Development of a 2A peptide-based multigene expression system and its application for enhanced production of ganoderic acids in Ganoderma lucidum.

Ganoderma has received much attention for its medicinal value, but the manipulation of multiple genes remains a challenge, hindering the genetic engineering of this species for the development of cell factories. Here, we first showed that the presence of an intron is necessary for the efficient expression of the endogenous cDNA of carboxin-resistant gene (cbx) in G. lucidum. Then, the self-cleaving function of 2 A peptide was investigated in G. lucidum by linking cbx cDNA to the codon-optimized hygromycin B-resistant gene (ophph) using the 2A-peptide sequence. The results showed that cbx cDNA and ophph can be successfully expressed in G. lucidum in a bicistronic manner from a single transcript. Moreover, the expression of both genes was not affected by the order within the 2 A cassette. In addition, simultaneous expression of cbx cDNA, ophph, and codon-optimized yellow fluorescent protein gene (opyfp) was conducted for the first time in G. lucidum using the 2 A peptide-based approach. The developed method was successfully applied to express both cDNA of the 3-hydroxy-3-methylglutaryl coenzyme A reductase (hmgr) and squalene epoxidase gene (se) for enhanced production of ganoderic acids (GAs) in G. lucidum. The engineered strain produced the maximum content of GA-Mk, GA-T, GA-S, and GA-Me were 26.56±3.53,39.58±3.75, 16.54±2.16, and 19.1±1.87 µg/100 mg dry weight, respectively. These values were 3.85-, 4.74-, 3.65-, and 3.23-fold higher than those produced by the control strain. The developed method will be useful for the manipulation of complex metabolic or regulatory pathways involving multiple genes in Ganoderma.

HERV-K np9 and HERV-R env: Two endogenous retrovirus products with potential Pathogenic roles in pediatric acute lymphoblastic leukemia.

OBJECTIVES: Human endogenous retroviruses (HERVs) are integral components of the human genome, and their reactivation has been implicated in the pathogenesis of some malignancies. External viral co-infections are suspected to play a role in HERV transactivation. This study aimed to investigate the expression of HERV-K np9 elements and HERV-R env gene in pediatric acute lymphoblastic leukemia (ALL) patients. Additionally, we explored potential correlations between HERV expression and common viral infections prevalent in this group of patients. METHODS: Blood samples were collected from 43 pediatric ALL patients and 48 age- and sex-matched healthy controls. Quantitative real-time PCR (qRT-PCR) was used to assess the expression of HERV-K np9 and HERV-R env, along with herpes simplex virus (HSV), parvovirus B19, and polyomavirus BK. RESULTS: HERV-K np9 and HERV-R env showed significantly higher expression in the peripheral blood of ALL patients compared to healthy controls (p < .001 and p = .003, respectively). HSV positivity was associated with significantly increased HERV-K np9 expression. No significant correlations were observed between other investigated viruses and HERV gene expression. CONCLUSION: The overexpression of HERV-K np9 and HERV-R env in pediatric ALL patients suggest their potential role in leukemogenesis. Our findings also suggest a possible link between HSV infection and HERV reactivation in this population. Future investigations are needed to understand the precise roles of these genes and viral infections in the development of ALL.

Therapeutic Application of Modulators of Endogenous Cannabinoid System in Parkinson's Disease.

The endogenous cannabinoid system (ECS) of the brain plays an important role in the molecular pathogenesis of Parkinson's disease (PD). It is involved in the formation of numerous clinical manifestations of the disease by regulating the level of endogenous cannabinoids and changing the activation of cannabinoid receptors (CBRs). Therefore, ECS modulation with new drugs specifically designed for this purpose may be a promising strategy in the treatment of PD. However, fine regulation of the ECS is quite a complex task due to the functional diversity of CBRs in the basal ganglia and other parts of the central nervous system. In this review, the effects of ECS modulators in various experimental models of PD in vivo and in vitro, as well as in patients with PD, are analyzed. Prospects for the development of new cannabinoid drugs for the treatment of motor and non-motor symptoms in PD are presented.

Schisandra chinensis lignans regulate and cooperate with endogenous cannabinoid systems to ameliorate intestinal barrier injury associated with depression.

BACKGROUND: Schisandra chinensis lignan (SCL), a major active component of the traditional functional Chinese medicine Schisandra chinensis, has been reported to have antidepressant effects. Its mechanisms include alleviating intestinal barrier injury (IBI) by resolving intestinal microflora, anti-inflammation, and neuroprotection. SCL also regulates endogenous cannabinoid system, and it is closely related to the onset and development of depression. PURPOSE: We investigated a new treatment strategy for depression, i.e., alleviating IBI by regulating the endogenous cannabinoid system for antidepressant effects, as well as conducted in-depth research to explore the specific mechanism. METHODS: Behavioral analysis was conducted to detect the occurrence of depressive-like behavior in C57BL/6 mice. We used hematoxylin-eosin staining, periodic acid-Schiff staining, and immunofluorescence to evaluate IBI. Network pharmacology and Western blotting (WB) were used to predict and confirm that the amelioration effect of SCL was associated with anti-inflammation and anti-apoptosis. Combined with the levels of anandamide (AEA) and 2-arachidonoylglycerol (2-AG), we conducted the Pearson analysis between the AEA, 2-AG levels and the major targets identified and validated by network pharmacology and WB. Subsequently, URB-597, a fatty acid amide hydrolase (FAAH) antagonist with an AEA hydrolase-inhibiting effect, was administered to the mice, and behavioral analysis and apoptotic proteins were verified. Plasma endocannabinoid levels after URB-597 supplementation were measured via 6470 Triple Quadrupole LC/MS. Finally, the cannabinoid receptor type 2 (CB2R) antagonist AM630 was administered to mice, and immunofluorescence and WB were performed to assess the proteins of IBI and anti-inflammation. RESULTS: The study demonstrated that SCL alleviated depressive-like behaviours and ameliorated IBI. Network pharmacology and WB confirmed that the improvement of IBI was related to the anti-inflammatory and anti-apoptotic pathways. Pearson results showed that AEA levels were positively correlated with inflammation and apoptosis, with a greater contribution to apoptosis. In-depth studies validated that the URB-597 administration reversed the positive effects of SCL on depressive-like behavior and anti-apoptosis. Similarly, URB-597 counteracted AEA levels reduced by SCL and decreased 2-AG levels. Furthermore, AM630 supplementation antagonized SCL's effect of improving IBI by reactivating the MAPK/NF-κB inflammation pathway. CONCLUSION: Overall, SCL, in collaboration with the endogenous cannabinoid system regulated by SCL, alleviates depression associated IBI. The specific mechanism involes SCL decreasing AEA levels to inhibit colon tissue cell apoptosis by up-regulating FAAH. Simultaneously, it directly triggers CB2R to reduce inflammation responses, further alleviating IBI.

BEROLECMI: a novel prediction method to infer circRNA-miRNA interaction from the role definition of molecular attributes and biological networks.

Circular RNA (CircRNA)-microRNA (miRNA) interaction (CMI) is an important model for the regulation of biological processes by non-coding RNA (ncRNA), which provides a new perspective for the study of human complex diseases. However, the existing CMI prediction models mainly rely on the nearest neighbor structure in the biological network, ignoring the molecular network topology, so it is difficult to improve the prediction performance. In this paper, we proposed a new CMI prediction method, BEROLECMI, which uses molecular sequence attributes, molecular self-similarity, and biological network topology to define the specific role feature representation for molecules to infer the new CMI. BEROLECMI effectively makes up for the lack of network topology in the CMI prediction model and achieves the highest prediction performance in three commonly used data sets. In the case study, 14 of the 15 pairs of unknown CMIs were correctly predicted.

Elastic Nanofibrous Dressings with Mesenchymal Stem Cell-Recruiting and Protecting Characteristics for Promoting Diabetic Wound Healing.

Diabetic wounds that do not heal for a long time challenge global healthcare. Mesenchymal stem cell (MSC) therapy has positive significance in promoting diabetic wound healing. However, traditional MSC therapy involves exogenous MSCs, which brings many limitations and unsatisfactory treatment. Moreover, the maintenance of MSC viability and function is difficult because of the high level of reactive oxygen species (ROS) in diabetic wounds. Therefore, we developed a nanofibrous dressing to recruit and protect endogenous MSCs while avoiding the inherent disadvantages of exogenous MSCs. Ceria nanoparticles capable of ROS scavenging are integrated into the nanofibrous dressings, together with Apt19S, a DNA aptamer with affinity and selectivity for MSCs. In addition, the homogenization and freeze-drying technology give the nanofibrous dressings good elasticity, which protects the wound from external pressure. Further experiments in diabetic mice show that the dressing has excellent endogenous MSC recruitment and anti-inflammatory properties, thereby synergistically promoting diabetic wound healing. This study is expected to explore an efficient method of stem cell therapy, providing a new way to construct high-performance wound dressings.

The ancient Z-DNA and Z-RNA specific Zα fold has evolved modern roles in immunity and transcription through the natural selection of flipons.

The Zα fold specifically binds to both Z-DNA and Z-RNA, left-handed nucleic acid structures that form under physiological conditions and are encoded by flipons. I trace the Zα fold back to unicellular organisms representing all three domains of life and to the realm of giant nucleocytoplasmic DNA viruses (NCVs). The canonical Zα fold is present in the earliest known holozoan unicellular symbiont Capsaspora owczarzaki and persists in vertebrates and some invertebrates, but not in plants or fungi. In metazoans, starting with porifera, Zα is incorporated into the double-stranded RNA editing enzyme ADAR and reflects an early symbiont relationship with NCV. In vertebrates, Zα is also present in ZBP1 and PKZ proteins that recognize host-derived Z-RNAs to defend against modern-day viruses. A related Zα fold, also likely to bind Z-DNA, is present in proteins thought to modulate gene expression, including a subset of prokaryote arsR proteins and the p15 (PC4) family present in algae. Other Zα variants that probably play a more general role in the reinitiation of transcription include the archaeal and human transcription factor E and the human RNA polymerase 3 subunit C proteins. The roles in immunity and transcription underlie the natural selection of flipons.

Endogenous Tissue Engineering for Chondral and Osteochondral Regeneration: Strategies and Mechanisms.

Increasing attention has been paid to the development of effective strategies for articular cartilage (AC) and osteochondral (OC) regeneration due to their limited self-reparative capacities and the shortage of timely and appropriate clinical treatments. Traditional cell-dependent tissue engineering faces various challenges such as restricted cell sources, phenotypic alterations, and immune rejection. In contrast, endogenous tissue engineering represents a promising alternative, leveraging acellular biomaterials to guide endogenous cells to the injury site and stimulate their intrinsic regenerative potential. This review provides a comprehensive overview of recent advancements in endogenous tissue engineering strategies for AC and OC regeneration, with a focus on the tissue engineering triad comprising endogenous stem/progenitor cells (ESPCs), scaffolds, and biomolecules. Multiple types of ESPCs present within the AC and OC microenvironment, including bone marrow-derived mesenchymal stem cells (BMSCs), adipose-derived mesenchymal stem cells (AD-MSCs), synovial membrane-derived mesenchymal stem cells (SM-MSCs), and AC-derived stem/progenitor cells (CSPCs), exhibit the ability to migrate toward injury sites and demonstrate pro-regenerative properties. The fabrication and characteristics of scaffolds in various formats including hydrogels, porous sponges, electrospun fibers, particles, films, multilayer scaffolds, bioceramics, and bioglass, highlighting their suitability for AC and OC repair, are systemically summarized. Furthermore, the review emphasizes the pivotal role of biomolecules in facilitating ESPCs migration, adhesion, chondrogenesis, osteogenesis, as well as regulating inflammation, aging, and hypertrophy-critical processes for endogenous AC and OC regeneration. Insights into the applications of endogenous tissue engineering strategies for in vivo AC and OC regeneration are provided along with a discussion on future perspectives to enhance regenerative outcomes.

Retro-age: A unique epigenetic biomarker of aging captured by DNA methylation states of retroelements.

Reactivation of retroelements in the human genome has been linked to aging. However, whether the epigenetic state of specific retroelements can predict chronological age remains unknown. We provide evidence that locus-specific retroelement DNA methylation can be used to create retroelement-based epigenetic clocks that accurately measure chronological age in the immune system, across human tissues, and pan-mammalian species. We also developed a highly accurate retroelement epigenetic clock compatible with EPICv.2.0 data that was constructed from CpGs that did not overlap with existing first- and second-generation epigenetic clocks, suggesting a unique signal for epigenetic clocks not previously captured. We found retroelement-based epigenetic clocks were reversed during transient epigenetic reprogramming, accelerated in people living with HIV-1, and responsive to antiretroviral therapy. Our findings highlight the utility of retroelement-based biomarkers of aging and support a renewed emphasis on the role of retroelements in geroscience.

ExpoNano: A Strategy Based on Hyper-Cross-Linked Polymers Achieves Urinary Exposome Assessment for Biomonitoring.

Urinary analysis of exogenous and endogenous molecules constitutes an efficient, noninvasive approach to evaluate human health status. However, the exposome characterization of urinary molecules remains extremely challenging with current techniques. Herein, we develop an ExpoNano strategy based on hyper-cross-linked polymers (HCPs) to achieve ultrahigh-throughput measurement of exo/endogenous molecules in urine. The strategy includes a simple trapping-detrapping procedure (15 min) with HCPs in enzymatically treated urine, followed by mass spectrometer determination. Molecules that can be determined by ExpoNano have a wide range of molecular weight (75-837 Da) and Log Kow (octanol-water partition coefficient; -9.86 to 10.56). The HCPs can be repeatedly used five times without decreasing the trapping efficiency. Application of ExpoNano in a biomonitoring study revealed a total of 63 environmental chemicals detected in >50% of the urine pools collected from Chinese adults living in 13 cities, with a median concentration of 0.026-47 ng/mL, while nontargeted analysis detected an additional 243 exogenous molecules. Targeted and nontargeted analysis also detected 926 endogenous molecules in pooled urine. Collectively, the ExpoNano strategy demonstrates unique advantages over traditional urine analysis approaches, including a wide range of analytes, satisfactory trapping efficiency, high simplicity and reusability, and extremely reduced time demand and financial cost.

Bioactive Materials That Promote the Homing of Endogenous Mesenchymal Stem Cells to Improve Wound Healing.

Endogenous stem cell homing refers to the transport of endogenous mesenchymal stem cells (MSCs) to damaged tissue. The paradigm of using well-designed biomaterials to induce resident stem cells to home in to the injured site while coordinating their behavior and function to promote tissue regeneration is known as endogenous regenerative medicine (ERM). ERM is a promising new avenue in regenerative therapy research, and it involves the mobilizing of endogenous stem cells for homing as the principal means through which to achieve it. Comprehending how mesenchymal stem cells home in and grasp the influencing factors of mesenchymal stem cell homing is essential for the understanding and design of tissue engineering. This review summarizes the process of MSC homing, the factors influencing the homing process, analyses endogenous stem cell homing studies of interest in the field of skin tissue repair, explores the integration of endogenous homing promotion strategies with cellular therapies and details tissue engineering strategies that can be used to modulate endogenous homing of stem cells. In addition to providing more systematic theories and ideas for improved materials for endogenous tissue repair, this review provides new perspectives to explore the complex process of tissue remodeling to enhance the rational design of biomaterial scaffolds and guide tissue regeneration strategies.

LncRNA ZFHX4-AS1 as a novel biomarker in adrenocortical carcinoma.

Background: Adrenocortical carcinoma (ACC) is a rare and highly aggressive malignant tumor. Currently, there is a lack of reliable prognostic markers in clinical practice. Extensive research has shown that long non-coding RNA (lncRNA) are critical factors in the initiation and progression of cancer, closely associated with early diagnosis and prognosis. Previous studies have identified that ZFHX4 antisense RNA 1 (ZFHX4-AS1) is aberrantly expressed in various cancers and is associated with poor outcomes. This study investigates whether ZFHX4-AS1 affects the prognosis of ACC patients and, if so, the potential mechanisms involved. Methods: In this study, utilizing four multi-center cohorts from The Cancer Genome Atlas (TCGA) program and Gene Expression Omnibus (GEO), we validated the prognostic capability of ZFHX4-AS1 in ACC patients through Kaplan-Meier survival analysis, cox regression models, and nomograms. Then, we explored the biological functions of ZFHX4-AS1 using gene set enrichment analysis (GSEA), competing endogenous RNA (ceRNA) networks, and analyses of somatic mutations and copy number variation (CNV). Finally, in vitro experiments were conducted to further validate the impact of ZFHX4-AS1 on proliferation and migration capabilities of ACC cell lines. Results: Survival analysis indicated that patients in the high ZFHX4-AS1 expression group of ACC had worse prognosis. Cox regression analyses suggested that ZFHX4-AS1 levels were independent risk factors for prognosis. Subsequently, we constructed nomograms based on clinical features and ZFHX4-AS1 levels, demonstrating good predictive performance under the time-dependent receiver operating characteristic (ROC) curve. Analysis based on somatic mutations and CNV revealed that CTNNB1 and 9p21.3-Del drove the expression of ZFHX4-AS1. Cell Counting Kit-8 (CCK-8), colony formation, and Transwell assays confirmed that knockdown of ZFHX4-AS1 inhibited proliferation and migration of ACC cells. Conclusions: This study demonstrates that ZFHX4-AS1 has a reliable predictive value for the prognosis of ACC patients and is a promising biomarker.

Advancing Scaffold-Assisted Modality for In Situ Osteochondral Regeneration: A Shift From Biodegradable to Bioadaptable.

Over the decades, the management of osteochondral lesions remains a significant yet unmet medical challenge without curative solutions to date. Owing to the complex nature of osteochondral units with multi-tissues and multicellularity, and inherently divergent cellular turnover capacities, current clinical practices often fall short of robust and satisfactory repair efficacy. Alternative strategies, particularly tissue engineering assisted with biomaterial scaffolds, achieve considerable advances, with the emerging pursuit of a more cost-effective approach of in situ osteochondral regeneration, as evolving toward cell-free modalities. By leveraging endogenous cell sources and innate regenerative potential facilitated with instructive scaffolds, promising results are anticipated and being evidenced. Accordingly, a paradigm shift is occurring in scaffold development, from biodegradable and biocompatible to bioadaptable in spatiotemporal control. Hence, this review summarizes the ongoing progress in deploying bioadaptable criteria for scaffold-based engineering in endogenous osteochondral repair, with emphases on precise control over the scaffolding material, degradation, structure and biomechanics, and surface and biointerfacial characteristics, alongside their distinguished impact on the outcomes. Future outlooks of a highlight on advanced, frontier materials, technologies, and tools tailoring precision medicine and smart healthcare are provided, which potentially paves the path toward the ultimate goal of complete osteochondral regeneration with function restoration.

Functional Validation of Endogenous Redox Partner Cytochrome P450 Reductase Reveals the Key P450s CYP6P9a/-b as Broad Substrate Metabolizers Conferring Cross-Resistance to Different Insecticide Classes in Anopheles funestus.

The versatility of cytochrome P450 reductase (CPR) in transferring electrons to P450s from other closely related species has been extensively exploited, e.g., by using An. gambiae CPR (AgCPR), as a homologous surrogate, to validate the role of An. funestus P450s in insecticide resistance. However, genomic variation between the AgCPR and An. funestus CPR (AfCPR) suggests that the full metabolism spectrum of An. funestus P450s might be missed when using AgCPR. To test this hypothesis, we expressed AgCPR and AfCPR side-by-side with CYP6P9a and CYP6P9b and functionally validated their role in the detoxification of insecticides from five different classes. Major variations were observed within the FAD- and NADP-binding domains of AgCPR and AfCPR, e.g., the coordinates of the second FAD stacking residue AfCPR-Y456 differ from that of AgCPR-His456. While no significant differences were observed in the cytochrome c reductase activities, when co-expressed with their endogenous AfCPR, the P450s significantly metabolized higher amounts of permethrin and deltamethrin, with CYP6P9b-AfCPR membrane metabolizing α-cypermethrin as well. Only the CYP6P9a-AfCPR membrane significantly metabolized DDT (producing dicofol), bendiocarb, clothianidin, and chlorfenapyr (bioactivation into tralopyril). This demonstrates the broad substrate specificity of An. funestus CYP6P9a/-b, capturing their role in conferring cross-resistance towards unrelated insecticide classes, which can complicate resistance management.

Response of Elymus nutans Griseb. seedling physiology and endogenous hormones to drought and salt stress.

Elymus nutans Griseb. (E. nutans), a pioneer plant for the restoration of high quality pasture and vegetation, is widely used to establish artificial grasslands and ecologically restore arid and salinized soils. To investigate the effects of drought stress and salt stress on the physiology and endogenous hormones of E. nutans seedlings, this experiment configured the same environmental water potential (0 (CK), - 0.04, - 0.14, - 0.29, - 0.49, - 0.73, and - 1.02 MPa) of PEG-6000 and NaCl stress to investigate the effects of drought stress and salt stress, respectively, on E. nutans seedlings under the same environmental water potential. The results showed that although the physiological indices and endogenous hormones of the E. nutans seedlings responded differently to drought stress and salt stress under the same environmental water potential, the physiological indices of E. nutans shoots and roots were comprehensively evaluated using the genus function method, and the physiological indices of the E. nutans seedlings under the same environmental water potential exhibited better salt tolerance than drought tolerance. The changes in endogenous hormones of the E. nutans seedlings under drought stress were analyzed to find that treatment with gibberellic acid (GA3), gibberellin A7 (GA7), 6-benzyladenine (6-BA), 6-(y,y-dimethylallylaminopurine) (2.IP), trans-zeatin (TZ), kinetin (KT), dihydrozeatin (DHZ), indole acetic acid (IAA), and 2,6-dichloroisonicotininc acid (INA) was more effective than those under drought stress. By analyzing the amplitude of changes in the endogenous hormones in E. nutans seedlings, the amplitude of changes in the contents of GA3, GA7, 6-BA, 2.IP, TZ, KT, DHZ, IAA, isopentenyl adenosine (IPA), indole-3-butyric acid (IBA), naphthalene acetic acid (NAA), and abscisic acid was larger in drought stress compared with salt stress, which could be because the endogenous hormones are important for the drought tolerance of E. nutans itself. The amplitude of the changes in the contents of DHZ, TZR, salicylic acid, and jasmonic acid was larger in salt stress compared with drought stress. Changes in the content of melatonin were larger in salt stress compared with drought stress, which could indicate that endogenous hormones and substances are important for the salt tolerance of E. nutans itself.

Metformin enhances endogenous neural stem cells proliferation, neuronal differentiation, and inhibits ferroptosis through activating AMPK pathway after spinal cord injury.

BACKGROUND: Inadequate nerve regeneration and an inhibitory local microenvironment are major obstacles to the repair of spinal cord injury (SCI). The activation and differentiation fate regulation of endogenous neural stem cells (NSCs) represent one of the most promising repair approaches. Metformin has been extensively studied for its antioxidative, anti-inflammatory, anti-aging, and autophagy-regulating properties in central nervous system diseases. However, the effects of metformin on endogenous NSCs remains to be elucidated. METHODS: The proliferation and differentiation abilities of NSCs were evaluated using CCK-8 assay, EdU/Ki67 staining and immunofluorescence staining. Changes in the expression of key proteins related to ferroptosis in NSCs were detected using Western Blot and immunofluorescence staining. The levels of reactive oxygen species, glutathione and tissue iron were measured using corresponding assay kits. Changes in mitochondrial morphology and membrane potential were observed using transmission electron microscopy and JC-1 fluorescence probe. Locomotor function recovery after SCI in rats was assessed through BBB score, LSS score, CatWalk gait analysis, and electrophysiological testing. The expression of the AMPK pathway was examined using Western Blot. RESULTS: Metformin promoted the proliferation and neuronal differentiation of NSCs both in vitro and in vivo. Furthermore, a ferroptosis model of NSCs using erastin treatment was established in vitro, and metformin treatment could reverse the changes in the expression of key ferroptosis-related proteins, increase glutathione synthesis, reduce reactive oxygen species production and improve mitochondrial membrane potential and morphology. Moreover, metformin administration improved locomotor function recovery and histological outcomes following SCI in rats. Notably, all the above beneficial effects of metformin were completely abolished upon addition of compound C, a specific inhibitor of AMP-activated protein kinase (AMPK). CONCLUSION: Metformin, driven by canonical AMPK-dependent regulation, promotes proliferation and neuronal differentiation of endogenous NSCs while inhibiting ferroptosis, thereby facilitating recovery of locomotor function following SCI. Our study further elucidates the protective mechanism of metformin in SCI, providing new mechanistic insights for its candidacy as a therapeutic agent for SCI.

Assessment of aortic perivascular and renal sinus fat in endogenous cortisol excess of different etiology.

OBJECTIVE: Endogenous cortisol excess is known to affect body fat distribution. Ectopic fat is the accumulation of triglycerides in non-adipose tissue regions that normally contain little fat. The aim of study was to investigate the amount of ectopic fat in aortic perivascular and renal sinus fat of patients with endogenous cortisol excess and its relationship with their comorbitidies and laboratory findings. DESIGN: A total of 119 patients, including 16 patients with pituitary Cushing's disease (CD), 21 patients with adrenal Cushing's syndrome (CS), 34 patients with mild autonomous cortisol secretion (MACS), and 48 patients with nonfunctioning adrenal adenomas were enrolled in this retrospective study. Aortic perivascular fat and renal sinus fat were evaluated with magnetic resonance imaging. RESULTS: It was determined that the amount of aortic perivascular fat was increased in patients with CD (P = 0.01). The linear regression analysis showed that the amount of perivascular fat was associated with triglyceride levels and cortisol levels after the 1 mg dexamethasone suppression test as well as with gender (P < 0.01). Renal sinus fat measurements were similar in the groups (P > 0.05). After adjusting for age, sex, and BMI, perivascular fat was found to be higher in pituitary the CD than in the MACS and the nonfunctioning adenoma groups, and renal sinus fat was seen to be higher in pituitary the CD than in the MACS groups (P < 0.05). Patients with diabetes mellitus had an increased amount of renal sinus fat (P = 0.008). CONCLUSION: The amount of perivascular and renal sinus fat may increase in patients with CD. Further studies are needed to elucidate ectopic fat distribution in patients with endogenous cortisol excess.

[Prolonged and chronic endogenous manic and manic-delusional states (psychopathology, typology, dynamics, clinic)]. / Zatyazhnye i khronicheskie endogennye maniakal'nye i maniakal'no-bredovye sostoyaniya (psikhopatologiya, tipologiya, dinamika, klinika).

OBJECTIVE: A clinical and psychopathological analysis, nosological differentiation of prolonged and chronic manic and manic-delusional states (PMDS) within the framework of the paroxysmal course of endogenous psychoses, determination of the patterns of their development, diagnostic criteria and prognosis. MATERIAL AND METHODS: The study included 76 female patients (average age 37.2±8.3 years) who were hospitalized for endogenous mental illnesses with a paroxysmal course that occurred with the clinical picture of PMDS. The patients were divided into two groups: clinical (n=43) and follow-up (n=33). Clinical-psychopathological, clinical-follow-up, psychometric, statistical methods were used. RESULTS: A clinical and dynamic typology of PMDS has been developed, according to which 2 groups have been identified: «monomorphic¼ PMDS and «polymorphic¼ PMDS. «Monomorphic¼ PMDS included 2 subtypes - «acute¼ and «chronified¼ and were characterized by the same clinical picture that remained unchanged throughout, while «polymorphic¼, which also included 2 subtypes - «developing¼ and «double mania subtype¼, were characterized by the variability of clinical picture. «Acute¼ and «developing¼ subtypes of PMDS predominantly developed in schizoaffective psychosis and bipolar disorder; the «chronified¼ subtype and the «double mania¼ subtype were more often observed within the framework of the schizoaffective variant of paroxysmal-progressive schizophrenia. CONCLUSION: The clinical and dynamic structure of PMDS is heterogeneous and differs in psychopathological structure, as well as in the level of stability of symptoms and characteristics of its course. The developed clinical typology of PMDS is prognostically significant and provides information about the further dynamics of the disease.

MicroRNA­325: A comprehensive exploration of its multifaceted roles in cancer pathogenesis and therapeutic implications (Review).

MicroRNA (miRNA/miR) represents a category of endogenous, short-chain non-coding RNA molecules comprising ~22 nucleotides. Specifically, miR-325 is situated within the first sub-band of region 2 on the short arm of the X chromosome. Notably, aberrant expression of miR-325 has been observed across various tumor systems, spanning the nervous, endocrine, respiratory, reproductive and digestive systems. miR-325 exhibits the capacity to target a minimum of 20 protein-coding genes, thereby influencing diverse cellular processes, including cell proliferation, epithelial-mesenchymal transition, apoptosis, invasion and migration. Moreover, miR-325 serves a pivotal role in the formation of six competing endogenous RNA (ceRNA) regulatory axes, involving one circular RNA, four long non-coding RNA and one additional miRNA. By participating in various signaling pathways through gene targeting, the abnormal expression of miR-325 has been associated with clinicopathological conditions in diverse patients with cancer, significantly impacting both the clinicopathology and prognosis of affected individuals. Additionally, miR-325 has been associated with the development of resistance to oxaliplatin, cisplatin and doxorubicin in cancer cells. Its involvement in the anticancer molecular mechanisms of these agents underscores its potential significance in therapeutic contexts. However, it is noteworthy that the current study did not specifically address sex-based cell line selection. In conclusion, the present review provides a comprehensive summary of the relevant findings concerning miR-325, offering valuable insights for future research endeavors focused on determining the molecular mechanisms associated with this miRNA.

Paraneoplastic Syndrome in Adrenocortical Carcinoma: The Unexpected Mime.

Adrenocortical carcinoma (ACC) is a malignancy of the adrenal cortex with a high morbidity and mortality. More than half of the cases are functional tumors. As different hormones can be co-secreted above physiologic levels, it causes a very broad variety of symptoms and makes differentiating from more common entities hard. Here we present a case of a patient with a newly diagnosed ACC who initially presented with acute pulmonary embolism and recurrent deep vein thromboses (DVT) in the setting of hypercortisolism. Imaging showed a left adrenal mass invading adjacent structures including a nonocclusive thrombus in the left renal vein. Intravenous anticoagulation and thrombectomy were initially performed, followed by removal of the tumor and adjacent metastatic disease. Pathology confirmed ACC. The patient underwent left adrenalectomy, left nephrectomy, splenectomy, distal pancreatectomy, and caval thrombectomy with inferior vena cava (IVC) filter placement. Intravenous anticoagulation and glucocorticoid replacement were also administered as part of the treatment plan. Unfortunately, the patient had multiple episodes of bleeding and thrombosis and was eventually discharged to hospice care. DVT in the setting of ACC can be caused by increased hypercoagulability from hypercortisolism, direct venous thrombosis, or vascular invasion. Thrombosis, especially in the inferior vena cava, has been associated with poor prognosis and survival rates. Clinicians should be aware of this rare complication given its immediate therapeutic repercussions and prognostic value.