HMG

Abstract

Nuclear factor erythroid-derived 2 like 1 (NFE2L1) is reported to be embedded in the endoplasmic reticulum (ER) membrane and subsequently undergo N-glycosylation at several asparagine residues as well as other ER-resident factors including cAMP response element binding protein 3 (CREB3)/ATF6 family members. In this study, we investigated the regulation of NFE2L1 protein expression by treating wild-type HEK293 cells and HEK293 cells deficient in selected ER-associated degradation (ERAD) factors with various reagents. NFE2L1 protein expression in wild-type HEK293 cells was negligible, but MG132/bortezomib treatment induced Endo H-resistant two bands. Suppressor/enhancer of lin-12-like (SEL1L)/hydroxymethylglutaryl-CoA (HMG-CoA) reductase degradation 1 (Hrd1) loss increased NFE2L1 protein expression without any stimuli. In these deficient cells, the band shift of NFE2L1 by MG132 was mostly suppressed. Treatment with the valosin containing protein (VCP) inhibitor CB-5083 increased NFE2L1 expression, but deficiencies in other ERAD-associated factors (ER degradation-enhancing α-mannosidase-like protein 2 (EDEM2), thioredoxin domain-containing protein 11 (TXNDC11), gp78, ring finger protein 5 (RNF5), ring finger protein 185 (RNF185), and USP19) did not affect its expression. Comparing the stability of the two intrinsic NFE2L1, which increases with proteasome inhibition, the higher molecular weight form corresponding to full-length form, was more unstable. Therefore, we constructed NFE2L1 genes with mutations in the site where NFE2L1 is cleaved by DDI2 and in the four asparagine residues where N-glycosylation occurs, and found that the high molecular weight form, especially a hypoglycosylated mutant, tended to be more unstable. Taken together, this study using several ERAD disordered models shows that the regulation of NFE2L1 is different in some ways from the regulation of CREB3/ATF6 family, and these findings implicate the diversity of N-glycosylated protein regulation in the ER.

Abstract

Chronic inflammation constitutes a well-established driver of colorectal carcinogenesis, yet the molecular circuitry linking inflammatory receptor signalling to tumour cell survival remains incompletely delineated. Here we demonstrate that the HMG-CoA reductase inhibitors atorvastatin and rosuvastatin modulate inflammatory survival pathways in colorectal cancer cells in a manner consistent with targeted interference with the protease-activated receptor 2 (PAR-2)-extracellular signal-regulated kinase (ERK)-tumour necrosis factor-α (TNF-α) signalling axis. Using lipopolysaccharide-stimulated HT-29 and Caco-2 cells as complementary models of inflammatory colorectal malignancy, we show that both statins selectively attenuate PAR-2 expression at the protein and transcript levels while leaving structurally related PAR-1 unaffected. This pattern of receptor modulation is accompanied by suppression of total ERK1/2 expression, ERK1/2 phosphorylation, and the transcriptional target DUSP6, together with attenuation of TNF-α secretion. Importantly, these signaling shifts are associated with dual apoptotic programs; the extrinsic pathway, reflected by transcriptional upregulation and proteolytic activation of caspase-8; and the intrinsic mitochondrial pathway, evidenced by reciprocal modulation of Bcl-2 family proteins favoring Bax over Bcl-2. Both pathways converge upon activation of executioner caspase-3 and an increase in Annexin V-defined apoptotic fractions, indicating re-engagement of programmed cell death under inflammatory stress. Notably, rosuvastatin consistently demonstrates superior potency across signaling endpoints, achieving comparable biological effects at lower concentrations than atorvastatin. Collectively, these data indicate that clinically deployed statins target the PAR-2-ERK axis and are associated with re-activation of apoptotic pathways in inflammatory colorectal cancer models, while leaving open the possibility that additional statin-responsive networks contribute to their pro-apoptotic effects. This mechanistic framework provides biological plausibility for epidemiologic observations linking statin use with reduced colorectal cancer risk and improved outcomes, and supports further translational evaluation of PAR-2-directed statin strategies in colorectal malignancy.

Abstract

Ixr1 is a yeast transcriptional regulator previously identified as a player in the response to stress conditions, such as oxidative stress, hypoxia, iron limitation or DNA damage. Little is known about the structure of the Ixr1 protein apart from their HMG-boxes, which conform two well-known folded DNA binding domains. Intrinsically disordered regions (IDRs) are predicted in Ixr1 by algorithms and analytical methods. Ixr1 protein is non-globular and prone to aggregation, sustaining a concentration-dependent equilibrium between monomeric and dimeric forms. Treatment with 150 µM glutaraldehyde, to stabilize and fix weak protein-protein interactions, induces Ixr1 to form large oligomers. Indeed, Ixr1 forms amyloids as demonstrated both by in vitro and in vivo approaches. Chimeras constructed between Ixr1 and the C-terminal domain of Sup35, which provides the translation termination function to the yeast prion [PSI+], show that IDRs from Ixr1 substitute the N-terminal region of Sup35 that is responsible of its priogenic nature. Finally, Artificial Intelligence (AI) assisted modeling of Ixr1 with Ssn8 (Srb11), which was already identified as a protein interacting with Ixr1 and related to yeast stress response, reveals that their interaction might diminish the disordered/priogenic nature of Ixr1 and increase the Ixr1 folding in the heterodimer.

Abstract

Poor ovarian response (POR) remains a major limitation in assisted reproductive medicine. Direct comparisons between r-hFSH alfa + r-LH and r-hFSH delta + hMG in this population are scarce.

Abstract

Camel (Camelus dromedarius) milk has been traditionally valued for its therapeutic properties, for intense managing autoimmune and metabolic disorders. Due to its unique composition, camel milk is more digestible than bovine milk and contains bioactive components with potential anti-diabetic effects. This study investigates the insulinotropic and anti-diabetic potential of enzymatically hydrolyzed camel milk proteins, focusing on their effects on insulin secretion, β-cell proliferation, and metabolic regulation in streptozotocin-induced diabetic rats.

Abstract

Intestinal stem cells (ISCs) promote tissue repair after genotoxic or immune-mediated injury. However, ISCs are particularly sensitive to various stressors and primary targets of overwhelming immune responses, such as interferon γ (IFNγ)-mediated killing. In mouse models of radiation therapy-induced gut damage and in biopsies from patients who underwent allogeneic hematopoietic stem cell transplantation, we observed IFNγ expression by intestinal Treg cells. Treg cells leverage combined IFNγ and interleukin 10 (IL-10) stimulation of ISCs to nurture the growth of intestinal organoids through the activation of the mTORC1 and Myc pathways. Similarly, Treg cells or the combined addition of recombinant IFNγ and IL-10 promoted the regeneration of organoids after irradiation, and both cytokines were essential for ensuring epithelial regeneration following acute intestinal tissue injury in vivo. The exposure of organoids to growth factor-free culture conditions revealed distinct EGF-like properties of IFNγ and Wnt-like properties of IL-10. While IFNγ rapidly induced epithelial proliferation, it depleted the pool of ISCs in vitro. Only the combination of IFNγ and IL-10 led to epithelial proliferation and organoid growth while simultaneously ensuring ISC maintenance over time. Our results reveal a context-dependent role of inflammatory signaling in ISCs, through which Treg cells promote epithelial repair following therapy-induced injury.

Abstract

Ulotaront is an investigational trace amine-associated receptor 1 (TAAR1) agonist demonstrated to slow gastric emptying in schizophrenia patients with metabolic syndrome (MetSyn) and prediabetes type 2. Here we evaluate the effects of ulotaront on glucose-insulin dynamics in schizophrenia patients with MetSyn and prediabetes.

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, mitochondrial dysfunction, and amyloid β-protein (Aβ) accumulation, with limited safe and effective treatments available. Kai-Xin-San (KXS), a traditional Chinese medicine formula (Panax ginseng, Poria cocos, Polygala tenuifolia, Acorus calamus), has shown potential in alleviating AD symptoms, but its mechanisms, especially mitochondrial regulation-related ones, remain unclear. Using Aβ-overexpressing Caenorhabditis elegans (Aβ-C. elegans) as an AD model, this study evaluated KXS's pharmacodynamic effects via serotonin sensitivity and chemotaxis assays, identified its absorbed components via UPLC-Q/TOF-MS, predicted anti-AD mechanisms via bioinformatics (GO/KEGG) and metabolomics, and assessed mitochondrial function via ROS, ATP, SOD, MDA, JC-1 assays, as well as RT-qPCR/Western blotting of mitochondrial pathways. Results showed that 10 mg/mL KXS significantly reduced Aβ-C. elegans paralysis by 27.1 % (P < 0.01) and improved associative learning (P < 0.01); 20 KXS components were characterized in vivo, and KXS reduced ROS/MDA, elevated ATP/SOD (P < 0.01), restored mitochondrial membrane potential, regulated mitochondrial biogenesis/autophagy (hmg-5, bec-1, lgg-1) and fission genes (drp-1, fis-1), and activated the AMPK/SIRT1 pathway (aak-1, sir-2.1, SIRT1/p-AMPK), thereby improving cognitive impairment in Aβ-C. elegans. This finding clarifies its neuroprotective mechanism and provides evidence for its potential as a therapeutic candidate for AD.

Abstract

Intrauterine insemination (IUI) is a popular method for the treatment of infertility, however, its success rate ranges from 7 to 13% in a cycle.

Abstract

The intestinal epithelium forms a selective barrier between the intestinal lumen and the subepithelial layer. Intestinal epithelium plays a critical role in initiating inflammatory tissue responses in vivo, which remains challenging to emulate in vitro. Caco-2 cells are commonly used models of the intestinal epithelium, but lack crucial receptors and pathways associated with pro-inflammatory reactions. Human-induced pluripotent stem cell (iPSC)-based in vitro models are assumed to provide a system that better emulates in vivo responses. This study evaluated the inflammatory response of iPSC-derived intestinal epithelial cells (IEC) and Caco-2-derived intestinal epithelial cells to the microbial toxins lipopolysaccharide (LPS) and nigericin. Here, iPSCs were differentiated towards enterocyte, goblet- and Paneth-like cells without using three-dimensional culture techniques. The formed monolayer barriers were exposed to a combination of 0-100 µM nigericin and 100 ng/mL LPS on either the apical or basolateral side. The treatment-induced expression of cytokine genes and cytokine secretion were compared between the iPSC-derived cell model and differentiated Caco-2 cell layers. Nigericin exposure in combination with LPS significantly reduced transepithelial electrical resistance in the iPSC-derived model, and resulted in a tenfold increased secretion of the pro-inflammatory cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha compared to the negative control. A similar increase was observed for the mRNA expression of these cytokines. No significant effect on TEER, cytokine secretion, or mRNA expression was observed in the Caco-2 model. Overall, this study shows that iPSC-IECs are a more sensitive model compared to Caco-2 to emulate inflammatory perturbations of the human intestinal epithelium.

Abstract

C3G (RapGEF1) regulates the biology of liver hepatic progenitor cells and hepatocarcinoma cells, but its role in hepatocytes remained unknown. Therefore, we generated a mouse model lacking C3G in hepatocytes (C3GKOAlb), which showed liver damage as evidenced by increased fibrosis, liver macrophages and serum transaminases activity. Furthermore, impaired liver maturation was observed in C3GKOAlb mice demonstrated by the low expression of hepatocyte specific proteins (i.e. HNF4α), but higher levels of Alpha-fetoprotein, and stemness markers (i.e. CD133). Glucose homeostasis was also altered in C3GKOAlb mice, as well as insulin and glucagon effects on hepatocytes, which resulted in reduced serum glucose levels and an enhanced response to glucagon. In addition, the expression of several glycolytic and gluconeogenic enzymes, as well as the levels of the active form of Glycogen phosphorylase (PYGL), were upregulated in livers from C3GKOAlb mice, being remarkable the increased Pyruvate kinase isoform 2 (PKM2) levels accompanied by higher serum lactate concentrations. An increased expression of the ketogenic enzyme 3-hydroxy 3-methylglutaryl-CoA (HMG) synthase (Hmgcs2) was also found in these livers in parallel to elevated blood levels of beta-hydroxy-butyrate. Moreover, the fasting response was enhanced in C3GKOAlb mice as compared to wt animals. Hence, livers lacking C3G in hepatocytes showed a higher expression of gluconeogenic, lipogenic and ketogenic enzymes than livers from wt mice and enhanced ketogenesis. Mechanistically, data support a PTBP1-mediated upregulation of PKM2 expression in hepatocytes lacking C3G, which leads to enhanced glycolysis. Other metabolic alterations are likely due to the defective insulin signaling and the enhanced glucagon signaling through a cAMP-PKA-dependent mechanism. In summary, we have identified a novel role for C3G in the liver as a key mediator of hepatocyte differentiation and metabolic functions of hepatocytes. Hence, its absence leads to an immature phenotype and an altered response to insulin and glucagon, favoring glucagon actions.

Abstract

Statins, primarily prescribed for their lipid-lowering effects, have garnered significant attention for their potent anti-inflammatory effects. This review explores the underlying molecular pathways and clinical relevance of statins' anti-inflammatory actions, extending beyond cardiovascular disease management to chronic inflammatory conditions and oncological applications. The lipid-lowering effect of statins stems from their ability to suppress HMG-CoA reductase, a crucial enzyme in cholesterol synthesis; however, their pleiotropic effects include modulation of critical inflammatory pathways such as the inhibition of NF-κB signalling, a reduction in pro-inflammatory cytokine production, and enhancement of endothelial function. We delve into the molecular pathways influenced by statins, including their effects on inflammatory mediators like C-reactive protein (CRP), interleukins (IL-6, IL-1β), and tumour necrosis factor-alpha (TNF-α). Clinical evidence supporting the efficacy of statins in managing chronic inflammatory diseases, such as rheumatoid arthritis, chronic obstructive pulmonary disease, diabetes, and osteoarthritis, is critically reviewed. Additionally, we investigate the emerging role of statins in oncology, examining their impact on inflammation-driven carcinogenesis, tumour microenvironment modulation, and cancer progression. Despite their broad therapeutic potential, the safety profile of statins, particularly concerning adverse effects such as myopathy, hepatotoxicity, and potential diabetes risk, is discussed. Controversies surrounding the extent of their anti-inflammatory benefits and the variability in patient responses are also addressed. This review consolidates the current literature, elucidating the biochemical mechanisms underlying the anti-inflammatory properties of statins and evaluating their clinical applications and associated controversies. Future research directions are identified, including the development of novel statin analogues with enhanced anti-inflammatory effects and the investigation of new therapeutic indications in inflammatory diseases and cancer. By providing an in-depth analysis, this review underscores the expanding therapeutic scope of statins and advocates for their integration into broader clinical strategies for the management of inflammation and cancer.

Abstract

Current antithrombotic therapies face dual constraints of bleeding complications and monitoring requirements. Although natural hirudin provides targeted thrombin inhibition, its clinical adoption is hindered by sourcing limitations. This study developed a recombinant hirudin variant HMg (rHMg) with enhanced anticoagulant activity through genetic engineering and established cost-effective large-scale production methods. The synthesised HMg gene was expressed in E. coli BL21 via a pET vector plasmid, followed by nickel-affinity purification. Systematic evaluations demonstrated rHMg's antithrombin activity of 9573 ATU/mg, dose-dependent prolongation of APTT/PT/TT. It has superior thrombin inhibition with the IC50 and Ki values were 2.8 and 0.323 nM respectively compared to FDA approved drug bivalirudin (p < 0.001). The high-yield prokaryotic expression of rHMg with enhanced anticoagulant efficacy provides a novel strategy for developing affordable antithrombotic drugs, showing significant potential for cardiovascular disease management.

Abstract

This study evaluated adherence to the 24-Hour Movement Guidelines (24-HMG) among youth aged 2-17 and its association with cardiometabolic risk factors (CMRFs). Searches were conducted using four databases. 38 observational studies met the inclusion criteria. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed- or random-effects models. Only 8.39% of participants adhered to all components of the 24-HMG, with adherence decreasing with age. Meta-analysis results indicated that adherence to 24-HMG was significantly associated with favourable CMRFs, including: Overweight/obesity (OR = 0.59, 95%CI = 0.47-0.74), waist circumference (OR = 0.29, 95%CI = 0.09-0.92)], triglycerides (OR = 0.86, 95%CI = 0.79-0.94), high density lipoprotein cholesterol (OR = 1.04, 95%CI = 1.02-1.05)],systolic blood pressure (OR = 0.99, 95%CI = 0.98-0.99)], glucose (OR = 0.97, 95%CI = 0.96-0.97), and insulin (OR = 0.55, 95%CI = 0.31-0.96)]. No association was found with diastolic blood pressure (OR = 0.99, 95%CI = 0.99-1.00). No significant association was observed between adherence to any single guideline (physical activity, sedentary behaviour and sleep) component and overall CMRFs. Subgroup analysis showed that European populations had higher adherence to all three guidelines (P < 0.01) and significantly lower waist circumference compared to North American populations (P = 0.03). Adherence to the full 24-HMG is low among youth but offers notable protection against cardiometabolic risks. Following individual components alone does not yield the same health benefits.

Abstract

We aimed to describe 1-year outcomes of eyes switched to faricimab from first-generation vascular endothelial growth factor (VEGF) inhibitors for neovascular age-related macular degeneration (nAMD) in routine care.

Abstract

HMG-CoA reductase inhibitors, statins, are extensively used to treat hyperlipidemia, coronary artery disease, and other atherosclerotic disorders. However, one of the common side effects of statin therapy is a mild elevation in liver aminotransferases, observed in less than 3% of patients. Atorvastatin and simvastatin, in particular, are most frequently associated with statin-induced liver injury, leading to treatment discontinuation. Recent research has highlighted the antioxidant and anti-inflammatory properties of glucagon-like peptide-1 receptor (GLP-1R) activation in protecting against liver injury. Nonetheless, the potential protective effects of liraglutide (LIRA), a GLP-1R agonist, against atorvastatin (ATO)-induced liver dysfunction have not been fully elucidated. In this context, the present study aimed to investigate the protective role of LIRA in mitigating ATO-induced liver injury in rats, offering new insights into managing statin-associated hepatotoxicity. Indeed, LIRA treatment improved liver function enzymes and attenuated histopathological alterations. LIRA treatment enhanced antioxidant defenses by increasing Nrf2 content and superoxide dismutase (SOD) activity, while reducing NADPH oxidase. Additionally, LIRA suppressed inflammation by downregulating the HMGB1/TLR-4/RAGE axis and inhibiting the protein expression of pY323-MAPK p38 and pS635-NFκB p65 content resulting in decreased proinflammatory cytokines (TNF-α and IL-1β). Furthermore, LIRA upregulated GLP-1R gene expression and promoted autophagic influx via the activation of the pS473-Akt/pS486-AMPK/pS758-ULK1/Beclin-1 signaling cascade, along with inhibiting apoptosis by reducing caspase-3 content. In conclusion, LIRA attenuated ATO-induced oxidative stress and inflammation via activation of the Nrf-2/SOD cascade and inhibition of the HMGB1/TLR-4/RAGE /MAPK p38/NFκB p65 axis. In parallel, LIRA stimulated autophagy via the AMPK/ULK1/Beclin-1 axis and suppressed apoptosis, thus restoring the balance between autophagy and apoptosis.

Abstract

Targeting glucose metabolism has emerged as a promising strategy for inhibiting tumor growth. However, we herein uncover an unexpected paradox: while glucose deprivation through a low-carbohydrate diet or impaired in situ metabolism suppresses primary tumor growth, it simultaneously promotes lung metastasis by depleting natural killer (NK) cells via lung macrophages. Mechanistically, glucose deprivation induces endoplasmic reticulum (ER) stress, activating HMG-CoA reductase degradation protein 1 (HRD1) to catalyze K63-linked ubiquitination of TRAIL, which is then packaged into exosomes via the endosomal sorting complex required for transport (ESCRT) complex. These exosomal TRAIL molecules polarize PVR+ macrophages, triggering NK cell exhaustion and establishing a pre-metastatic niche. Notably, TIGIT blockade not only prevents metastasis induced by glucose deprivation but also enhances its anti-tumor effects. Clinically, low glucose metabolism correlates with higher 2-year postoperative recurrence across 15 cancer types. Furthermore, plasma exosomal TRAIL outperforms traditional markers, such as α-fetoprotein (AFP) and tumor size, in predicting early postoperative lung metastasis, revealing both the risks and therapeutic potential of targeting glucose metabolism.

Abstract

Simvastatin, a 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor, was used in cardiovascular diseases and could decrease low-density lipoprotein cholesterol, and may have a repurposed role in cancer therapy. However, the effects of simvastatin on endometrial cancer remain controversial. We aimed to elucidate the role and mechanisms of simvastatin in regulating previously identified endometrial cancer-associated mesenchymal stem cells (EmCaMSCs)-mediated immunosuppressive effects and anti-tumor progression. Coculture of EmCaMSCs and peripheral blood mononuclear cells (PBMC) was used to assay the population of CD8 + T cells, natural killer (NK) cells, and cytotoxicity of NK cells. The mechanisms were elucidated by applying recombinant proteins and inhibitors of candidate proteins, transforming growth factor-beta 2 (TGF-β2). Finally, the humanized mouse model was generated to study the effects of simvastatin-mediated immunotherapy in treating endometrial cancer. The protein expressions of TGF-β2, CD56, CD8, and PD-L1 in xenograft tumors were analyzed by Western blot or immunohistochemistry assay. In this study, simvastatin inhibited the proliferation of endometrial cancer cells (HEC-1 A and RL95-2) and EmCaMSCs, and the half-maximal inhibitory concentration (IC50) values of EmCaMSCs were much higher. Simvastatin rescued the proliferation and the population of CD8 + T cells and natural killer (NK) cells from PBMC coculturing with EmCaMSC. Simvastatin treatment reduced the expression of TGF-β2 in EmCaMSCs at both the gene and protein levels. TGF-β2 activated the downstream SMAD2/3 signaling, and their inhibition by simvastatin could enhance the cytotoxicity of NK cells against endometrial cancer cells in vitro. Additionally, a combination of simvastatin and NK cell therapy inhibited xenograft growth, potentially by reducing TGF-β2 expression. In conclusion, simvastatin could rescue the population of CD8 + T cells and NK cells from PBMC cocultured with EmCaMSCs. Furthermore, simvastatin could enhance the cytotoxicity of NK cells in vitro and inhibit tumor growth in vivo in a humanized mouse model. These results suggested that simvastatin may be considered as a repurposed and combination drug for treating endometrial cancer.

Abstract

Controlled ovarian stimulation (COS) is an essential step in most assisted conception cycles. Different treatment combinations (termed protocols) exist in COS, yet there is no consensus on their relative effectiveness and safety.

Abstract

This study compared the efficacy and safety of two highly purified (HP) human menopausal gonadotropin (hMG) preparations, Gynogen HP and Menopur, in women undergoing controlled ovarian stimulation (COS) for in vitro fertilization (IVF). A multicenter, randomized, active-controlled noninferiority comparative study was conducted between 2019 and 2021. Women aged 21-40 undergoing COS for their first or second IVF cycle, with or without intracytoplasmic sperm injection, were randomized to receive either Gynogen HP or Menopur. The primary endpoint was to determine the total number of oocytes retrieved. Key secondary endpoints included total hMG dose, days of hMG stimulation, fertilization rate, implantation rate, clinical pregnancy rate and safety. A total of 150 patients were randomized into two groups: 77 received Gynogen HP and 73 received Menopur COS. The primary endpoint, the number of oocytes retrieved (mean ± standard deviation (SD)), was similar between the Gynogen HP (6.3 ± 3.39) and Menopur (6.7 ± 4.52) groups. The least square (LS) mean values were 5.9 for the Gynogen HP and 6.3 for Menopur, with an LS mean difference of - 0.4 (95% CI: -1.83, 1.07; P = 0.6067), indicating that noninferiority as the lower limit of the 95% CI was above the non-inferiority threshold of -2.0. Secondary efficacy endpoints and safety analysis showed no significant differences between groups. Gynogen HP is noninferior and therapeutically equivalent to Menopur in terms of the number of oocytes retrieval, with a comparable safety profile. These results support the use of Gynogen HP for COS in women undergoing IVF as a part of assisted reproduction techniques.

Abstract

Pancreatitis is an inflammatory disease of the exocrine pancreas and a known risk factor for pancreatic ductal adenocarcinoma (PDAC). Previously, we identified HMG-box transcription factor 1 (HBP1) as a potential master transcription factor (TF) in the early progression of PDAC, with its expression associated with poor patient survival, underscoring its significance in pancreatic disease. However, the functional role of HBP1 in the onset and progression of acute pancreatitis (AP) remains unknown.

Abstract

During or after chemotherapy, cognitive impairments characterized by forgetfulness, difficulty concentrating, and depressive and anxiety-like symptoms are observed. There is limited research examining the effects of rosuvastatin (RVS), an HMG-CoA reductase inhibitor, in the context of neuroinflammation-related cognitive disruption. Here, we aimed to investigate the neuroprotective potential of RVS against doxorubicin (DOX)-induced cognitive impairments. Experimental groups were planned as control (normal saline, intraperitoneal), DOX (total cumulative dose 10 mg/kg, intraperitoneal), RVS (10 mg/kg, oral, 20 days), and RVS + DOX. Efficacy was monitored by applying a battery of behavioral assessments, as well as biochemical, genetic, histopathological, and immunohistochemical examinations. Results from Morris water maze (MWM), passive avoidance, locomotion activity, and elevated plus maze (EPM) tests showed that DOX administration caused behavioral disorders. Moreover, DOX increased the levels of inducible nitric oxide synthase (iNOS), malondialdehyde (MDA), and tumor necrosis factor-α (TNF-α), while decreasing the levels of interleukin-10 (IL-10), glutathione (GSH), superoxide dismutase, catalase (SOD), endothelial nitric oxide (eNOS), and catalase (CAT). Co-treatment with RSV significantly attenuated DOX-induced behavioral changes and oxidative stress markers. In addition, similar to the immunohistochemical results, we determined that it increased the expression levels of extracellular signal-related kinases 1/2 (ERK1/2), cyclic adenosine monophosphate response element binding protein (CREB), and brain-derived neurotrophic factor (BDNF) and restored the histopathological structure of the brain. Therefore, these results indicated that RSV has a neuroprotective effect against DOX-induced cognitive impairment by reducing neurobehavioral impairments, exerting antioxidant and anti-inflammatory effects, and modulating brain growth factors.

Abstract

Biological molecules such as integral membrane proteins, peptides, and nucleic acids that are not soluble or sufficiently stable in aqueous solutions can be stabilized through encapsulation in lipid nanoparticles. Discovering the potential of lipid liquid-crystalline nanoparticles opens up exciting possibilities for housing sensitive membrane proteins. Lipid mesophases provide an environment that protects the cargo, usually a drug, from rapid clearance or degradation. This study employed the mentioned platform to stabilize a different cargo-an essential transmembrane enzyme, HMG-CoA reductase (HMGR). The nanostructured lipid liquid-crystalline (LLC) nanoparticles known as hexosomes are selected as a convenient nanocontainer for the redox-active protein for real-time monitoring of its functions in the bulk of the solution and point to the applicability of the proposed platform in the evaluation of therapeutic functions of the protein by standard physicochemical methods. Instead of using detergents, which usually affect the functions and stability of sensitive membrane proteins, we provide a suitable environment, protecting them in the bulk of the solution against other present species, e.g., toxic compounds or degrading proteins. The objective was to optimize the composition and structure of the lipid nanoparticles to meet the needs of such sensitive and flexible membrane proteins as HMGR and compare the functioning of the encapsulated enzyme with that of the same protein free in the aqueous solution. The catalytic reaction of HMGR involves the 4-electron reduction of HMG-CoA to mevalonate and CoA while simultaneously oxidizing NADPH to NADP+. Subsequently, mevalonate is transformed into cholesterol. The hexosomes we selected as lipid nano-containers were composed of monoolein, 1-oleoyl-rac-glycerol (GMO), Pluronic® F127, and poly(ethylene glycol) (PEG). These specific structural characteristics of the lipid nanoparticles were found optimal for enhancing the stability of HMGR. We characterized these hexosomes using dynamic light scattering (DLS), small-angle X-ray scattering (SAXS), and cryogenic electron microscopy (Cryo-TEM) methods, both with and without the encapsulated protein. In our innovative approach, the enzyme activity was assessed by monitoring changes in NADPH concentration outside the nanocarrier. We tracked fluctuations in NADPH levels during the catalytic reaction using two independent methods: UV-Vis spectrophotometry and cyclic voltammetry. Significantly, we could demonstrate the inhibition of the nano-encapsulated enzyme by fluvastatin, an enzyme inhibitor and cholesterol-lowering drug. This paves the way for the discovery of new enzymatic inhibitors and activators as therapeutic agents controlling the activity of membrane proteins, thereby inspiring future cholesterol-lowering therapies in our case and, in general, further research and potential new treatments.

Abstract

This review evaluates the effect of HCG and LH supplementation during ovarian stimulation. Controlled trials were divided into four groups comparing the treatment effect of recombinant FSH (r-FSH) with urinary FSH (u-FSH), with human menopausal gonadotrophin (HMG), with r-FSH + recombinant LH (r-LH) and with rFSH + recombinant HCG (r-HCG). First r-FSH seemed to be more potent than u-FSH in downregulated women, which translated into more follicles and oocytes. In line, numerous trials comparing HMG (containing u-FSH + u-HCG) with r-FSH demonstrated that HMG recruited fewer follicles, thus providing fewer oocytes but resulted in slightly higher pregnancy rates after a first fresh embryo transfer. The latter may be explained by the higher potency of r-FSH resulting in more and higher premature progesterone rises. Prospective trials addressing r-FSH + r-LH compared with r-FSH could not demonstrate any difference in pregnancy rates in normal or poor responders. A placebo-controlled trial of r-HCG added to a fixed daily r-FSH dose revealed that r-HCG inhibited the growth of intermediate follicles, resulting in fewer oocytes, fewer embryos and lower pregnancy rates. In conclusion, the beneficial effect of HCG and LH supplementation on clinical outcome has never been definitely proven for any of the combined gonadotrophin products.

Abstract

The bioavailability of biopeptide compounds is a development challenge, mainly because of their resistance to the digestion system. This study aimed to determine the bioavailability of HMG CoA reductase biopeptide inhibitors from germinated and ungerminated Kara Kratok (Phaseolus lunatus L.).

Abstract

Although Penicillium brevicompactum is widely used for industrial mycophenolic acid (MPA) production, research on its metabolic engineering and gene regulation remains limited. Efficient, coordinated expression of multiple genes is crucial for optimizing biosynthetic circuits and metabolic pathways, yet current strategies often suffer from inefficiencies and imbalances. These challenges not only limit the production of the desired metabolic products but can also result in wasted resources and inhibited cell growth. In this study, we optimized the 2A peptide multi-gene expression system in P. brevicompactum by introducing the Kozak sequence. This modification significantly enhanced the transcription of two key genes in the mevalonate (MVA) pathway precursor farnesyl pyrophosphate (FPP): the Acetyl-CoA acetyltransferase gene (ERG10) and the HMG-CoA synthetase gene (ERG13). In the PP-K10K13 strain, the transcription levels of the ERG10 and ERG13 genes increased by 77.02 % and 67.63 %, respectively, compared to the PP-1013 strain, which lacked the Kozak sequence. Consequently, the mycophenolic acid (MPA) production reached 4.30 g/L, representing a 49.31 % increase relative to the wild-type strain (WT). Additionally, observations of the engineered strains incorporating the introduced Kozak sequence showed improved growth, evident in an increase in mycelial dry weight, indicating reduced growth inhibition from metabolic engineering modifications. These results demonstrated that the optimized 2A peptide expression system not only effectively enhanced product synthesis efficiency but also helped restore the normal growth state of the engineered strains. This system is poised to serve as an effective tool for multi-gene expression and further genetic engineering modifications in P. brevicompactum. The study provides a new strategy for constructing more efficient 2A peptide multi-gene expression systems in Penicillium or filamentous fungi in future research endeavors.

Abstract

Multiforme glioblastoma-homing peptides, particularly targeting plasma membrane-bound heat shock protein mHsp70, demonstrate great application potential for tumor theranostics. In the current study, to further increase the bioavailability as well as penetration capacity through the blood-brain barrier (BBB) of the mHsp70-targeted peptide TKDNNLLGRFELSG, which is known to bind to the oligomerization sequence of mHsp70 chaperone, the latter was conjugated with tripeptide RGD (forming chimeric peptide termed RAS70). In the model BBB system RAS70 efficiently crossed the barrier accumulating in the glioblastoma cells. Subsequently, in the orthotopic glioma models, intravenous administration of the fluorescently labeled agent (RAS70-sCy7.5) resulted in the tumor retention of peptide (further confirmed by histological studies). Thus, as shown by the biodistribution studies employing epifluorescence imaging, accumulation of RAS70-sCy7.5 in C6 glioma was significantly enhanced as compared to scramble peptide. Local application of the RAS70-sCy7.5 peptide that was sprayed over the dissected brain tissues helped to efficiently delineate the tumors in glioma-bearing animals employing an intraoperative fluorescent imaging system. Tumor-specific internalization of the peptide was further confirmed on the ex vivo primary GBM samples obtained from adult neurooncological patients. In conclusion, RAS70 peptide demonstrated high glioma-homing properties which could be employed for the intraoperative tumor visualization as well as for developing a potential carrier for drug delivery.

Abstract

Ovulation induction with follicle-stimulating hormone (FSH) is a second-line treatment in women with polycystic ovary syndrome (PCOS) who do not ovulate or conceive on clomiphene citrate or letrozole, though induction protocols and types of gonadotropins used vary greatly.

Abstract

To optimize ovulation induction protocols for infertile women with PCOS, ovulation effect and adverse reactions of different doses of letrozole (2.5 vs 5.0 mg) combined sequentially HMG therapy were compared in infertility PCOS patients.

Abstract

The transcription factor SRY-related HMG-box 4 (SOX4) has been implicated in intervertebral disc diseases. This study aimed to investigate the role of SOX4 in intervertebral disc degeneration (IDD) and explore the underlying molecular mechanisms.