Integrated transcriptomic and proteomic analyses reveal the effects of chronic benzene exposure on the central nervous system in mice.

Benzene exposure is known to cause serious damage to the human hematopoietic system. However, recent studies have found that chronic benzene exposure may also cause neurological damage, but there were few studies in this issue. The aim of this study was to investigate the mechanism of damage to the central nervous system (CNS) by chronic benzene exposure with a multi-omics analysis. We established a chronic benzene exposure model in C57BL/6J mice by gavage of benzene-corn oil suspension, identified the differentially expressed proteins (DEPs) and differentially expressed genes (DEGs) in mice brain using 4D Label-free proteomic and RNA-seq transcriptomic. We observed that the benzene exposure mice had a significant loss of body weight, reduction in complete blood counts, abnormally high MRI signals in brain white matter, as well as extensive brain edema and neural demyelination. 162 DEPs were identified by the proteome, including 98 up-regulated and 64 down-regulated proteins. KEGG pathway analysis of DEPs showed that they were mainly involved in the neuro-related signaling pathways such as metabolic pathways, pathways of neurodegeneration, chemical carcinogenesis, Alzheimer disease, and autophagy. EPHX1, GSTM1, and LIMK1 were identified as important candidate DEGs/DEPs by integrated proteomic and transcriptomic analyses. We further performed multiple validation of the above DEGs/DEPs using fluorescence quantitative PCR (qPCR), parallel reaction monitoring (PRM), immunohistochemistry, and immunoblotting to confirm the reliability of the multi-omics study. The functions of these DEGs/DEPs were further explored and analyzed, providing a theoretical basis for the mechanism of nerve damage caused by benzene exposure.

Apocarotenoids from Equisetum debile Roxb. ex Vaucher regulate the lipid metabolism via the activation of the AMPK/ACC/SREBP-1c signaling pathway.

Sixteen undescribed apocarotenoids (1-16), along with 22 known analogues, were isolated from the aerial parts of Equisetum debile. Their structures, including absolute configurations, were elucidated by NMR, HRESIMS, X-ray diffraction analysis, the modified Mosher's method and the quantum-chemical calculation of electronic circular dichroism (ECD) spectra. Compounds 1-9, 11-12 are the first example of C16-apocarotenoids appeared in nature. The plausible biosynthetic pathway of 1-16 was proposed. Moreover, the isolates were evaluated for their lipid-lowering activity, and the results showed that 13, 14, 15, 22, 31, 32 and 33 could remarkably decrease the levels of both TC and TG in FFA induced HepG2 cells at 20 µM. The oil red staining assay further demonstrated the lipid-lowering effects of 13, 14 and 15. The western blot results indicated that compounds 13, 14 and 15 could regulate the lipid metabolism via the activation of the AMPK/ACC/SREBP-1c signaling pathway. A preliminary structure-activity relationship (SAR) study of the isolates indicated that the apocarotenoids with 6/5 ring system displayed more potent lipid-lowering effects.

Age Estimation Based on DNA Methylation and Its Application Prospects in Forensic Medicine.

With the improvement of DNA methylation detection techniques, studies on age-related methylation sites have found more age-specific ones across tissues, which improves the sensitivity and accuracy of age estimation. In addition, the establishment of various statistical models also provides a new direction for the age estimation of tissues from different sources. This review summarizes the related studies of age estimation based on DNA methylation from the aspects of detection technology, age-related cytosine phosphate guanine site and model selection in recent years.

Knockdown of circMYOF inhibits cell growth, metastasis, and glycolysis through miR-145-5p/OTX1 regulatory axis in laryngeal squamous cell carcinoma.

New evidence suggests that abnormal expression of circular RNA (circRNA) is associated with the development of human cancers. This study aims to reveal circMYOF roles in the malignant phenotype of laryngeal squamous cell carcinoma (LSCC). The expression of circMYOF, microRNA (miR)-145-5p, and orthodenticle homeobox 1 (OTX1) was detected by quantitative real-time PCR. Cell proliferation, migration, invasion, and apoptosis were determined using colony formation assay and EdU assay, wound healing assay, transwell assay, and flow cytometry, respectively. Protein expression was examined by western blot analysis. Cell glycolysis was assessed by detecting glucose consumption and lactate production. Mice xenograft models were constructed to evaluate the regulation of circMYOF on LSCC tumorigenesis. The regulatory relationships among circMYOF, miR-145-5p, and OTX1 were identified using dual-luciferase reporter assay and RIP assay. Serum exosomes were isolated to confirm the existence of circMYOF in LSCC patients. CircMYOF was upregulated in LSCC tissues and cells, and its knockdown suppressed LSCC cell growth, metastasis, and glycolysis, as well as inhibited LSCC tumor growth. MiR-145-5p had decreased expression in LSCC, and it could be sponged by circMYOF. The inhibition effect of circMYOF lentivirus short hairpin RNA (sh-circMYOF) on LSCC progression was restored by the inhibitor of miR-145-5p (in-miR-145-5p). Also, OTX1 was targeted by miR-145-5p and was positively regulated by circMYOF. MiR-145-5p could repress LSCC progression, and OTX1 overexpression also eliminated this effect. In addition, we found that circMYOF was significantly overexpressed in the serum exosomes of LSCC patients. Our data revealed that circMYOF contributed to LSCC progression by promoting cell growth, metastasis, and glycolysis through miR-145-5p/OTX1 axis.

Tautomeric phytosterols from Vernonia amygdalina Delile and their anti-cervical cancer activity.

Vernonia amygdalina Delile is generally used as green vegetables for cuisine in Nigeria and health tea or products in southeast of china. It was also used as folk medicine for the treatment of anti-helminth, febrifuge, digestive tonic and wounds. In this study, eleven undescribed phytosterols (1-2, 4-12) and six known analogues (3, 13-17) were isolated from the stems of V. amygdalina. Their structures including absolute configurations were elucidated by comprehensive spectroscopic methods (1D and 2D NMR, HRESIMS), X-ray diffraction and comparison of their ECD spectra. Besides, the tautomerism of phytosterols (1, 3-6, 12-17) with hemiacetal moiety were analyzed by solution NMR with different deuterated solvent and variable-temperature experiments. In addition, the cytotoxic activities of isolates against HeLa cells were evaluated. As a result, compound 10 exhibited the most potent anti-cervical cancer activity with the IC50 of 22.44 µM. Mechanism studies indicated that 10 triggered HeLa cells apoptosis through activating caspase signaling pathway. Furthermore, 10 could arrest the cell cycle in S phase and suppress the activation of the PI3K/AKT/mTOR pathway, leading to the inhibition of HeLa cells proliferation.

Effects of Peripheral Blood Different Pretreatment Methods and Preservation Time on RNA Quality.

OBJECTIVES: To evaluate the effects of different pretreatment methods and preservation time on RNA quality of peripheral blood samples, and to optimize the preservation method of peripheral blood samples. METHODS: Eight pretreatment methods were used to preprocess the peripheral blood from 3 healthy unrelated individuals and the treated samples were stored at -80 ℃. Total RNA of samples was extracted using Quick-RNATM Miniprep Plus kit. DNA/RNA ShieldTM was added to peripheral blood and total RNA was extracted after preservation at -80 ℃ for 0, 5, 10, 15, 30 and 60 days, respectively. The concentration, purity and integrity of RNA were determined. Statistical analyses were performed by SPSS 22.0 software to compare the differences in RNA yield, purity and integrity among the eight pretreatment methods. RESULTS: In terms of purity, leukocyte pretreated with RNAlaterTM and directly cryopreservation peripheral blood showed the worst purity. The other six methods showed better purity. In terms of yield, blood cells with DNA/RNA ShieldTM came out with the highest yield, followed by peripheral blood with DNA/RNA ShieldTM. In terms of integrity, peripheral blood preserved in PAXgene Blood RNA tube method had the best integrity. Except for peripheral blood pretreated with DNA/RNA ShieldTM and blood cells pretreated with DNA/RNA shieldTM, the other five methods had statistical differences when compared to the method by keeping peripheral blood in PAXgene Blood RNA tube. The purity of RNA stored at six-time gradients ranged from 1.815 to 1.952. With the increase of storage time, RNA yield decreased from 4.516 ng to 1.039 ng, and RNA integrity decreased from 8.533 to 7.150. CONCLUSIONS: According to the results of total RNA's yield, purity and integrity, peripheral blood pretreated with DNA/RNA ShieldTM was the best pretreatment method. After the pretreatment, samples can be preserved for up to 60 days in low temperature.

Development and validation of a novel SiFaSTRTM 23-plex system.

Human identification and paternity testing are usually based on the study of STRs depending on their particular characteristics in the forensic investigation. In this paper, we developed a sensitive genotyping system, SiFaSTR™ 23-plex, which is able to characterize 18 expanded Combined DNA Index System STRs (D3S1358, D5S818, D2S1338, TPOX, CSF1PO, TH01, vWA, D7S820, D21S11, D10S1248, D8S1179, D1S1656, D18S51, D12S391, D19S433, D16S539, D13S317, and FGA), three highly polymorphic STRs among Chinese people (Penta D, Penta E, and D6S1043), one Y-chromosome Indel and amelogenin using a multiplex PCR; the PCR amplified products were analyzed using the Applied Biosystems 3500 Genetic Analyzer. Full genotyping profiles were obtained using only 31.25 pg of control DNA; various case-type specimens, as well as ten-year-old samples were also successfully genotyped. Additionally, in the validation studies, this multiplex was demonstrated to be human-specific and compatible with the interference of multiple PCR inhibitors. The system also enabled the detection of mixtures, and complete profiles could be obtained at the mixed ratios of 1:1, 1:3, and 3:1. The development and validation study here illustrated that the SiFaSTR™ 23-plex system is accurate, powerful, and more sensitive than many other systems. What's more, the population data in our study not only illustrated that this 23-plex typing system was straightforward and efficient but also expanded the Chinese STR database, which could facilitate the appropriate application of the 23 genetic markers in forensic genetics, especially in the Chinese population.

Intrarenal Arterial Lesions Are Associated with Higher Blood Pressure, Reduced Renal Function and Poorer Renal Outcomes in Patients with IgA Nephropathy.

BACKGROUND/AIMS: Arterial fibrotic intimal thickening and arteriolar hyaline are considered common pathological features in immunoglobulin A nephropathy (IgAN), whereas little is known about the acute pathological manifestations of endothelial cell injury. The aim of this study was to investigate characteristics of intrarenal arterial lesions and to estimate their prognostic values in patients with IgAN. The primary renal endpoint was a 50% reduction in estimated glomerular filtration rate (eGFR) or end-stage renal disease (ESRD). METHODS: Various renal arterial lesions (arterial fibrotic intimal thickening, arteriolar hyaline, arteriolar endotheliocyte swelling, arteriolar inflammatory cell infiltration, and arteriolar thrombosis) in 1683 patients with IgAN were reviewed and reclassified using a semi-quantitative scoring system. Their correlations with clinical features, pathological characteristics, and renal outcomes were evaluated. RESULTS: The prevalence of intrarenal arterial lesions was up to 72.2% in IgAN patients. There were 978 patients (58.1%) with arterial fibrotic intimal thickening, 350 patients (20.8%) with arteriolar hyaline, 432 patients (25.7%) with arteriolar endotheliocyte swelling, 356 patients (21.2%) with arteriolar inflammatory cell infiltration and 43 patients (2.6%) with arteriolar thrombosis. Arterial fibrotic intimal thickening and arteriolar hyaline were strongly associated with higher mean arterial pressure (MAP) and reduced eGFR (P < 0.001) but were not related to proteinuria at the time of renal biopsy. In contrast, arteriolar endotheliocyte swelling and arteriolar thrombosis were correlated with heavier proteinuria as well as higher MAP and reduced eGFR. During follow-up, patients with vascular lesions received more renin-angiotensin system (RAS) blockade and less glucocorticoid and showed poorer renal outcomes. Univariate Cox model showed that the presence of renal vascular lesions [hazard ratio (HR) = 25.01, 95% confidence interval (CI): 6.19 to 101.03, P < 0.001] was a risk factor for renal outcomes. However, in multivariable Cox analysis, which included clinical factors and the Oxford-MEST-C, vascular lesions were not significantly associated with an increased risk of renal failure. Remarkably, the impact of vascular lesions on the survival from ESRD or 50% reduction in renal function was eliminated by the use of RAS blockade after adjustment for eGFR, proteinuria, and MAP. CONCLUSION: Our study demonstrates the high prevalence of vascular lesions, including the chronic and acute arterial pathological changes, in patients with IgAN. The presence of vascular lesions is associated with higher MAP, reduced eGFR and poorer renal outcomes, which could be influenced by the RAS blockade treatment.

Multiple-Octave-Spanning Vibration Sensing Based on Simultaneous Vector Demodulation of 499 Fizeau Interference Signals from Identical Ultra-Weak Fiber Bragg Gratings Over 2.5 km.

Multi-point vibration sensing at the low frequency range of 0.5-100 Hz is of vital importance for applications such as seismic monitoring and underwater acoustic imaging. Location-resolved multi-point sensing using a single fiber and a single demodulation system can greatly reduce system deployment and maintenance costs. We propose and demonstrate the demodulation of a fiber-optic system consisting of 500 identical ultra-weak Fiber Bragg gratings (uwFBGs), capable of measuring the amplitude, frequency and phase of acoustic signals from 499 sensing fibers covering a total range of 2.5 km. For demonstration purposes, we arbitrarily chose six consecutive sensors and studied their performance in detail. Using a passive demodulation method, we interrogated the six sensors simultaneously, and achieved a high signal-to-noise ratio of 22.1 dB, excellent linearity, phase sensitivity of around 0.024 rad/Pa, and a dynamic range of about 38 dB. We demonstrated a frequency response flatness of <1.2 dB in the range of 0.5-100 Hz. Compared to the prior state-of-the-art demonstration using a similar method, we have increased the sensing range from 1 km to 2.5 km, and increased the frequency range from 0.4 octaves to 7.6 octaves, in addition to achieving sensing in the very challenging low-frequency range of 0.5-100 Hz.

Hydrogen Gas Attenuates Myocardial Ischemia Reperfusion Injury Independent of Postconditioning in Rats by Attenuating Endoplasmic Reticulum Stress-Induced Autophagy.

BACKGROUND/AIMS: To study the effect of inhaling hydrogen gas on myocardial ischemic/reperfusion(I/R) injury in rats. METHODS: Seventy male Wistar albino rats were divided into five groups at random as the sham group (Sham). The I/R group (I/R), The ischemic postconditioning group (IPo), The I/R plus hydrogen group (IH2) and the ischemic postconditioning plus hydrogen group (IPoH2). The Sham group was without coronary occlusion. In I/R group, Ischemic/reperfusion injury was induced by coronary occlusion for 1 hour. Followed by 2 hours of reperfusion. In the IPo and IPoH2 group, four cycles of 1 min reperfusion/1 min ischemia was given at the end of 1 hour coronary occlusion. While 2% hydrogen was administered by inhalation 5 min before reperfusion till 2 hours after reperfusion in both the IPoH2 and IH2 group. The heart and blood samples were harvested at the end of the surgical protocol. Then the myocardium cell endoplasmic reticulum(ER) stress and autophagy was observed by electron microscope. In addition, the cardiac ER stress and autophagy related proteins expression were detected by Western blotting analysis. RESULTS: Both inhaling 2% hydrogen and ischemic postconditioning treatment reduced the ischemic size and serum troponin I level in rats with I/R injury, and inhaling hydrogen showed a more curative effect compared with ischemic postconditioning treatment. Meanwhile inhaling hydrogen showed a better protective effect in attenuating tissue reactive oxygen species. Malondialdehyde levels and immunoreactivities against 8-hydroxy-2'-deoxyguanosine and inhibiting cardiac endoplasmic reticulum stress and down-regulating autophagy as compared with ischemic postconditioning treatment. CONCLUSION: These results revealed a better protective effect of hydrogen on myocardial ischemic/reperfusion injury in rats by attenuating endoplasmic reticulum stress and down-regulating autophagy compared with ischemic postconditioning treatment.

CREB3 facilitates Donafenib resistance in hepatocellular carcinoma cells via the LSD1/CoREST/p65 axis by transcriptionally activating long noncoding RNA ZFAS1.

OBJECTIVE: Drug resistance greatly limits the therapeutic effect of a drug. This study aimed to explore the role of long noncoding RNA ZFAS1 in Donafenib resistance of hepatocellular carcinoma (HCC) cells. METHODS: The expression of CREB3, ZFAS1, and p65 in HCC cell lines was measured by RT-qPCR and western blotting. After transfection with sh-ZFAS1, sh-CREB3, or sh-CREB3 + oe-p65 in Donafenib-resistent (DR) HCC cell lines, the transfection efficiency was evaluated by RT-qPCR and western blotting. The proliferation and IC50 to Donafenib of HCC cell lines was examined by MTT assay. Cell proliferation and apoptosis were examined by colony formation and flow cytometry assays. Then, the correlation amongst CREB3, ZFAS1, LSD1/CoREST, and p65 was analysed by ChIP, dual-luciferase reporter gene, and RIP assays. RESULTS: ZFAS1, CREB3, and p65 were upregulated in HepG2-DR and Huh7-DR cells. Silencing of ZFAS1 or CREB3 enhanced the sensitivity of HCC cells to Donafenib, inhibited cell proliferation and IC50, and increased cell apoptosis, which were reversed by p65 overexpression. Mechanistically, CREB3 bound to ZFAS1 promoter to augment ZFAS1 transcriptional expression, and ZFAS1 recruited LSD1/CoREST to the p65 promoter region to decrease H3K4 methylation and elevate p65 transcriptional expression. CONCLUSION: CREB3 overexpression contributed to Donafenib resistance in HCC cells by activating the ZFAS1/p65 axis.

Higher percentage of CD34+ stem cells and elevated efficacy in androgenetic alopecia treatment observed in CGF prepared from 640 nm laser-pretreated blood: A preliminary study.

BACKGROUND: Concentrated growth factor (CGF) injection has proven effective in treating androgenetic alopecia (AGA). The primary mechanism of CGF in treating AGA is thought to be the CD34+ stem cells and platelets-associated growth factors being injected into the scalp. CGF efficacy in treating AGA may rely on the activation level of these stem cells and platelets. The 640 nm laser is a United States Food and Drug Administration approved AGA treatment that activates follicle stem cells. Therefore, we hypothesize that pretreating CGF with a 640 nm laser may further activate CD34+ stem cells and platelets, thereby improving the efficacy of CGF in treating AGA. OBJECTIVE: This study aims to investigate whether 640 nm laser pretreated CGF (640CGF) has a greater effect in treating AGA than 640 nm laser non-pretreated CGF (N640CGF) and evaluate whether 640 nm laser pretreatment changed CD34+ cell percentage. METHODS: This study enrolled 10 patients (8 male, 2 female) with AGA aged 18-60 years who received CGF injections. The 640CGF group was pretreated with a 640 nm laser at an energy density of 4 J/cm2, with a 30 cm irradiation distance for 30 min. Half of the scalp was treated with 640CGF, whereas the other half was treated with N640CGF. The injection was prepared by a doctor who did not know which blood tube had been pretreated. The treatment efficacy was evaluated using a trichoscope 1 month after injection. RESULTS: All 10 (100%) patients participated in the follow-up visit, and a higher quantity of new hairs was observed on the side injected with 640CGF than N640CGF (p = 0.019). Additionally, fewer malnourished hairs were observed on the 640CGF pretreated side (p = 0.015). No serious adverse events were reported. CONCLUSIONS: A higher percentage of CD34+ stem cells and improved efficacy in AGA treatment could be observed with CGF prepared from 640 nm laser-pretreated blood.

CGF therapy: bridging androgenetic alopecia observations to psoriasis treatment via IL-17 pathway.

INTRODUCTION: Concentrated Growth Factor (CGF), rich in CD34 + stem cells, is widely used in treatments for androgenetic alopecia and skin rejuvenation due to its immune-modulating properties. Psoriasis, a chronic inflammatory skin condition, presents significant treatment challenges, particularly for patients who cannot use biologics due to conditions such as cancer and lesions resistant to treatments. The potential of CGF in treating psoriasis is promising, given its broad immunoregulatory effects which confirmed in our previous androgenetic alopecia work. METHODS: We evaluated the impact of CGF on IL-17 levels in two contexts: patients treated for androgenetic alopecia and a psoriasis mouse model. Twelve patients received three monthly injections of CGF, with serum IL-17 levels measured before and after treatment. In the psoriasis mouse model, groups were treated with CGF, and outcomes were assessed using the Psoriasis Area and Severity Index (PASI), skin barrier scores, histological analysis, and RNA sequencing. Additionally, in vitro experiments applied CD34 + cells from CGF to keratinocytes to measure levels of TNF-α, IFN-γ, IL-23, and IL-17. RESULTS: In patients with androgenetic alopecia, three monthly CGF injections resulted in significantly reduced serum IL-17 levels. In the psoriatic mouse model, CGF-treated groups exhibited lower PASI scores and improved skin barrier scores compared to controls. Histological analysis revealed enhanced skin characteristics, while RNA sequencing demonstrated downregulated IL-17 and upregulated CD34 expression, as well as improved expression of barrier-related genes. In vitro, the application of CD34 + cells from CGF to keratinocytes led to a significant reduction in TNF-α, IFN-γ, IL-23, and IL-17 levels, indicating strong anti-inflammatory effects. A clinical case of a psoriasis patient unresponsive to IL-23 therapy (Guselkumab) showed significant improvement following CGF treatment. CONCLUSION: These findings indicate that CGF could serve as an effective and versatile treatment for psoriasis, especially for patients who have already undergone biologic therapies but continue to experience resistant lesions.

Molybdenum Nanoparticles Alleviate MC903-Induced Atopic Dermatitis-Like Symptoms in Mice by Modulating the ROS-Mediated NF-κB and Nrf2 /HO-1 Signaling Pathways.

Purpose: Atopic dermatitis (AD) is a chronic inflammatory skin condition that can affect individuals of all ages. Recent research has shown that oxidative stress plays a crucial role in the development of AD. Therefore, inhibiting oxidative stress may be an effective therapeutic approach for AD. Nano-molybdenum is a promising material for use as an antioxidant. We aimed to evaluate the therapeutic effects and preliminary mechanisms of molybdenum nanoparticles (Mo NPs) by using a murine model of chemically induced AD-like disease. Methods: HaCaT cells, a spontaneously immortalized human keratinocyte cell line, were stimulated by tumor necrosis factor-alpha /interferon-gamma after pre-treatment with Mo NPs. Reactive oxygen species levels, production of inflammatory factors, and activation of the nuclear factor kappa-B and the nuclear factor erythroid 2-related factor pathways were then evaluated. Mo NPs was topically applied to treat a murine model of AD-like disease induced by MC903, a vitamin D3 analog. Dermatitis scores, pruritus scores, transepidermal water loss and body weight were evaluated. AD-related inflammatory factors and chemokines were evaluated. Activation of the nuclear factor kappa-B and nuclear factor erythroid 2-related factor / heme oxygenase-1 pathways was assessed. Results: Our data showed that the topical application of Mo NPs dispersion could significantly alleviate AD skin lesions and itching and promote skin barrier repair. Further mechanistic experiments revealed that Mo NPs could inhibit the excessive activation of the nuclear factor kappa-B pathway, promote the expression of nuclear factor erythroid 2-related factor and heme oxygenase-1 proteins, and suppress oxidative stress reactions. Additionally, they inhibited the expression of thymic stromal lymphopoietin, inflammatory factors, and chemokines, thereby alleviating skin inflammation. Conclusion: Mo NPs present a promising alternative treatment option for patients with AD as they could address three pivotal mechanisms in the pathogenesis of AD concurrently.

Molybdenum nanoparticles as a potential topical medication for alopecia treatment through antioxidant pathways that differ from minoxidil.

BACKGROUND: Hair loss is a common dermatological condition including various types such as alopecia areata, androgenetic alopecia, etc. Minoxidil is a topical medication used for treating hair loss, which is effective for various types of alopecia. However, minoxidil has limitations in treating hair loss, such as slow onset of action and low efficacy, and it cannot effectively inhibit one of the major pathogenic factors of hair loss - excessive oxidative stress. METHODS: Transition metal elements with rapid electron transfer, such as molybdenum, have been extensively studied and applied for inhibiting oxidative stress. We established a mouse model for hair growth and intervened with nano-sized molybdenum, minoxidil, and a combination of both. The physicochemical properties of nano-sized molybdenum enabled it to mediate oxidative stress more quickly. RESULTS: The results showed that nano-sized molybdenum can accelerate hair growth, increase the number of local hair follicles, and reduce the expression of oxidative stress-related molecules such as iNOS, COX2, and androgen receptors. The combination of nano-sized molybdenum and minoxidil showed an additive effect in promoting hair growth. CONCLUSION: Our findings suggest that nano-sized molybdenum might be a potential topical medication for treating hair loss by inhibiting the oxidative stress pathway. Nano-sized molybdenum, alone or in combination with minoxidil, could be a promising therapeutic approach for patients with hair loss, particularly those who do not respond well to current treatments. Further clinical studies are warranted to confirm the efficacy and safety of this novel treatment.

MAPK1 Mediates MAM Disruption and Mitochondrial Dysfunction in Diabetic Kidney Disease via the PACS-2-Dependent Mechanism.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD). Mitochondrial dysfunction in renal tubules, occurring early in the disease, is linked to the development of DKD, although the underlying pathways remain unclear. Here, we examine diabetic human and mouse kidneys, and HK-2 cells exposed to high glucose, to show that high glucose disrupts mitochondria-associated endoplasmic reticulum membrane (MAM) and causes mitochondrial fragmentation. We find that high glucose conditions increase mitogen-activated protein kinase 1(MAPK1), a member of the MAP kinase signal transduction pathway, which in turn lowers the level of phosphofurin acidic cluster sorting protein 2 (PACS-2), a key component of MAM that tethers mitochondria to the ER. MAPK1-induced disruption of MAM leads to mitochondrial fragmentation but this can be rescued in HK-2 cells by increasing PACS-2 levels. Functional studies in diabetic mice show that inhibition of MAPK1 increases PACS-2 and protects against the loss of MAM and the mitochondrial fragmentation. Taken together, these results identify the MAPK1-PACS-2 axis as a key pathway to therapeutically target as well as provide new insights into the pathogenesis of DKD.

JAK Inhibitors as Potential Therapeutic Strategy for the Dilemma of Psoriasis Concurrent with Dermatomyositis in the SARS-CoV-2 Era.

Dermatomyositis is a rare inflammatory disease with potentially life-threatening systemic involvement that is treated with systemic corticosteroids. However, when psoriasis coexists with dermatomyositis, the administration of corticosteroids may exacerbate psoriasis after withdrawal, posing a treatment dilemma. Our search of the literature revealed 14 cases where various treatments were used, including methotrexate, corticosteroids, cyclosporin, ustekinumab, mycophenolate mofetil, and azathioprine. While methotrexate showed promise, it carries risks, and corticosteroids were used despite their potential to exacerbate psoriasis. Based on transcriptomic data analysis of psoriasis and dermatomyositis, the type II interferon-mediated signaling pathway was enriched in both diseases. Medication targeting this pathway, such as JAK inhibitors, could be a potential solution for the psoriasis concurrent with dermatomyositis dilemma, as JAK inhibitors have been proven effective in treating both dermatomyositis and psoriasis, with some being FDA-approved for treating COVID-19. Therefore, JAK inhibitors may be a potential therapeutic strategy for psoriasis concurrent with dermatomyositis in the SARS-CoV-2 era.

Prognostic prediction and immunotherapy response analysis of the fatty acid metabolism-related genes in clear cell renal cell carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) is a common urinary cancer. Although diagnostic and therapeutic approaches for ccRCC have been improved, the survival outcomes of patients with advanced ccRCC remain unsatisfactory. Fatty acid metabolism (FAM) has been increasingly recognized as a critical modulator of cancer development. However, the significance of the FAM in ccRCC remains unclear. Herein, we explored the function of a FAM-related risk score in the stratification and prediction of treatment responses in patients with ccRCC. Methods: First, we applied an unsupervised clustering method to categorize patients from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets into subtypes and retrieved FAM-related genes from the MSigDB database. We discern differentially expressed genes (DEGs) among different subtypes. Then, we applied univariate Cox regression analysis followed by least absolute shrinkage and selection operator (LASSO) linear regression based on DEGs expression to establish a FAM-related risk score for ccRCC. Results: We stratified the three ccRCC subtypes based on FAM-related genes with distinct overall survival (OS), clinical features, immune infiltration patterns, and treatment sensitivities. We screened nine genes from the FAM-related DEGs in the three subtypes to establish a risk prediction model for ccRCC. Nine FAM-related genes were differentially expressed in the ccRCC cell line ACHN compared to the normal kidney cell line HK2. High-risk patients had worse OS, higher genomic heterogeneity, a more complex tumor microenvironment (TME), and elevated expression of immune checkpoints. This phenomenon was validated in the ICGC cohort. Conclusion: We constructed a FAM-related risk score that predicts the prognosis and therapeutic response of ccRCC. The close association between FAM and ccRCC progression lays a foundation for further exploring FAM-related functions in ccRCC.

Improving the system power of complex kinship analysis by combining multiple systems.

Complex kinship analysis is a critical issue in forensic genetics. To address this issue, 55 STRs and 94 SNPs collected from four commercial forensic typing kits [three kits were based on a capillary electrophoresis (CE) platform and one was based on a next-generation sequencing (NGS) platform] were employed to test the system power for 2nd-degree and 3rd-degree kinship analysis. To measure the kinship index in related individuals, likelihood ratios (LRs) were calculated based on length and sequence polymorphism information (LRlength and LRsequence, respectively) from simulation as well as true pedigree samples. LRs calculated based on sequence information are generally higher than those based on length information. The sensitivity, specificity, and effectiveness to distinguish the 2nd- and 3rd-degree kinship were estimated from four marker sets with different numbers of markers. As expected, system power for kinship analysis improved by increasing the number of markers and using LRsequence, instead of LRlength. Furthermore, the system power based on 55 STRs from the CE platform is equal to the 40 STRs and 94 SNPs from one CE kit and the kit based on NGS platform for both 2nd-degree and 3rd-degree kinship analysis. For discrimination of 2nd-degree kinship, the system effectiveness is 86.63% with an error ratio < 0.01 using the 55 STRs from the CE platform. Using sequence information from the 55 STRs and 94 SNPs, the system effectiveness is 94.43%, with an error ratio < 0.001 for 2nd-degree kinship analysis and 64.34% with an error ratio < 0.05 for 3rd-degree kinship analysis, indicating that these markers are powerful for 2nd-degree kinship analysis and can be used for 3rd-degree kinship analysis.