First in human intraarterial delivery of tislelizumab for the treatment of pMMR locally advanced rectal cancer: A single-arm, open label, phase II clinical trial.

BACKGROUND: Intravenous immune checkpoint inhibitors (ICIs) have shown efficacy in treating locally advanced rectal cancer (LARC), but concerns about systemic toxicity persist. This study developed a unique approach termed chemo-immuno-embolization with transcatheter rectal arterial intervention (CIETAI), aiming to enhance the anti-tumor response while minimizing systemic toxicity. METHOD: This is a prospective, single-arm, phase II clinical trial conducted in Daping hospital. Patients with previously untreated stage II/III LARC underwent preoperative CIETAI combined with PD-1 inhibitor tislelizumab plus oxaliplatin, followed by standard concomitant chemoradiotherapy (capecitabine and 50.4 Gy radiation). Intravenous tislelizumab was administered for an additional two cycles. RESULTS: Between January 2023 and December 2023, a total of 38 patients were enrolled. As the primary endpoint, 17 (44.74 %) patients achieved pathological complete response (TRG0), with a major pathologic response (MPR) rate of 65.79 %. The anal preservation rate was 84.21 % (32/38), and importantly, 15 of 21 patients with low rectal cancer achieved organ preservation with functional maintenance. Eight patients experienced grade 3-4 adverse events (AEs). All immune-related AEs were grade 1-2, with the most common being endocrine toxicity (5/6, 83.33 %). No grade 5 AEs occurred. CONCLUSION: This study provides preliminary evidence supporting the safety and efficacy of intraarterial tislelizumab delivery in the neoadjuvant setting for LARC. These promising results encourage further exploration in larger cohorts to validate the clinical impact of this novel CIETAI strategy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05957016.

Gustative Roussy Immune Score is a Predictor for Major Pathological Response in Rectal Cancer: A Result from the Preoperative Intraarterial Chemoembolization Combined with Radiotherapy (PCAR) Study.

Despite the emergence of various treatment strategies for rectal cancer based on neoadjuvant chemoradiotherapy, there is currently a lack of reliable biomarkers to determine which patients will respond well to neoadjuvant chemoradiotherapy. Through collecting hematological and biochemical parameters data of patients prior to receiving neoadjuvant chemoradiotherapy, we evaluated the predictive value of systemic inflammatory indices for pathological response and prognosis in rectal cancer patients. We found that baseline GRIm-Score was an independent predictor for MPR in rectal cancer patients. However, no association was observed between several commonly systemic inflammation indices and long-term outcome.

Negative prognostic impact of Co-mutations in TGFß and TP53 pathways in surgically resected rectal tumors following neoadjuvant chemoradiotherapy.

BACKGROUND: Preoperative neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME) is a common approach for treating patients with locally advanced rectal cancer. Nevertheless, the mutational profile and its prognostic impact in surgically resected tumor specimens after nCRT remains to be clarified. METHODS: The comprehensive analysis of mutational landscape was retrospectively conducted by target regions sequencing approach that covered 150 tumor-related genes. Univariate and multivariate logistic regression and Cox regression was used to examine the association of mutation status in genes and pathways with pathological response and prognosis. Data from Memorial Sloan Kettering Cancer Center (MSK) cohort was used for comparison with our results. RESULTS: The top five commonly mutated genes in resected rectal tumor tissue samples following nCRT were TP53 (42%), APC (31%), KRAS (27%), PIK3CA (14%) and FBXW7 (11%). Mutations in the WNT pathway, which was mainly represented by APC mutation, were found to be significantly associated with tumor regression grade (TRG) 3. In our cohort, co-mutations in the receptor tyrosine kinase (RTK)/RAS and WNT pathways were found to be independently associated with reduced risk of recurrent and significantly associated with longer disease-free survival (DFS). In both our cohort and the MSK cohort, co-mutations in the TGF-ß and TP53 pathways were significantly associated with worse DFS. CONCLUSIONS: Resected rectal tumor samples from patients without complete pathological response can be appropriately used to detect mutations. Co-mutations in the TGF-ß and TP53 pathways may provide more prognostic information beyond commonly used clinical factors.

TREM2 Inhibits Tau Hyperphosphorylation and Neuronal Apoptosis via the PI3K/Akt/GSK-3ß Signaling Pathway In vivo and In vitro.

Triggering receptor expressed on myeloid cells-2 (TREM2), a cell surface receptor mainly expressed on microglia, has been shown to play a critical role in Alzheimer's disease (AD) pathogenesis and progression. Our recent results showed that overexpression of TREM2 inhibited inflammatory response in APP/PS1 mice and BV2 cells. Several studies indicated that TREM2 ameliorated tau hyperphosphorylation might be ascribed to the inhibition of neuroinflammation. However, the precise signaling pathways underlying the effect of TREM2 on tau pathology and neuronal apoptosis have not been fully elucidated. In the present study, upregulation of TREM2 significantly inhibited tau hyperphosphorylation at Ser199, Ser396, and Thr205, respectively, as well as prevented neuronal loss and apoptosis. We also found that upregulation of TREM2 alleviated behavioral deficits and improved the spatial cognitive ability of APP/PS1 mice. Further study revealed that TREM2 could activate phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, resulting in an inhibitory effect on glycogen synthase kinase-3ß (GSK-3ß), which is a major kinase responsible for tau hyperphosphorylation in AD. In line with in vivo findings, TREM2-overexpressing BV2 microglia following ß-amyloid (Aß) stimulation led to a significant increase in the phosphorylation of PI3K, Akt, and GSK-3ß, accompanied by a decrease in tau hyperphosphorylation and apoptosis in co-cultured SH-SY5Y cells. Furthermore, LY294002, a specific PI3K inhibitor, was observed to abolish the beneficial effects of TREM2 on tau hyperphosphorylation, neuronal apoptosis, and spatial cognitive impairments in vivo and in vitro. Thus, our findings indicated that TREM2 inhibits tau hyperphosphorylation and neuronal apoptosis, at least in part, by the activation of the PI3K/Akt/GSK-3ß signaling pathway. Taken together, the above results allow us to better understand how TREM2 protects against tau pathology and suggest that upregulation of TREM2 may provide new ideas and therapeutic targets for AD.

A Study of Heat Shock Protein 90 and Serum CCL21 Expression in Pregnant Women with Preeclampsia.

Objective: The purpose of the study was to determine the significance of heat shock protein 90 (HSP 90) and serum chemokine ligand 21 (CCL-21) in pregnant women with preeclampsia (PE). Methods: From June 2021 to June 2022, the study enrolled 100 women undergoing obstetric examinations and delivering in our hospital; 50 PE patients undergoing routine obstetric examinations and delivering during the same period were enrolled in the research group; according to the severity, they were divided into mild PE and severe PE groups, while 50 healthy pregnant women undergoing obstetric examinations and delivering in our hospital during the same period were enrolled in the control group. In a subsequent analysis, serum levels of CCL-21 and HSP90 were compared between the two groups, and the correlation among CCL-21, HSP 90, and PE severity was analyzed. Results: An overall total of 50 patients with PE were enrolled in the study, which included 32 patients with mild PE and 18 patients with severe PE. Patients with severe PE had lower mean arterial pressure (MAP), HSP 90, and CCL21 index levels than those with mild PE; MAP, HSP 90, and CCL21 in the severe PE group were higher than those in the mild PE group, but the difference was not statistically significant; In the research group, MAP was weakly correlated with HSP90 concentration and CCL21 concentration, with correlation coefficients of 0.33 and 0.30, respectively, and the correlation analysis was significant. Conclusion: Patients with PE showed significantly increased serum concentrations of HSP90 and CCL-21, but a significant difference did not exist between mild and severe PE. In addition, there was a weak relationship between HSP90 and CCL-21 concentrations in PE patients and MAP, suggesting that HSP90 and CCL-21 play an instrumental role in the pathogenesis of PE, although more studies are needed to clarify the exact mechanisms.

Correlation of Serum Chemokine (C-C Motif) Ligand 21 and Heat Shock Protein 90 with Preeclampsia.

Objective: The study aimed to explore the correlation of serum chemokine (C-C motif) ligand 21 (CCL21) and heat shock protein 90 (Hsp90) with preeclampsia (PE). Methods: Between June 2021 and June 2022, 50 pregnant women with PE were included in the PE group, and 50 healthy pregnant women were included in the control group. The serum levels of CCL21 and Hsp90 were compared between the two groups. Results: PE patients showed significantly higher levels of CCL21 and Hsp90 than healthy pregnant women (P < 0.05). Correlation analysis showed a positive correlation between CCL21 and Hsp90 levels (r > 0, (P < 0.05)). Binary logistic regression analysis suggested that high expression of CCL21 and Hsp90 were influencing factors for PE (OR >1, (P < 0.05)). The area under the receiver operating characteristic (AUC) curves of Hsp90 and CCL21 levels for predicting PE were 0.895 and 0.864, respectively, suggesting a good predictive value. Conclusion: Serum CCL21 and Hsp90 show great potential as disease markers for PE prediction. Further trials are, however, required prior to clinical promotion.

Characterization of a Conjugative Multidrug Resistance IncP-2 Megaplasmid, pPAG5, from a Clinical Pseudomonas aeruginosa Isolate.

The spread of resistance genes via horizontal plasmid transfer plays a significant role in the formation of multidrug-resistant (MDR) Pseudomonas aeruginosa strains. Here, we identified a megaplasmid (ca. 513 kb), designated pPAG5, which was recovered from a clinical multidrug-resistant P. aeruginosa PAG5 strain. The pPAG5 plasmid belonged to the IncP-2 incompatibility group. Two large multidrug resistance regions (MDR-1 and MDR-2) and two heavy metal resistance operons (merEDACPTR and terZABCDE) were identified in the pPAG5 plasmid. Genetic analysis demonstrated that the formation of MDR regions was mediated by several homologous recombination events. Further conjugation assays identified that pPAG5 could be transferred to P. aeruginosa but not Escherichia coli. Antimicrobial susceptibility testing on transconjugants demonstrated that pPAG5 was capable of transferring resistance genes to transconjugants and producing a multidrug-resistant phenotype. Comparative analysis revealed that pPAG5 and related plasmids shared an overall similar backbone, including genes essential for replication (repA), partition (par), and conjugal transfer (tra). Further phylogenetic analysis showed that pPAG5 was closely related to plasmids pOZ176 and pJB37, both of which are members of the IncP-2-type plasmid group. IMPORTANCE The emergence and spread of plasmid-associated multidrug resistance in bacterial pathogens is a key global threat to public health. It is important to understand the mechanisms of the formation and evolution of these plasmids in patients, hospitals, and the environment. In this study, we detailed the genetic characteristics of a multidrug resistance IncP-2 megaplasmid, pPAG5, and investigated the formation of its MDR regions and evolution. To the best of our knowledge, plasmid pPAG5 is the largest multidrug resistance plasmid ever sequenced in the Pseudomonas genus. Our results may provide further insight into the formation of multidrug resistance plasmids in bacteria and the molecular evolution of plasmids.

Tanshinone IIA regulates glycogen synthase kinase-3ß-related signaling pathway and ameliorates memory impairment in APP/PS1 transgenic mice.

Our previous findings indicated that tanshinone IIA (tan IIA), a natural component extracted from the root and rhizome of danshen, significantly attenuated ß-amyloid accumulation, neuroinflammation, and endoplasmic reticulum stress, as well as improved learning and memory deficits in APP/PS1 transgenic mouse model of Alzheimer's disease (AD). However, whether tan IIA can ameliorate tau pathology and the underlying mechanism in APP/PS1 mice remains unclear. In the current study, tan IIA (15 mg/kg and 30 mg/kg) or saline was intraperitoneally administered to the 5-month-old APP/PS1 mice once daily for 4 weeks. The open-field test, novel object recognition test, Y-maze test, and Morris water maze test were performed to assess the cognitive function. Nissl staining, immunohistochemistry, TUNEL, and western blotting were conducted to explore tau hyperphosphorylation, neuronal injury, and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt)/glycogen synthase kinase-3ß (GSK-3ß) signaling pathway. The activity of GSK-3ß, acetylcholinesterase (AChE), choline acetyltransferase (ChAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), and the level of malondialdehyde (MDA) were measured using commercial kits. Our results revealed that tan IIA treatment significantly ameliorated behavioral deficits and improved spatial learning and memory ability of APP/PS1 mice. Additionally, tan IIA markedly attenuated tau hyperphosphorylation and prevented neuronal loss and apoptosis in the parietal cortex and hippocampus. Simultaneously, tan IIA reversed cholinergic dysfunction and reduced oxidative stress. Furthermore, tan IIA activated the PI3K/Akt signaling pathway and suppressed GSK-3ß. Taken together, the above findings suggested that tan IIA improves cognitive decline and tau pathology may through modulation of PI3K/Akt/GSK-3ß signaling pathway.

Downregulation of TREM2 expression exacerbates neuroinflammatory responses through TLR4-mediated MAPK signaling pathway in a transgenic mouse model of Alzheimer's disease.

Activation of glial cells and neuroinflammation play an important role in the onset and development of Alzheimer's disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor in the brain that is involved in regulating neuroinflammation. However, the precise effects of TREM2 on neuroinflammatory responses and its underlying molecular mechanisms in AD have not been studied in detail. Here, we employed a lentiviral-mediated strategy to downregulation of TREM2 expression on microglia in the brain of APPswe/PS1dE9 (APP/PS1) transgenic mice and BV2 cells. Our results showed that downregulation of TREM2 significantly aggravated AD-related neuropathology including Aß accumulation, peri-plaque microgliosis and astrocytosis, as well as neuronal and synapse-associated proteins loss, which was accompanied by a decline in cognitive ability. The further mechanistic study revealed that downregulation of TREM2 expression initiated neuroinflammatory responses through toll-like receptor 4 (TLR4)-mediated mitogen-activated protein kinase (MAPK) signaling pathway and subsequent stimulating the production of pro-inflammatory cytokines in vivo and in vitro. Moreover, blockade of p38, JNK, and ERK1/2 inhibited the release of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) induced by Aß1-42 in TREM2-knocked down BV2 cells. Taken together, these findings indicated that TREM2 might be a potential therapeutic target for AD and other neuroinflammation-related diseases.

High D-arabitol production with osmotic pressure control fed-batch fermentation by Yarrowia lipolytica and proteomic analysis under nitrogen source perturbation.

D-arabitol, a five-carbon sugar alcohol, is widely used in food and pharmacy industry as a lower calorie sweetener or intermediate. Appropriate osmotic pressure was confirmed to facilitate polyol production by an osmophilic yeast strain of Yarrowia lipolytica with glycerol. In this study, an osmotic pressure control fed-batch fermentation strategy was used for high D-arabitol producing by Y. lipolytica ARA9 with crude glycerol. Glycerol was added to the broth quantitatively not only as a substrate but also as an osmotic agent. Meanwhile, NH3·H2O was fed as a nitrogen source and pH regulator. The maximum D-arabitol production reached 118.5 g/L at 108 h with the yield of 0.49 g/g and productivity of 1.10 g/L/h, respectively. Furthermore, a comparative proteomic analysis was used to study the cellular responses under excess and deficient nitrogen sources. Thirty-one differentially expressed protein spots belonging to seven different biological processes were identified. Excess nitrogen source enhanced gluconeogenesis and pentose phosphate pathways, both of which were involved in arabitol synthesis. In addition, cell growth was facilitated by increased expression of nucleotide and structural proteins. Enhanced energy and NADPH biosynthesis were employed to create a reductive environment and quell reactive oxygen species, improving D-arabitol production. Nitrogen deficiency resulted in cell rescue and stress response mechanisms such as reactive oxygen species elimination and heat shock protein response. The identified differentially expressed proteins provide information to reveal the mechanisms of the cellular responses under nitrogen source perturbation, and also provide guidance to improve D-arabitol production in metabolic engineering or process optimization methodologies.

Thymosin ß4 reverses phenotypic polarization of glial cells and cognitive impairment via negative regulation of NF-κB signaling axis in APP/PS1 mice.

BACKGROUND: Thymosin ß4 (Tß4) is the most abundant member of the ß-thymosins and plays an important role in the control of actin polymerization in eukaryotic cells. While its effects in multiple organs and diseases are being widely investigated, the safety profile has been established in animals and humans, currently, little is known about its influence on Alzheimer's disease (AD) and the possible mechanisms. Thus, we aimed to evaluate the effects and mechanisms of Tß4 on glial polarization and cognitive performance in APP/PS1 transgenic mice. METHODS: Behavior tests were conducted to assess the learning and memory, anxiety and depression in APP/PS1 mice. Thioflavin S staining, Nissl staining, immunohistochemistry/immunofluorescence, ELISA, qRT-PCR, and immunoblotting were performed to explore Aß accumulation, phenotypic polarization of glial cells, neuronal loss and function, and TLR4/NF-κB axis in APP/PS1 mice. RESULTS: We demonstrated that Tß4 protein level elevated in all APP/PS1 mice. Over-expression of Tß4 alone alleviated AD-like phenotypes of APP/PS1 mice, showed less brain Aß accumulation and more Insulin-degrading enzyme (IDE), reversed phenotypic polarization of microglia and astrocyte to a healthy state, improved neuronal function and cognitive behavior performance, and accidentally displayed antidepressant-like effect. Besides, Tß4 could downregulate both TLR4/MyD88/NF-κB p65 and p52-dependent inflammatory pathways in the APP/PS1 mice. While combination drug of TLR4 antagonist TAK242 or NF-κB p65 inhibitor PDTC exerted no further effects. CONCLUSIONS: These results suggest that Tß4 may exert its function by regulating both classical and non-canonical NF-κB signaling and is restoring its function as a potential therapeutic target against AD.

Response to stress in biological disorders: Implications of stress granule assembly and function.

It is indispensable for cells to adapt and respond to environmental stresses, in order for organisms to survive. Stress granules (SGs) are condensed membrane-less organelles dynamically formed in the cytoplasm of eukaryotes cells to cope with diverse intracellular or extracellular stress factors, with features of liquid-liquid phase separation. They are composed of multiple constituents, including translationally stalled mRNAs, translation initiation factors, RNA-binding proteins and also non-RNA-binding proteins. SG formation is triggered by stress stimuli, viral infection and signal transduction, while aberrant assembly of SGs may contribute to tissue degenerative diseases. Recently, a growing body of evidence has emerged on SG response mechanisms for cells facing high temperatures, oxidative stress and osmotic stress. In this review, we aim to summarize factors affecting SGs assembly, present the impact of SGs on germ cell development and other biological processes. We particularly emphasize the significance of recently reported RNA modifications in SG stress responses. In parallel, we also review all current perspectives on the roles of SGs in male germ cells, with a particular focus on the dynamics of SG assembly.

B7 homolog 6 promotes the progression of cervical cancer.

B7 homolog 6 (B7-H6) was recently discovered to act as a co-stimulatory molecule. In particular, the expression of B7-H6 has been found to play an important biological role in several types of tumors. The aim of the present study was to determine the role of B7-H6 in cervical cancer. Immunohistochemistry was used to analyze the expression levels of B7-H6 in cervical precancerous and cancerous tissues. Furthermore, the expression of B7-H6 was knocked down in HeLa cells using short hairpin RNA and the effects of B7-H6 on HeLa cell proliferation, migration and invasion were determined using Cell Counting Kit-8, colony formation, wound healing and Transwell invasion assays, respectively. In addition, flow cytometry was used to analyze the levels of cell apoptosis and the cell cycle distribution. The results of the immunohistochemical staining revealed that the expression levels of B7-H6 were upregulated in cervical lesions. Furthermore, the expression levels of B7-H6 were positively associated with the clinical stage of the cervical lesions. B7-H6 knockdown suppressed the invasive, migratory and proliferative abilities of HeLa cells, and promoted G1 cell cycle arrest and apoptosis. In conclusion, the findings of the present study suggested that B7-H6 may serve as a novel oncogene and may hold promise as a potential therapeutic target for cervical cancer.

TREM2 overexpression rescues cognitive deficits in APP/PS1 transgenic mice by reducing neuroinflammation via the JAK/STAT/SOCS signaling pathway.

Overactivated microglia and neuroinflammation are considered to play a crucial role in the progression of Alzheimer's disease (AD). Triggering receptor expressed on myeloid cells-2 (TREM2), a type I transmembrane receptor, expressed uniquely by microglia in the brain, is involved in the neuroinflammatory responses of AD. In this study, to further explore the precise effects of TREM2 on neuroinflammation and the underlying mechanisms in AD, we employed a lentiviral-mediated strategy to overexpress TREM2 in the brain of APPswe/PS1dE9 (APP/PS1) transgenic mice and cultured BV2 cells. Our results showed that TREM2 overexpression rescued cognitive deficits, decreased ß-amyloid (Aß) plaques deposition, reduced synaptic and neuronal loss, as well as ameliorated neuroinflammation. The mechanistic study revealed that these protective effects were likely attributed to inhibition of neuroinflammatory responses through the JAK/STAT/SOCS signaling pathway and subsequent attenuation of pro-inflammatory cytokines. Furthermore, suppression of neuroinflammation might be ascribed to activation of the M2 microglia, as the levels of M2 phenotype markers Arg-1, IL-10 and Ym1 were markedly increased. Similarly, overexpression of TREM2 in BV2 cells also promoted M2 polarization and led to the alleviation of M1 microglial inflammatory responses through JAK/STAT/SOCS signaling pathway, suggesting that TREM2 is an important factor in shifting the microglia from M1 to M2 phenotype. Taken together, our results further provide insights into the role of TREM2 in AD pathogenesis and highlight TREM2 as a potential target against AD.

LINC01133 and LINC01243 are positively correlated with endometrial carcinoma pathogenesis.

PURPOSE: To characterize the role of two long non-coding RNAs (lncRNAs), LINC01133 and LINC01243, in endometrial carcinoma (EC) pathogenesis. LINC01133 is an lncRNA that has been implicated in many cancers, and LINC01243 is a newly identified lncRNA identified from the NCBI GEO database. METHODS: We studied the effect of LINC01133 and LINC01243 on EC malignancy using siRNA knockdown and real-time quantitative polymerase chain reaction (RT-qPCR), flow cytometry, Annexin V-FITC/propidium iodide double staining, Transwell, and scratch invasion assays in two EC cell lines (Ishikawa and HEC-1-A cells). RESULTS: We first confirmed the partial knockdown of both LINC01133 and LINC01243 expression in Ishikawa and HEC-1-A cells using RT-qPCR. Following confirmation of lncRNA knockdown, we assessed the effect of knockdown on EC malignancy. We observed reduced EC cell proliferation using the CCK-8 assay, as well as cell cycle arrest and increased apoptosis in both EC cell lines. Furthermore, Transwell and scratch invasion assays revealed decreased migration and invasion of the two EC cell lines, respectively. CONCLUSION: We demonstrated that LINC01133 and LINC01243 expression are associated with EC development and progression. Our findings suggest a potential role for these lncRNAs as novel EC biomarkers.

Roles of AMP-Activated Protein Kinase (AMPK) in Mammalian Reproduction.

Reproduction is an energy demanding function and only take place in case of sufficient available energy status in mammals. Metabolic diseases such as anorexia nervosa are clinically associated with reduced fertility. AMP-activated protein kinase (AMPK), as a major regulator of cellular energy homeostasis, is activated in limited energy reserves to ensure the orderly progress of various physiological activities. In recent years, mounting evidence shows that AMPK is involved in the regulation of reproductive function through multiple mechanisms. AMPK is likely to be a metabolic sensor integrating central and peripheral signals. In this review, we aim to explore the preclinical studies published in the last decade that investigate the role of AMP-activated protein kinase in the reproductive field, and its role as a target for drug therapy of reproductive system-related diseases. We also emphasized the emerging roles of AMPK in transcriptional regulation of reproduction processes and metabolisms, which are tightly related to the energy state and fertility of an organism.

The Vehicle Determines the Destination: The Significance of Seminal Plasma Factors for Male Fertility.

Of all human infertility cases, up to 50% show contributing factors leading to defects in the male reproductive physiology. Seminal plasma (SP) is the biological fluid derived from the male accessory sex gland which carries spermatozoa passing throughout the male and female reproductive tract during ejaculation. It contains a complicated set of heterogeneous molecular structures, including proteins, cell-free nucleic acid (DNA, microRNA and LncRNA), and small-molecule metabolites as well as inorganic chemicals (ions). For a long time, the substantial significance of seminal plasma factors' functions has been underestimated, which is restricted to spermatozoa transport and protection. Notably, significant advancements have been made in dissecting seminal plasma components, revealing new insights into multiple aspects of sperm function, as well as fertilization and pregnancy outcomes in recent years. In this review, we summarize the state-of-art discoveries regarding SP compositions and their implications in male fertility, particularly describing the novel understanding of seminal plasma components and related modifications using "omics" approaches and mainly focusing on proteome and RNA-seq data in the latest decade. Meanwhile, we highlighted the proposed mechanism of the regulation of SP molecules on immunomodulation in the female reproductive tract. Moreover, we also discussed the proteins investigated as non-invasive diagnosis biomarkers for male infertility in the clinic.

The Factors and Pathways Regulating the Activation of Mammalian Primordial Follicles in vivo.

Mammalian ovaries consist of follicles as basic functional units. Each follicle comprised an innermost oocyte and several surrounding flattened granulosa cells. Unlike males, according to the initial size of the primordial follicle pool and the rate of its activation and depletion, a female's reproductive life has been determined early in life. Primordial follicles, once activated, will get into an irreversible process of development. Most follicles undergo atretic degeneration, and only a few of them could mature and ovulate. Although there are a lot of researches contributing to exploring the activation of primordial follicles, little is known about its underlying mechanisms. Thus, in this review, we collected the latest papers and summarized the signaling pathways as well as some factors involved in the activation of primordial follicles, hoping to lead to a more profound understanding of the cellular and molecular mechanisms of primordial follicle activation.

Tanshinone IIA attenuates neuroinflammation via inhibiting RAGE/NF-κB signaling pathway in vivo and in vitro.

BACKGROUND: Glial activation and neuroinflammation play a crucial role in the pathogenesis and development of Alzheimer's disease (AD). The receptor for advanced glycation end products (RAGE)-mediated signaling pathway is related to amyloid beta (Aß)-induced neuroinflammation. This study aimed to investigate the neuroprotective effects of tanshinone IIA (tan IIA), a natural product isolated from traditional Chinese herbal Salvia miltiorrhiza Bunge, against Aß-induced neuroinflammation, cognitive impairment, and neurotoxicity as well as the underlying mechanisms in vivo and in vitro. METHODS: Open-field test, Y-maze test, and Morris water maze test were conducted to assess the cognitive function in APP/PS1 mice. Immunohistochemistry, immunofluorescence, thioflavin S (Th-S) staining, enzyme-linked immunosorbent assay (ELISA), real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and western blotting were performed to explore Aß deposition, synaptic and neuronal loss, microglial and astrocytic activation, RAGE-dependent signaling, and the production of pro-inflammatory cytokines in APP/PS1 mice and cultured BV2 and U87 cells. RESULTS: Tan IIA treatment prevented spatial learning and memory deficits in APP/PS1 mice. Additionally, tan IIA attenuated Aß accumulation, synapse-associated proteins (Syn and PSD-95) and neuronal loss, as well as peri-plaque microgliosis and astrocytosis in the cortex and hippocampus of APP/PS1 mice. Furthermore, tan IIA significantly suppressed RAGE/nuclear factor-κB (NF-κB) signaling pathway and the production of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß) in APP/PS1 mice and cultured BV2 and U87 cells. CONCLUSIONS: Taken together, the present results indicated that tan IIA improves cognitive decline and neuroinflammation partly via inhibiting RAGE/NF-κB signaling pathway in vivo and in vitro. Thus, tan IIA might be a promising therapeutic drug for halting and preventing AD progression.