Current Pharmaceutical Biotechnology - Online First

Nephrotoxicity limits the clinical application of digoxin. One area that might be useful is the mechanical knowledge of altered renal function and renal impairment. We hypothesized that co-administration of naringin would affect digoxin nephrotoxicity by alleviating the altered renal oxidative/ antioxidant redox and apoptotic cascade.

40 male Wistar Albino rats (200 ± 50 g) were grouped into 4, every group included (n= 7), control, Nar., Dig. and Nar. + dig. Groups. Colorimetric estimation of kidney functions and renal oxidative/ antioxidant redox were done.

Comparing digoxin alone, the concomitant administration of digoxin and naringin restored renal antioxidant/ oxidative redox, redistributed Nrf2, HO-1 mRNA exposure with a concomitant down-regulation of NF-κB, AKT and PI3K mRNA expressions. Moreover, a significant decrease of Smad3 and transforming growth factor-β (TGF- β) protein concentrations with a simultaneous rise of Smad7 were noticed in Nar. + dig. Arm when compared to Dig. group.

The co-administration of naringin and digoxin can mitigate digoxin-mediated nephrotoxicity by introducing antioxidant action. This is done by maintaining effects on renal oxidative/antioxidant cycle and lethality via regulating AKT/ PI3k/ Smad3/ Smad7 signaling pathways.

Through comprehensive transcriptome sequencing of liver RNA in mice induced with streptozotocin (STZ) to develop hyperglycemia, we uncovered crucial genes associated with hyperglycemic processes, shedding light on their respective functions. Furthermore, we delved deeply into a discussion surrounding the mechanism behind plasma glucagon-like peptide 1 (PGLP-1) and its role in inhibiting gluconeogenesis.

Liver tissues from mice induced with STZ to develop hyperglycemia (M group), as well as those treated with PGLP-1 (P11 group) and Exendin-4 (E group), were collected. RNA extraction was performed for comprehensive transcriptome sequencing. Differentially expressed mRNA, microRNA (miRNA), and long-chain non-coding RNA (lncRNA) were identified and subjected to analysis of their respective GO and KEGG pathways. An association network involving mRNA-miRNA-lncRNA was constructed to pinpoint target molecules associated with gluconeogenesis. Furthermore, personalized analysis focused on eight gluconeogenesis-related signal pathways obtained from KEGG.

A total of 289 differentially expressed mRNA (dif-mRNA), 21 differentially expressed miRNA (dif-miRNA), and 463 differentially expressed lncRNA (dif-lncRNA) were screened from the M group and P11 group. 182 dif-mRNA, 239 dif-miRNA, and 384 dif-lncRNA were screened from the M group and E group. A total of 427 dif-mRNA, 261 dif-miRNA, and 525 dif-lncRNA were screened from the E group and the P11 group. Among them, mRNA was enriched to the PI3K-Akt signaling pathway, Type ll diabetes mellitus, the Insulin signaling pathway, and the PPAR signaling pathway, while lncRNA was mainly enriched in PI3K-Akt signaling pathway. Similar to the whole transcriptome sequencing, the results of gluconeogenesis personalized analysis showed that the PI3K-Akt signaling pathway was the key pathway, and Gck and Cyp7a1 were highly expressed after PGLP-1 was administered.

According to our findings, we believe that PGLP-1 is a potential regulator of non-coding RNAs, including miRNAs and lncRNAs. Additionally, it modulates the PI3K-Akt signaling pathway, resulting in the upregulation of GcK and Cyp7a1. In this way, it effectively inhibits gluconeogenesis.

Psoriasis is a chronic skin disease that affects patients' quality of life. Treating psoriasis remains a significant challenge due to various factors, including individual response variability, drug resistance, and the range of side effects associated with currently available medications. Nowadays, numerous research efforts are being made aiming at overcoming the obstacles of the available psoriasis treatments are still taking place.

This research aims to develop and evaluate a nanogel formulation loaded with khellin for the effective treatment of psoriasis.

Khellin nanogel was prepared using the self-assembly method with a synthesized gelatin-pluronic copolymer. The novel formulation was characterized via size, size distribution, encapsulation efficiency, in vitro release, and ex vivo skin deposition.

The final nanogel formulation had an average size of 119.6 nm, a polydispersity index of 0.248 and an excellent encapsulation efficiency of 88%. In vitro drug release study demonstrated that nanogels showed a great accelerated drug release profile by releasing khellin within 2 hours, which is suitable for photochemotherapy applications. In addition, khellin-loaded nanogel formulation had 1.7 times better skin deposition potential than the control gel formulation.

The prepared nanogel formulation provides a high potential to be an ideal drug delivery system of khellin in combination with phototherapy for more efficient psoriasis treatment.

To predict and assist in the treatment of colorectal cancer.

Precision medicine systems can provide strategy optimization for the diagnosis and treatment of colorectal cancer to meet the needs of clinical pricing institutions.

To design an artificial intelligence multimodal gastrointestinal disease clinical information system based on neuroimmune gene regulation.

The system includes the use of cell gene expression levels to predict the 5-year survival rate of cancer patients, and the development of disease incidence rate prediction models based on immune cell status and living habits in somatic cell testing. The biological mechanism of feature selection in survival prediction systems was elucidated using single-cell sequencing technology, and this mechanism was analyzed in depth using molecular simulation techniques. Based on NCAM1 and CADM1 genes, biological activation pathway analysis was conducted to explore the biological mechanism of their synergistic immune genome regulation of gastrointestinal tumor proliferation.

The accuracy of each model is higher than 0.70. The experimental credibility is high.

The research team conducted a detailed analysis of the biological characteristics of AI algorithms and reached a consensus with clinical experts. The ethical approval number of Chifeng Cancer Hospital is 202401, which has been reported by the World Health Organization.

Current medicine could benefit from gene and cell therapies for genetic defects, cancer, and degenerative disorders. These therapies modify genetic material or biological components. CRISPR-Cas9 gene editing, stem cell, and CAR-T treatments are examples. Complex products need rigorous regulations to ensure quality, efficacy, and patient safety.

This paper discusses international gene and cell-based treatment regulatory regimes, highlighting key issues and recent developments. It also includes gene and cell-based therapy classes and mechanisms.

The publications on gene and cell therapy challenges and their regulatory approvals in the US, Europe, Japan, Australia, Brazil, Canada, and China were collected over the last 20 years from PubMed, Scopus, and Google Scholar and analyzed to determine the differences.

Gene treatments correct genetic defects or disease processes by adding, removing, or changing cell genetic information. In contrast, cell-based therapies restore damaged tissues with modified or unmodified cells. Highly customized and patient-specific drugs make regulatory monitoring challenging. US FDA CBER controls gene and cell-based therapies. Before clinical trials, these biologic drugs must file BLAs for market approval and INDs.

FDA's Breakthrough Therapy and Regenerative Medicine Advanced Therapy (RMAT) designations accelerate biological development. The EMA oversees EU Advanced Therapy Medicinal Products. ATMP quality, safety, and efficacy are CAT's top priorities. The Conditional Marketing Authorization process expedites access to life-threatening disease medicines while the MAA regulates them. Japan's PMDA's Conditional Time-Limited Approval for regenerative medicines provides early commercialization and rigorous post-market supervision. Similarly, each country has adopted some ways to expedite the approval of biologicals. Gene-editing drugs require specialized methods, long-term follow-up, and better safety to avoid off-target effects. GMPs ensure production uniformity, sterility, and safety, complicating manufacturing and quality control.

The review concludes that there is a need for worldwide regulatory harmonization and regulatory framework developments, including R.W.E., adaptive pathways, and personalization of biologics.

The purpose of the present research was to assess the protective role of coffee in thioacetamide-induced nephrotoxicity.

The experimental period consisted of 18 weeks, divided into two phases. Four experimental groups were designed, each consisting of six rats. Group I was considered an untreated control group. Groups II and III were intraperitoneally injected with thioacetamide at a dose of 200 mg/kg body weight twice a week for twelve weeks during the first phase of the study. In the second phase, group II received saline, and group III and group IV received 0.4 mg/Kg of coffee daily for six weeks. The biochemical analysis was evaluated by the estimation of plasma urea, uric acid, creatinine, Malondialdehyde (MDA), Superoxide Dismutase (SOD), and catalase.

Thiocetamide-induced nephrotoxicity resulted in the reduction of body weight, superoxide dismutase, and catalase activities, and an increase in kidney weight, plasma urea, uric acid, creatinine, and tissue malondialdehyde. Supplementation with coffee effectively increased body weight while reducing elevated levels of urea, uric acid, creatinine, and MDA. It also restored SOD and catalase activities in Group III (TAA + Coffee-treated).

This work shows that coffee can protect the kidneys against thioacetamide-induced nephrotoxicity in a rat model. It highlights the antioxidant potential of coffee by its ability to restore enzymatic antioxidant activity (SOD and catalase), lower oxidative stress markers (MDA), and enhance renal function measures (urea, creatinine, and uric acid). The study fills a significant gap by demonstrating coffee as a viable natural therapeutic agent for oxidative stress-induced kidney impairment, providing an alternative to conventional treatments with fewer side effects.

Diabetic Kidney Disease (DKD) is a major cause of End-Stage Renal Disease (ESRD) and lacks effective treatments. Tangmaikang Granules (TMK), a multi-herb traditional Chinese medicine formulation, have shown potential in managing DKD. However, the precise active components, molecular mechanisms, and therapeutic advantages of TMK remain unclear.

This study tests the hypothesis that TMK granules exert protective effects on DKD by targeting multiple pathways involved in oxidative stress, inflammation, and apoptosis in podocytes through a multi-targeted approach. The aim was to identify TMK’s bioactive components, evaluate its therapeutic potential, and uncover its molecular mechanisms in DKD.

The bioactive constituents in TMK were determined through ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Drug targets were identified using SwissTargetPrediction and SuperPred, whereas DKD-associated targets were obtained from the GeneCards, DisGeNET, OMIM, and TTD databases. A Protein-Protein Interaction (PPI) network was constructed, and key targets were identified via topological analysis. Molecular docking and dynamics simulations were performed to evaluate stable binding interactions. GO and KEGG pathway enrichment analyses were conducted to uncover relevant signaling pathways. TMK's effects on oxidative stress, inflammation, and apoptosis in podocytes were assessed using CCK-8, flow cytometry, RT-qPCR, ELISA, and Western blot assays.

Thirty active compounds and 384 potential therapeutic targets were identified, with eight key targets. Pathway enrichment analysis revealed TMK’s involvement in AGE-RAGE, EGFR, HIF-1, and apoptosis pathways, affecting inflammatory cytokine responses and oxidative stress. In vitro experiments demonstrated that TMK significantly reduced oxidative stress, inflammation, and apoptosis in podocytes by inhibiting the MAPK and NF-κB pathways.

TMK granules target DKD through a multi-component, multi-target strategy, effectively mitigating oxidative stress and suppressing inflammatory and apoptotic pathways. This study integrates advanced computational and experimental methods, demonstrating TMK’s unique therapeutic potential and providing a robust foundation for its clinical application in DKD management.