Biomolecules & Therapeutics最新文献

Thyroid cancer is one of the most prevalent cancers in the world, accounting for the increased sensitivity of diagnostic assessments, the environment, and extensive imaging. While open thyroidectomy still forms the base surgical treatment of differentiated thyroid carcinoma (DTC), its visible scarring and postoperative morbidity have mandatorily propelled a longitudinal shift to minimally invasive techniques. Robotic thyroidectomy using the bilateral axillo-breast approach (BABA) is an emerging transformative technique that combines robotic precision and visualization with oncologic efficacy and superior cosmetic outcomes to enhance recovery. Molecular diagnostics such as next-generation sequencing (NGS) and microRNA classifiers have transformed preoperative planning. These tools aid in accurate risk stratification, enabling clinicians to determine the course of surgery and avoid overtreatment. Artificial intelligence (AI) enhances precision medicine by improving nodule classification, predicting surgical risks, providing intraoperative navigation guidance, and supporting postoperative histopathological evaluations. Despite these innovations, cost, accessibility, and ethical governance issues highlight persistent challenges. This review consolidates the current state of robotic-assisted surgery for thyroid cancer with molecular profiling and AI. It proposes future aims and strides toward precision surgery that is accessible worldwide.

The transglutaminase family is roughly 250 million years old. Horseshoe crabs have been described as a 'living fossil' and have remained virtually unchanged since first appearing around the Triassic period. The horseshoe crab, a living fossil, carries a primitive form of TG that helps it defend against infection and survive. Transglutaminase 2 (TG2, EC 2.3.2.13, gene name TGM2) is mainly known as a cross-linking enzyme in vertebrates. Although TG2 is not an oncogene, its high levels are linked to worse outcomes in many cancers. However, how TG2 cross-linking activity relates to its role in promoting cancer growth remains unclear. A recent discovery sheds light on this. In ovarian cancer cells, TG2 binds directly to GSK3β, leading to its removal by autophagosomes, which activates β-catenin. Stopping this interaction allows GSK3β levels to recover, thereby decreasing β-catenin activity. Even in the absence of cross-linking, cancer cells use TG2 as a chaperone to promote growth and support metastasis. This suggests intracellular calcium levels are too low for TG2 to perform cross-linking. It also indicates that anticancer treatments may increase TG2 levels in cancer cells, helping them recover by removing tumor suppressors. As a result, TG2 plays a role in developing drug resistance, acting as a primitive systemic defense mechanism linked with survival signals. I suggest that blocking TG2 binding, combined with inhibiting autophagy or alternative signaling pathways, is essential for effectively overcoming drug resistance, since it is rooted in TG2's primordial role.

Osteoblasts primarily originate from mesenchymal stem cells (MSCs) within the bone marrow. These stem cells possess the ability to differentiate into osteoblasts, which are responsible for secreting bone matrix, promoting bone formation, and contributing to bone remodeling. Dysfunction in osteoblast activity can lead to various bone-related disorders, such as osteoporosis, delayed fracture healing, and skeletal deformities. In recent years, due to the adverse effects associated with the use of parathyroid hormone (PTH) analogs, bisphosphonates, and calmodulin-targeting drugs, there has been growing interest in exploring the mechanisms underlying osteoblast differentiation. Researchers are increasingly focusing on identifying natural compounds as potential treatments for osteoporosis. Among the signaling pathways involved, the Wnt/β-catenin pathway is recognized as a key regulator of osteoblast differentiation and a crucial therapeutic target in osteoporosis. However, both upregulation and downregulation of this pathway have been implicated in various diseases, including cancers. This review highlights the role of the Wnt/β-catenin signaling pathway in osteoblast differentiation, examines the association between pathway-related proteins and human diseases, and summarizes recent advancements in the development of natural compounds targeting this pathway for osteoporosis therapy.

Knee osteoarthritis (KOA) is a progressive and chronic musculoskeletal condition that continues to be the leading cause of disability worldwide. Conventional treatment approaches for the management of KOA largely focus on symptom alleviation rather than halting or reversing disease progression. However, recent advancements have highlighted the integrated interplay of mechanical stress, inflammation, cellular senescence, and chondrocyte dysfunction in the progression of KOA, in turn prompting new therapeutic strategies. Therefore, emerging interventions such as regenerative medicine, gene therapy, senolytic, platelet-rich plasma (PRP), disease-modifying osteoarthritis drugs (DMODs), and biologics have broadened the therapeutic options. Additionally, natural compounds demonstrated potential in KOA treatment with promising chondroprotective and anti-inflammatory effects. Moreover, digital technologies and clinical and molecular phenotyping enhanced early diagnosis, monitoring, and personalized management of the disease. Therefore, the current narrative review focuses on the molecular insights, clinical outcomes and prospects for the rapidly evolving landscape of current and emerging treatment approaches for the management of knee osteoarthritis (KOA).

Anticancer drug resistance remains a significant challenge to the efficacy of cancer treatment, with DNA repair enzymes contributing to this resistance. We hypothesized that thymine DNA glycosylases (TDGs) may be involved in anticancer drug resistance given their dual function of DNA repair and demethylation as well as investigated their possible involvement in the induction of β-catenin in SNUC5 cells resistant to 5-fluorouracil (SNUC5/5-FUR) and oxaliplatin (SNUC5/OXTR). The expression of TDG and phospho-β-catenin increased in both resistant cell types when compared to that in SNUC5 cells. Moreover, knockdown of TDG significantly suppressed phospho-β-catenin expression in both resistant cell types, resulting in enhanced sensitivity to anticancer drugs. TDG binding to the β-catenin promoter was stronger in both resistant cell types than in SNUC5 cells, showing a decreased methylation pattern in the CpG islands of the β-catenin promoter. Furthermore, another DNA demethylase, ten-eleven translocation 1 (TET1), showed the same pattern as TDG in both resistant cell types. Additionally, TDG significantly interacted more with TET1 in both resistant cell types than in SNUC5 cells, enhancing binding to the same locus in the β-catenin promoter. These findings suggest that TDG may be a promising target molecule for overcoming drug resistance in colorectal cancer.

Chimeric Antigen Receptor (CAR)-based cell and gene therapies have become transformative treatments, offering targeted and durable responses, especially in hematologic malignancies. This review analyzes 1,744 CAR clinical trials registered on Clinical-Trials.gov as of 2024, focusing on platform types, indications, target antigens, therapeutic strategies, and late-phase development. CAR-T therapies predominate, followed by CAR-NK, CAR-NKT, CAR-M and CAR-DC platforms. Approximately 92% of trials target tumors, with hematologic malignancies accounting for 65% of indications; CD19 and BCMA are primary targets in Phase 3 studies. Solid tumor applications are expanding steadily, driven by unmet clinical needs and advances in CAR engineering. Although monospecific CARs dominate, dual, bispecific, and universal designs are gaining traction to overcome antigen heterogeneity and tumor escape. Combination therapies, such as CAR-T with chemotherapy or monoclonal antibodies, are increasingly used to improve efficacy. CAR-NK therapies, while in early development, show promise due to favorable safety profiles and off-the-shelf allogeneic potential. The United States and China lead global development, supported by robust research ecosystems and industrial investment. Overall, CAR-based therapeutics are evolving from hematologic specialization toward broader clinical application, addressing challenges and guiding future strategies.

Suzetrigine is a novel non-opioid analgesic that selectively inhibits the Nav1.8 sodium channel, which plays a key role in peripheral pain signaling. By blocking action potential propagation in nociceptors, it effectively reduces pain without affecting the central nervous system, thus avoiding the risks associated with opioids, such as addiction and respiratory depression. In two phase 2 clinical trials, suzetrigine demonstrated superior pain control compared to placebo and showed comparable effectiveness to hydrocodone/acetaminophen for treating moderate to severe acute pain after abdominoplasty and bunionectomy with an acceptable safety profile. Current findings support suzetrigine's potential role as a safer alternative to opioids in managing moderate to severe pain.

Topically applied hyaluronic acid (HA) hydrates the skin without efficient penetration. This study compared the penetration efficiency of liposomal hyaluronic acid (LPS-HA) against that of conventional HA across different models. Dynamic light scattering revealed that particles of LPS-HA (226.1 nm, PDI 0.2898) were smaller than those of HA (798.4 nm, PDI 0.8709). In Strat-M® membrane assays, permeability over 24 h was higher with LPS-HA (629.37 ± 103.26%) than that of HA (508.04 ± 93.80%; p<0.05). In keratinocytes, LPS-HA increased differentiation markers filaggrin and caspase-14 in a concentration-dependent manner, with maximal induction at 1% (186.6 ± 6.99% and 249.3 ± 8.60%) vs. HA (117.9 ± 7.64% and 130.1 ± 2.90%; p<0.05). In fibroblasts, LPS-HA increased the expression of type I and type III collagens (138.4 and 133.6%) without increasing that of elastin (68.3-94.7%) and reduced UVB-induced IL-6 (79.1-90.2% of UVB; p<0.05). Ex vivo, LPS-HA enhanced HAS-3 mRNA (3.03 ± 0.19-fold vs. 1.31 ± 0.13-fold with HA; p<0.05) and increased epidermal hyaluronan staining. In PM10-treated human skin, LPS-HA reduced inflammatory cytokines (TNF-α, IL-6, IL-8, and IL-1β) and suppressed mast cell degranulation, similar to dexamethasone, and reduced ROS formation (124.46 ± 8.45% vs. 169.35 ± 9.40% in PM10-only, p<0.01) without histological abnormalities. In a 20-subject clinical study, corneometric hydration with LPS-HA was higher than that of control (96.99% vs. 36.31%; RM-ANOVA, p<0.001). Collectively, LPS-HA enhanced skin permeation, hydration, and anti-inflammatory responses, supporting its potential as a cosmetic moisturizing ingredient.

Ubiquitination of RIPK1 serves as a critical regulatory switch in determining the outcome of prosurvival NF-κB signaling by linking the TNFR1 signaling complex to upstream IKK activation. Therefore, identifying bioactive compounds that modulate RIPK1 ubiquitination has emerged as a promising strategy to enhance the therapeutic efficacy of TNF, particularly in cancers with constitutively active NF-κB signaling. In our previous in vitro phytochemical study, we demonstrated that brazilin, isolated from Caesalpinia sappan L., inhibits the catalytic activity of the IKK complex during TNF-mediated NF-κB activation without affecting RIPK1 ubiquitination at high concentrations (~50 μM), raising concerns about off-target effects. In this study, we now report that brazilein, an oxidized derivative of brazilin, acts as a potent inhibitor of RIPK1-dependent NF-κB activation upon TNFR1 engagement. Our findings reveal that brazilein markedly suppresses upstream IKK signaling events, including TNFR1-associated RIPK1 polyubiquitination and its interaction with IKKβ. In contrast, brazilein does not affect NIK/IKKα-mediated non-canonical NF-κB activation induced by LIGHT, indicating its specificity for the canonical NF-κB pathway. Moreover, brazilein not only sensitizes cells to TNF-induced apoptosis but also induces apoptosis in A20-deficient and oncogenically transformed cells with constitutive NF-κB activity. Taken together, these results suggest a novel mechanism by which brazilein exerts anti-IKK activity through inhibition of RIPK1 ubiquitination, highlighting its potential as a candidate for NF-κB-targeted cancer therapy.

Obesity is a global health problem associated with several metabolic disorders. Conventional dietary supplements such as Garcinia cambogia, catechin, and conjugated linoleic acid (GC complex) are widely used for weight loss but raise concerns about long-term efficacy and safety. Recent advances in nutritional research suggest that combining dietary mineral elements might enhance obesity therapeutic outcomes. The objective of this study is to investigate the potential synergistic effects of potassium in combination with GC complex in a mouse model of high-fat diet (HFD)-induced obesity. When administered daily orally for 12 weeks, the HFD+GC+Potassium group exhibited synergistically reduced adipocyte size in both white and brown adipose tissue compared to the HFD group, indicating a reduction in fat storage. In addition, HFD+GC+Potassium group exhibited a marked improvement in metabolic profiles, characterized by reduced fasting glucose and total cholesterol levels without toxicity, compared with HFD group. Histological analyses confirmed the effectiveness of the treatment, showing marked reductions in hepatic steatosis and lipid accumulation, as evidenced by H&E and Oil Red-O staining in the HFD+GC+Potassium group. Significantly, the study showed that potassium supplementation in combination with GC complex improved lipid metabolism and energy expenditure by increasing the expression of phosphorylated acetyl-CoA carboxylase 1 (p-ACC1) and carnitine palmitoyltransferase I (CPT1), while decreasing the levels of fatty acid synthase (FAS) and sterol regulatory element-binding protein 1 (SREBP1) through IGF1R/PI3K/AKT/GSK3β axis. These findings suggest that the combination of GC complex and dietary potassium may offer a synergistic effect and a safe strategy for managing obesity by reducing fat accumulation and enhancing metabolic health.