Long noncoding RNAs (lncRNAs) are pivotal regulators in the pathophysiology of diabetes mellitus and its complications, including diabetic retinopathy, nephropathy, and cardiomyopathy. They influence essential cellular processes such as angiogenesis, vascular smooth muscle cell behavior, inflammation, extracellular matrix remodeling, and apoptosis. In cardiomyopathy, lncRNA H19 promotes cardiomyocyte survival by regulating autophagy, highlighting its role in cardiovascular outcomes. In addition, lncRNAs hold promise as noninvasive biomarkers, detectable in extracellular fluids such as serum and urine, providing novel diagnostic tools. For example, elevated levels of HOX transcript antisense RNA and promoter of CDKN1A antisense DNA damage-activated RNA correlate with hyperglycemia and its complications, whereas maternally expressed gene 3 and metastasis-associated lung adenocarcinoma transcript 1 are linked to insulin resistance. However, the full scope of lncRNA mechanisms and therapeutic potential remains unclear. Recent research emphasizes the importance of studying the molecular pathways influenced by lncRNAs, such as the Janus kinase/signal transducer and activator of transcription and p38 mitogen-activated protein kinase pathways, which regulate inflammation and insulin signaling. Preclinical studies show promising outcomes for lncRNA-targeted therapies; however, challenges remain in precise detection and delivery. Addressing these gaps through advanced RNA sequencing and targeted therapies is crucial for developing lncRNA-based diagnostics and treatments for diabetes complications. This review explores lncRNAs as biomarkers and therapeutic targets, focusing on their regulatory mechanisms in diabetic complications such as retinopathy, nephropathy, and cardiomyopathy.

Altered circadian rhythms occur in several types of cancer cells. Expression of PER2, a core component of the circadian oscillator mechanism, and the related PER3 gene is suppressed in adult glioblastoma (GBM). GBM cell survival depends on the activity of the core clock gene ARNTL that expresses BMAL1 protein, and pharmacological manipulations of BMAL1 activity are promising novel anticancer treatments. Because circadian clock gene activity in pediatric gliomas is poorly understood relative to adult GBM, we completed a meta-analysis using 19 public transcriptome datasets to evaluate expression of core clock genes and selected clock-controlled genes in adult and pediatric GBM as well as medulloblastoma (MB), pilocytic astrocytoma (PA), and ependymoma (EP) tumors. Unlike adult GBM, PER2, and PER3 were not significantly downregulated in pediatric gliomas relative to non-tumor tissue. Adult GBM tissue displayed elevated expression of core clock gene CRY1 and clock-controlled gene NFIL3, unlike the pediatric GBM and low-grade gliomas. The TIMELESS clock gene was upregulated in all glioma types except PA. The clock gene set was differentially expressed across the four standard MB subtypes in pediatric datasets and was elevated in bulk-tumor measurements and single-cell RNA sequencing results from the Group 3 and 4 subtypes. Relative to older patients, MB samples from patients under 10 years of age had six repressed core clock genes. This study found that several types of malignant pediatric brain tumors have predictable expression patterns of specific circadian clock genes and may respond to treatments using pharmacological treatments exploiting these features.

Orexin - a neuropeptide - is extensively distributed in the central nervous system and is involved in the regulation of diverse physiological functions and behaviors. Orexin is strongly associated with the onset and development of depression. The most important function of orexin is to interact with the transport system, mediating arousal, and energy homeostasis. Hypothalamic-ventral tegmental and hypothalamic-ventral thalamic pathways provide clues for understanding the function of orexin and related disorders, such as sleep disorders, eating disorders, and substance abuse. This article summarizes the basic and clinical studies on the role of the orexin system in regulating and treating depression, including the relationship between the expression level of orexin in specific brain areas and diseases, relationship between adolescent depression and orexin, orexin receptor antagonists as a treatment for depression, and narcolepsy, which is closely associated with depression. Research progress on the role of orexin in depression and recent relevant studies are summarized, providing novel directions for developing depression treatment strategies.

Stem cell therapy represents a burgeoning and swiftly advancing modality for the treatment of a diverse array of neurological disorders. However, despite continued clinical trials, the underlying mechanisms of action often remain elusive. Traditional Chinese medicine (TCM), with its holistic approach, provides a valuable resource for the identification and evaluation of potential neuroprotective agents. Research has shown that TCM, including herbs, herbal extracts, and specific Chinese herbal constituents, can modulate the proliferation and differentiation of neural stem cells (NSCs) to some extent. This review examines the potential of TCM as a treatment for neurodegenerative diseases. Given the limitations of current therapies due to a lack of understanding of disease pathogenesis, a holistic approach to TCM offers a promising alternative. This paper also summarizes the role of stem cells in the management of neurological disorders and evaluates prior studies concerning stem cell transplantation. In addition, it explores the capacity of TCM to influence the proliferation and differentiation of NSCs. The ultimate aim of this review is to enhance our understanding of how TCM can be utilized to influence stem cell behavior and potentially treat neurodegenerative diseases.

MXRA7, a gene associated with matrix remodeling, exhibits diverse expression profiles across various cancers, including bladder cancer (BLCA). Previous studies have linked elevated MXRA7 levels to poor clinical outcomes in multiple cancer types, although its precise biological role remains unclear. In this study, bioinformatic analyses were conducted using the Cancer Genome Atlas (TCGA) data to explore MXRA7 expression levels in BLCA. Database for annotation, visualization, and integrated discovery enrichment analysis was then employed to identify pathways associated with differentially expressed genes (DEGs) between the high expression (MXRA7-H) and low expression (MXRA7-L) groups. A least absolute shrinkage and selection operator regression model was applied to MXRA7 and the DEGs in BLCA to generate a risk score. Multifactor Cox regression analysis, conducted using statistical product and service software automatically, was performed to identify reliable prognostic factors for patient survival. The results suggested that MXRA7 may play a role in invasion, migration, and microenvironment remodeling in BLCA. Kaplan-Meier survival analysis revealed that higher MXRA7 expression was significantly associated with poorer survival outcomes in BLCA. Seven key factors - “Age”, “MXRA7”, “MXRA7 expression level”, “Risk score”, “Tumor grade”, “Cancer status”, and “Clinical_N” - were identified as components of a robust predictive model, achieving an area under curve above 0.80. These findings suggest that MXRA7 could serve as a prognostic biomarker for BLCA and may aid in the development of targeted therapeutic strategies.

Wilson’s disease (WD) is a rare autosomal recessive copper metabolism disorder that primarily affects hepatic and neuronal tissues. The condition is caused by mutations in the ATP7B gene. Our group conducted extensive molecular genetic studies, identifying 13 clinically diagnosed Indian WD patients lacking the coding variant of ATP7B and 17 patients with a single mutated allele. We hypothesize that in these patients, unidentified mutations may reside in cis-regulatory elements of ATP7B or that a WD-like phenotype results from the cumulative effect of hypofunctional alleles of other key genes in the copper metabolism pathway. In this study, we employed an established bioinformatic pipeline to identify and screen cis-regulatory elements of ATP7B in WD patients with missing heritability through polymerase chain reaction sequencing. Although no pathogenic variants were identified, our analysis revealed two heterozygous single nucleotide polymorphisms (rs2181891 and rs747781) in two patients. Notably, rs2181891 showed strong regulatory potential with a RegulomeDB score of 1d. The genotype-specific expression profile for rs2181891 revealed it to be an expression quantitative trait locus for ATP7B in the cerebellum. In addition, the Genotype-Tissue Expression portal data suggest that the T allele of rs2181891 is associated with higher expression of ATP7B, making it unlikely to contribute to the WD phenotype. This novel study is the first to identify and screen ATP7B cis-regulatory elements in Indian WD patients with missing heritability.

Nearly a century has passed since Cecil A. Alport first described the triad of nephritis, hearing loss, and ocular abnormalities that would later be recognized as the second most common inherited nephropathy and a significant cause of end-stage kidney disease. Pathogenic variants in COL4A3, COL4A4, and COL4A5 genes lead to compromised synthesis, assembly, and/or function of α3, α4, and α5 chains of type IV collagen (COL4). This disruption leads to an abnormal trimerization of COL4 into a stable network, impairing the integrity and function of glomerular, cochlear, and ocular basement membranes. The gold standard for Alport syndrome diagnosis is molecular genetic testing, which provides a non-invasive and highly specific approach. In settings with limited access to genetic testing, kidney biopsy with electron microscopy remains essential, revealing characteristic glomerular basement membrane abnormalities. Despite significant advancements in understanding its genetic and molecular basis, Alport syndrome remains a relentlessly progressive disorder, often culminating in end-stage kidney disease during early adulthood. While no disease-specific therapy exists, early initiation of renin-angiotensin-aldosterone system blockade is the cornerstone of AS management, delaying disease progression. Emerging therapies, including sodium-glucose cotransporter-2 inhibitors and mineralocorticoid receptor antagonists, are being investigated for their nephroprotective potential. In addition, recent breakthroughs in therapeutic research - including gene- and cell-based treatments - hold the potential to transform disease management. Genetic factors influence treatment response, reinforcing the need for personalized therapeutic approaches. In this review, we discuss the genetic background and phenotypic correlations of Alport syndrome, the pathophysiological mechanisms driving both renal and extrarenal manifestations, and explore diagnostic approaches and emerging strategies aimed at modifying the natural course of this disease.

B-cell lymphoma/leukemia 11A (BCL11A) is a zinc-finger transcription factor that plays a crucial role in B-cell development. It is highly expressed in numerous neoplasias, making it a potential risk factor for cancer. Recently, we identified a subset of plasmacytoid dendritic cells (pDC) in mice that are derived from common lymphoid progenitors, which primarily give rise to lymphocytes. We further demonstrated that transcription of B cell-derived pDC (B-pDC) genes in this murine subset is highly regulated by BCL11A. To investigate whether a similar lineage exists in humans, we identified direct BCL11A transcription targets and chromatin binding patterns shared between malignant human pDC and B-cell leukemias. We focused on cell lines such as NALM6 (pre-B leukemia), Raji (B-cell Burkitt’s lymphoma), and GM12878 (pre-B-cell leukemia) and compared BCL11A targets to those in the CAL-1 human pDC cell line. Our findings revealed that BCL11A bound to promoter regions of genes such as PAX5, TCF3, and ID3 in B-cell leukemias, while it exclusively bound AXL, SIGLEC1, and IGLL1 in CAL-1 human pDCs. These results suggest that an evolutionarily conserved transcriptional hierarchy underlies B-pDC commitment, distinguishing it in human leukemias.

Dengue virus (DENV) and West Nile virus (WNV) are mosquito-borne pathogens that cause severe health burdens globally. Despite their impact, no clinically approved antiviral therapies are currently available. The NS2B-NS3 protease is essential for viral genome replication in both viruses, increasing viral loads in infected individuals. Therefore, targeting and inhibiting this protease would significantly reduce viral replication. In a recent molecular dynamics (MD) simulation study, N-(((2,6-dibromophenyl) amino) methyl)-4-morpholinobenzamide (11q) was found to bind more strongly to the NS2B-NS3 protease of the Zika virus (ZIKV) than SYC-1307, a known ZIKV protease inhibitor. Notably, 11q was also observed to inhibit influenza virus replication. Given the high structural and sequence similarity of the NS2B-NS3 protease across ZIKV, DENV, and WNV, it was necessary to evaluate whether 11q can bind to the proteases of DENV and WNV to inhibit their activities. Using molecular docking, MD, and binding free energy studies, we found that 11q strongly binds to the NS2B-NS3 proteases of DENV and WNV with binding free energies of −15.80 ± 3.34 kcal/mol and −13.13 ± 2.56 kcal/mol, respectively. The slightly more favorable binding of 11q to the DENV protease is comparable to that observed with the ZIKV protease. Interestingly, the binding affinities of 11q for all three viral proteases surpass that of the ZIKV-SYC-1307 complex. Therefore, it is proposed that 11q may act as a pan-antiviral agent against ZIKV, DENV, and WNV proteases. However, experimental verification of its protease inhibition activities is required before it can be repurposed for therapeutic use against these viral diseases.

Autoimmune disorders are complex, heterogeneous conditions that can severely impact an individual’s quality of life. These diseases are associated with a breakdown of central and peripheral processes controlling self-tolerance, causing the presence of circulating autoreactive immune cells that target the body’s own cells and tissues. Some data suggest that autoimmune diseases (ADs) are becoming increasingly prevalent in modern society. Possibly, both genetic and environmental factors contribute to the rise. ADs disproportionally affect females compared to males. Hormonal determinants, particularly sex-steroid hormones, have historically been proposed as key modulators of the differential susceptibility to ADs between the mammalian sexes. Emerging evidence has more recently generated significant focus on the X chromosome as a potential key player in ADs pathogenesis. The X chromosome, one of the largest chromosomes in the mammalian genome, exhibits a different pattern of inheritance between the sexes. In females, one X chromosome is typically silenced in somatic cells to balance the active X dosage between the sexes. The X-inactivation process is not fully efficient as a proportion of X-linked genes is capable to escape silencing and maintaining variable, biallelic expression degree within each cell. Notably, the X chromosome is rich in genes related to immune functions; variations in X chromosome dosage can alter the susceptibility of developing autoimmune traits. Both X-linked genes and X-linked mechanisms have been associated with ADs. In this review, we discuss the X chromosome’s crucial roles in ADs.