Cathepsin proteases have captivated the scientific community for many years owing to their deregulated expression, activation status, and potential role in the proliferation and progression of specific cancer types. These efforts have led to the development of several therapeutic strategies targeting specific cathepsin proteases. This development has been further driven by the identification of important cathepsin protease-specific target proteins. Despite the limitations of these approaches, primarily due to the lack of known specificity of cathepsin proteases in targeting substrate proteins, an alternative strategy may involve the identification and development of dual-acting therapeutics. We propose that these dual-acting therapeutics can selectively interfere with the protein constituents involved in forming a cathepsin-targeted protein complex while simultaneously inhibiting the cognate cathepsin protease. Considering this novel paradigm, we evaluated the potential of dual-acting therapeutics against other well-documented mimetic therapeutics designed to target intermediates in the apoptosis pathway. Some of these therapeutics may represent promising candidates for further testing as dual-acting anticancer therapeutics, either alone or in combination regimens.

The tumor necrosis factor-alpha (TNFA) gene plays a pivotal role in modulating inflammatory responses, and its variants have been hypothesized to influence susceptibility to endometriosis, a complex and multifactorial gynecological condition. Among the notable polymorphisms investigated are -238 G>A, -308 G>A, -850 C>T, -857 C>T, -863 C>A, and -1031 T>C. Despite substantial research, the evidence regarding their role as genetic risk factors for endometriosis remains inconclusive. To address this uncertainty, the present study conducted a systematic review of the literature to evaluate the association between TNFA variants and endometriosis risk. A comprehensive search of electronic databases was performed to identify relevant studies. Data extraction and quality assessment were carried out using the Newcastle-Ottawa Scale. Pooled odds ratios and 95% confidence intervals were calculated across various genetic models, with adjustments for multiple comparisons using the Bonferroni correction. Trial sequential analysis (TSA) was employed to determine the required sample size for conclusive results, and Egger’s test was used to assess publication bias. The analysis included 18 studies examining different TNFA polymorphisms, but no significant associations with endometriosis risk were identified. TSA revealed that the existing sample sizes were inadequate to detect definitive links. While the findings suggest that upstream variants of the TNFA gene are not associated with endometriosis risk, this does not conclusively rule out a role for TNFA in the disease pathogenesis. Further research involving larger, ethnically diverse populations is warranted to confirm these results and provide deeper insights into the genetic factors contributing to endometriosis.

Spinal cord injury (SCI) is a severe traumatic condition with increasing prevalence in developing countries. Characterized by a complex pathophysiology and a scarcity of treatment options, SCI often leads to long-term disabilities that adversely affect patients’ quality of life. A hallmark of SCI is substantial neuroinflammation and neurological damage, which may be either temporary or permanent. Inflammation is a key factor in SCI, particularly through the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome - an essential component of the body’s innate immune response. NLRP3 inflammasome activation contributes to secondary injury following SCI by releasing pro-inflammatory cytokines such as interleukin (IL)-1β and IL-18. Furthermore, NLRP3 activation exacerbates tissue damage and delays recovery. Pharmacological inhibition of NLRP3 inflammasome activation has shown potential in managing neuroinflammation, mitigating mitochondrial dysfunction, reducing the severity of spinal cord damage, and promoting neurological recovery after SCI. Recently, Chinese herbal medicine (CHM) has garnered interest as a novel therapeutic approach for SCI treatment. Various herbal compounds, including curcumin, resveratrol, and quercetin, have demonstrated the ability to target the NLRP3 inflammasome, reduce pro-inflammatory cytokines release, and protect neural tissue in SCI models. This review explores the inhibitory effects of CHM on NLRP3 inflammasome activation, highlighting the therapeutic potential of these natural compounds in improving outcomes for SCI patients. Ultimately, a deeper understanding of the interaction between NLRP3 and CHM may pave the way for innovative therapeutic strategies to enhance recovery following SCI.

For years, valuable clinical samples preserved in formalin-fixed paraffin-embedded tissues were underutilized. However, with advanced spatial multiomics profiling tools, crucial information has become increasingly accessible. Integrating genomic data with spatial information has unveiled crucial insights into cellular activities, enhancing our comprehension of biology. Measuring cellular gene expression while capturing spatial context - including morphology and intercellular relationships - is vital for understanding both normal and diseased biological processes. To date, this approach has illuminated the mechanisms of complex diseases, such as cancer and has facilitated the discovery of biomarkers for early disease detection and new therapeutic targets, accelerating progress in cancer immunotherapies. Cutting-edge single-cell analysis tools are rapidly emerging as the gold standard for investigating intricate biological systems and medical specimens, fueling a multi-billion-dollar industry. Single-cell spatial research, in particular, is inherently cross-disciplinary and addresses questions that remain hidden when focusing solely on the genome or transcriptome of large cell populations. Leveraging advances in single-cell spatial profiling can offer insights into improving cancer immunotherapy and other modern medical treatments. This review will delve into the diverse applications of spatial profiling technology, showcasing examples that demonstrate its ability to provide a detailed picture of the underlying molecular and cellular mechanisms within cells. As a comprehensive reference, this review empowers researchers and industry leaders to harness single-cell and spatial omics for breakthroughs in biomedicine and translational science.

Although obesity primarily stems from an imbalance between energy intake and expenditure, recent research over the past years has highlighted the role of various other contributing factors, including fetal growth and birth weight. Although the link between birth weight and adult body mass index remains unclear, some genomic alterations are thought to influence both fetal growth and post-natal body mass. Specifically, potential involvement of gene variants and epigenetic modifications associated with both birth weight and adipose tissue regulation could be proposed, suggesting that a genetic pleiotropy may modify growth efficiency during the fetal stage, contributing to the development of diseases later in life and serving as a link between birth weight and obesity. Given the dual role of the insulin-like growth factor 1/insulin axis, insulin-like growth factor 2, and peroxisome proliferator-activated receptors in fetal growth and adipogenesis, the potential involvement of a pleiotropic genetic effect in the relationship between birth weight and obesity warrants further consideration. Understanding the genetic interplay between birth weight and adipose tissue regulation offers valuable insights into the developmental origins of childhood obesity. These findings highlight the critical importance of prioritizing both maternal and fetal health during pregnancy. Future research should aim to integrate genetic, epigenetic, and environmental factors to develop early, targeted interventions for high-risk populations, ultimately helping to alleviate the global obesity burden.

Kidney renal clear cell carcinoma (KIRC) is a prevalent histological subtype of kidney cancer and one of the most invasive urinary tumors. Members of the cullin family play a pivotal role in driving the development and progression of neoplasms. Accumulating evidence suggests that cullins might play a significant part in the initiation and advancement of KIRC. In this study, the messenger ribonucleic acid expression profiles for eight members of the cullin family (CUL1 - 9) were noticeably upregulated in KIRC compared to normal tissue, whereas CUL3, CUL5, and CUL7 were downregulated. Moreover, our analysis demonstrated that higher expression levels of CUL1 - 3, CUL4A, CUL4B, CUL5, and CUL7 were significantly correlated with enhanced overall survival (OS) in KIRC patients. Co-expression gene analysis showed that the differential expression of cullins in KIRC was predominantly associated with 20 genes. Functional enrichment analysis indicated that cullins in KIRC primarily participated in ubiquitin-mediated protein degradation, facilitated protein polyubiquitylation, and regulated APC/C activators during the G1/S phase transition and early anaphase. Furthermore, cullin gene expression exhibited a positive correlation with the activity of tumor-infiltrating immune cells. These findings suggest that cullins may serve as diagnostic and prognostic biomarkers in KIRC patients.

The convergence of neurogenetics, epigenetics, and functional neuroimaging presented in this article marks a critical inflection point in our understanding and management of reward deficiency syndrome (RDS) and its behavioral expressions across pain and addiction medicine. The evidence for a hypodopaminergic state, now supported by decades of molecular, clinical, and imaging data, has culminated in the formulation of a scientifically grounded, personalized, and preventative paradigm— anchored by the concept of early genetic testing to provide risk information linked to “prediction” predominantly due to dopaminergic dysfunction. From a translational standpoint, this model offers more than a framework for understanding neurobiological vulnerability; it provides a practical roadmap for early identification of “pre-addiction,” informed opioid prescribing, relapse prevention, and long-term neurorecovery. The coupling of Genetic Addiction Risk Severity (GARS) with dopaminergic modulation—via safe, non-addictive interventions—could redefine standard treatment algorithms not only for substance use disorders but also for a broader spectrum of compulsive and comorbid behaviors. This study by members of the RDS Consortium explores the concept of “pre-addiction” within addiction biology through a comprehensive in silico analysis of 88,788,381 genome-wide association study-based samples from 1,373 studies, identifying 18 significant genes (e.g., APOE with p=1.0E-126) linked to opioids, pain, aging, and apoptosis pathways. It aims to correlate these genes with GARS, which includes 10 specific genes, and highlights the most connected genes, such as MAOA, COMT, APOE, and SLC4A6, through a STRING model. The analysis expanded to 27 unique genes, emphasizing significant interactions with hsa-miR-16-5p and hsa-miR-24-3p, especially SLC6A4. Through pharmacogenomics mining, 1,173 variant annotations were identified for these genes. Enrichment analysis and meta-analysis further validated these findings, illustrating the pivotal role of dopaminergic pathways in connecting addictive behaviors and depressive symptoms. The results support the conceptualization of RDS as the fundamental preaddiction phenotype, with pain, opioid dependence, aging, and apoptosis as critical endophenotypes.

Harlequin ichthyosis (HI) is a rare, severe, and congenital disorder that is often life-threatening, characterized by thick, rigid skin and large, diamond-shaped plates. These skin changes are not only aesthetically distressing but also pose significant functional challenges for affected individuals, such as impaired thermoregulation, restricted mobility, and heightened susceptibility to infections. The condition arises due to mutations in the ABCA12 gene, which encodes a critical lipid transporter protein essential for skin barrier function. Historically, HI was nearly fatal in the neonatal period due to complications such as sepsis, respiratory distress, and electrolyte imbalances from excessive transepidermal water loss. However, advances in intensive neonatal care-including humidified incubators, prophylactic antibiotics, and early nutritional support-have improved survival rates to over 50% in recent decades. Despite these gains, lifelong morbidity persists, with survivors often facing chronic skin inflammation, recurrent infections, and psychosocial challenges stemming from disease visibility. This review paper explores the genetic underpinnings of HI, focusing on ABCA12 mutations and their effects on epidermal differentiation and the formation of the skin’s stratum corneum. By utilizing advanced bioinformatics tools, including whole-exome sequencing, researchers are now able to identify mutations with high precision and investigate the genotype-phenotype correlations in HI. The review also examines the clinical challenges posed by HI, therapeutic strategies currently available, and the potential for innovative treatments such as gene therapy and skin-engineering. The paper aims to highlight the vital role bioinformatics plays in understanding the molecular mechanisms of HI, facilitating earlier diagnosis and personalized management for affected individuals. Advances in genetic research have provided new hope for improved outcomes and better quality of life for those affected by this debilitating condition.

Monogenic lupus is a highly complex condition with marked variability, resulting from diverse immune system etiopathogenesis linked to various pathogenic genetic variants. There is substantial overlap with newly described systemic autoinflammatory disorders. We present two cases of monogenic lupus and highlight the intersection between monogenic lupus and autoinflammatory disorders. This report emphasizes the concept of monogenic interferonopathies as an umbrella term for various conditions arising from genetic aberrations in type I interferon (IFN-I) signaling, which are associated with significant IFN-I activation.