations on the large intestine are presented. During the preoperative period, 62 patients of the control group were treated with phthalylsulfathiazole, nevigramon and nystatin. Thirty-nine patients of the test group were treated with metronidazole and kanamycin monosulfate. Kanamycin monosulfate was used 3 days before the operation in a dose of 0.5 g orally 4 times a day whereas metronidazole in a dose of 0.5 g 3 times a day. The last doses of the drugs were administered 4-5 hours before the operation. After the operations the patients were treated with kanamycin sulfate for 3-5 days in a daily dose of 2 g intramuscularly. The number of the postoperative suppurative complications decreased from 22 to 5 per cent. No lethal outcomes were registered in the test group. The number of lethal outcomes in the control group amounted to 8 per cent.

Drug Evaluation↗
PubMed1964

SURGICAL MANAGEMENT OF REGIONAL ENTERITIS.

The present-day concepts concerning the surgical management of regional enteritis are reviewed and the multitude of problems that may arise in surgical treatment are discussed. The primary treatment of regional enteritis remains medical. Surgical intervention is necessary only for the complications of intractability, obstruction, fistula, abscess formation, anal and rectal complications, massive hemorrhage and perforation. To ensure the best possible results, medical treatment should continue after surgery. A perfect operation for this disease does not exist. Operations for regional enteritis can now be performed with a mortality rate of less than 2%, and although the recurrence rate following surgery averages approximately 30%, the disease is well controlled in the majority of patients with medical and/or surgical treatment.

Appendectomy↗