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Current Molecular Medicine - Volume 25, Issue 2, 2025

Volume 25, Issue 2

Volume 25, Issue 2, 2025

    • A Narrative Review of Signaling Pathway and Treatment Options for Diabetic Nephropathy

      https://doi.org/10.2174/1566524023666230727093911
      Background

      Diabetic nephropathy is a progressive kidney disease that frequently results in end-stage renal disorders and is characterized by proteinuria, albuminuria, decreased filtration, and renal fibrosis. Despite the fact that there are a number of therapeutic alternatives available, DN continues to be the main contributor to end-stage renal disease. Therefore, significant innovation is required to enhance outcomes in DN patients.

      Methods

      Information was collected from online search engines like, Google Scholar, Web of Science, PubMed, Scopus, and Sci-Hub databases using keywords like diabetes, nephropathy, kidney disease, autophagy, .

      Results

      Natural compounds have anti-inflammatory and antioxidant properties and impact various signaling pathways. They ameliorate kidney damage by decreasing oxidative stress, inflammatory process, and fibrosis and enhance the antioxidant system, most likely by activating and deactivating several signaling pathways. This review focuses on the role of metabolic memory and various signaling pathways involved in the pathogenesis of DN and therapeutic approaches available for the management of DN. Special attention is given to the various pathways modulated by the phytoconstituents.

    • The Multiple Roles of Heat Shock Proteins in the Development of Inflammatory Bowel Disease

      https://doi.org/10.2174/0115665240286793240306053111

      Inflammatory bowel disease (IBD), a chronic inflammatory condition of the human intestine, comprises Crohn’s disease (CD) and ulcerative colitis (UC). IBD causes severe gastrointestinal symptoms and increases the risk of developing colorectal carcinoma. Although the etiology of IBD remains ambiguous, complex interactions between genetic predisposition, microbiota, epithelial barrier, and immune factors have been implicated. The disruption of intestinal homeostasis is a cardinal characteristic of IBD. Patients with IBD exhibit intestinal microbiota dysbiosis, impaired epithelial tight junctions, and immune dysregulation; however, the relationship between them is not completely understood. As the largest body surface is exposed to the external environment, the gastrointestinal tract epithelium is continuously subjected to environmental and endogenous stressors that can disrupt cellular homeostasis and survival. Heat shock proteins (HSPs) are endogenous factors that play crucial roles in various physiological processes, such as maintaining intestinal homeostasis and influencing IBD progression. Specifically, HSPs share an intricate association with microbes, intestinal epithelium, and the immune system. In this review, we aim to elucidate the impact of HSPs on IBD development by examining their involvement in the interactions between the intestinal microbiota, epithelial barrier, and immune system. The recent clinical and animal models and cellular research delineating the relationship between HSPs and IBD are summarized. Additionally, new perspectives on IBD treatment approaches have been proposed.

    • Stem Cells as a Novel Source for Regenerative Medicinal Applications in Alzheimer's Disease: An Update

      https://doi.org/10.2174/0115665240334785240913071442

      Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder characterized by loss of the neurons, excessive accumulation of misfolded Aβ and Tau proteins, and degeneration of neural synapses, primarily occurring in the neocortex and the hippocampus regions of the brain. AD Progression is marked by cognitive deterioration, memory decline, disorientation, and loss of problem-solving skills, as well as language. Due to limited comprehension of the factors contributing to AD and its severity due to neuronal loss, even today, the medications approved by the U.S. Food and Drug Administration (FDA) are not precisely efficient and curative. Stem cells possess great potential in aiding AD due to their self-renewal, proliferation, and differentiation properties. Stem cell therapy can aid by replacing the lost neurons, enhancing neurogenesis, and providing an enriched environment to the pre-existing neural cells. Stem cell therapy has provided us with promising results in regard to the animal AD models, and even pre-clinical studies have shown rather positive results. Cell replacement therapies are potential curative means to treat AD, and there are a number of undergoing human clinical trials to make Stem Cell therapy accessible for AD patients. In this review, we aim to discuss the AD pathophysiology and varied stem cell types and their application.

    • DFT Study of Interaction between Teriflunomide and β-cyclodextrin

      https://doi.org/10.2174/0115665240270161231112120838
      Introduction

      This study employs Density Functional Theory (DFT) to investigate the interactions between Teriflunomide and β-cyclodextrin in the gas phase.

      Methods

      The non-bonded interaction effects of the Teriflunomide compound with β-cyclodextrin on the chemical shift tensors, electronic properties, and natural charge were also observed. An analysis of the natural bond orbital (NBO) indicated that the molecule β-cyclodextrin as an electron donor functions while Teriflunomide functions as an electron acceptor in the complex β-cyclodextrin/Teriflunomide.

      Results

      The electronic spectra of the Teriflunomide drug and complex β-cyclodextrin/ Teriflunomide were calculated by Time-Dependent Density Functional Theory (TD-DFT) to investigate the adsorption effects of the Teriflunomide drug over β-cyclodextrin on maximum wavelength.

      Conclusion

      As a result, the possibility of the use of β-cyclodextrin for Teriflunomide delivery to the diseased cells has been established.

    • Polyphyllin I Mitigated IL-1β-Induced Chondrocytes Damage through Downregulating TWIST1 Expression

      https://doi.org/10.2174/0115665240258324231009115920
      Background

      Osteoarthritis (OA) is a chronic joint disease characterized by the degradation of articular cartilage. Polyphyllin I (PPI) has anti-inflammatory effects in many diseases. However, the mechanism of PPI in OA remains unclear.

      Methods

      HC-a cells treated with IL-1β were identified by immunofluorescence staining and microscopic observation. The expression of collagen II and DAPI in HC-a cells was detected by immunofluorescence. The effects of gradient concentration of PPI on IL-1β-induced cell viability, apoptosis, senescence, and inflammatory factor release were detected by MTT, flow cytometry, SA-β-Gal assay and ELISA, respectively. Expressions of apoptosis-related genes, extracellular matrix (ECM)-related genes, and TWIST1 were determined by qRT-PCR and western blot as needed. The above-mentioned experiments were conducted again after TWIST1 overexpression in IL-1β-induced chondrocytes.

      Results

      IL-1β reduced the number of chondrocytes and the density of collagen II. PPI (0.25, 0.5, 1 μmol/L) had no effect on cell viability, but it dose-dependently elevated the inhibition of cell viability regulated by IL-1β. The elevation of cell apoptosis, senescence and expression of IL-6 and TNF-α were suppressed by PPI in a dose-dependent manner. Additionally, PPI reduced the expression of cleaved caspase-3, bax, MMP-3, and MMP-13 and promoted the expression of collagen II. TWIST1 expression was diminished by PPI. TWIST1 overexpression reversed the above-mentioned effects of PPI on chondrocytes.

      Conclusion

      PPI suppressed apoptosis, senescence, inflammation, and ECM degradation of OA chondrocytes by downregulating the expression of TWIST1.

    • Targeting Ubiquitin-specific Protease 5 Overcomes Chemoresistance Negatively Regulating p53 in Gastric Cancer

      Authors: Jing Song, Lei Liu, Fang Wang and Di Bao
      https://doi.org/10.2174/0115665240278762240202103722
      Background

      Resistance to chemotherapy is a major obstacle in the clinical management of gastric cancer, and the mechanisms underlying chemoresistance remain largely unknown.

      Aims

      This study aimed to investigate the involvement of ubiquitin-specific protease 5 (USP5), a deubiquitinating enzyme, in gastric cancer chemoresistance

      Methods

      USP5 expression was analyzed in fifty paired gastric cancer and adjacent normal tissues, chemo-sensitive and chemo-resistant gastric cancer lines using quantitative ELISA. The role of USP5 was determined using loss-of-function and gain-of-function methods. USP5-mediated downstream effectors were analyzed using biochemical methods focusing on p53.

      Results

      USP5 expression was comparable in tumors and normal in the majority of the cohort. Following chemotherapy treatment, USP5 expression significantly increased in gastric cancer cells, while p53 levels remained unaltered. Overexpression of USP5 amplified growth and migration while decreasing apoptosis induced by serum withdrawal across multiple gastric cancer cell lines. Conversely, USP5 knockdown effectively heightened gastric cancer sensitivity to paclitaxel and 5-FU treatments, particularly targeting chemo-resistant gastric cancer cells by inhibiting proliferation and migration and inducing apoptosis. Additionally, USP5 knockdown increased levels of p53 but not MDM2, increased p53 activity and increased transcription of p53 target genes. In contrast, USP5 overexpression decreased the level and activity of p53 and inhibited transcription of p53 target genes. The anti-proliferative, anti-migratory, and pro-apoptotic effects of USP5 were significantly diminished upon p53 depletion, highlighting the interplay between p53 and USP5 in regulating gastric cancer cell activities. Additionally, USP5 inhibition suppressed chemo-resistant gastric cancer cell migration suppressing epithelial-mesenchymal transition (EMT) and RhoA activity.

      Conclusion

      Targeting USP5 inhibition has emerged as a promising alternative therapeutic approach to overcoming chemoresistance in gastric cancer. Additionally, our study sheds light on the novel role of USP5 as a regulator of p53 in gastric cancer.

    • Extracorporeal Shock Wave and Melatonin Alleviate Joint Capsule Fibrosis after Knee Trauma in Rats by Regulating Autophagy

      https://doi.org/10.2174/0115665240339436240909100847
      Background

      Joint contracture is a common clinical problem affecting joint function. Capsule fibrosis plays a pivotal role in the progression of joint contracture. Previous studies have reported that autophagy plays a regulatory role in visceral fibrosis.

      Objective

      This study aimed to investigate whether extracorporeal shock wave therapy (ESWT) and melatonin alleviate joint capsule fibrosis in rats with extended knee joint contracture by regulating autophagy.

      Methods

      A rat traumatic knee joint extension contracture model was made. Then, the rats were treated with ESWT, melatonin, ESWT + melatonin, or ESWT + melatonin + mTOR agonist for 4 weeks. The range of motion (ROM) of the knee joints was measured. Joint capsules were collected and observed for pathological changes by H&E and Masson staining. LC3B protein expression was evaluated by immuno-fluorescence staining. TGF-β1, MMP-1, Col-I, Col-III, LC3, ATG7, Beclin1, p-AMPK, p-mTOR and p-ULK1 protein expressions were measured by Western blot assay.

      Results

      The intervention groups had significantly improved ROM of knee joint ( < 0.05), significantly improved pathological changes on HE and Masson staining, significantly decreased protein expressions of TGF-β1, MMP-1, Col-I, Col-III and p-mTOR ( < 0.05), and significantly increased protein expressions of LC3B, LC3II/LC3I ratio, ATG7, Beclin1, p-AMPK, and p-ULK1 ( < 0.05). Among these groups, the effects demonstrated by the ESWT + melatonin group were the best. With the mTOR agonist supplement, the therapeutic effects of extracorporeal shock waves and melatonin were significantly reduced.

      Conclusion

      ESWT plus melatonin alleviated knee joint capsule fibrosis in rats by regulating autophagy.

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