Brain-derived serotonin (5-HT) is a key neurotransmitter that regulates diverse central and peripheral physiological processes, including endocrine function, mood, and circadian rhythms. Patients with anxiety and depression often exhibit reduced brain 5-HT levels, which contribute significantly to female infertility. However, the role of brain-derived 5-HT in maintaining ovarian reserve function remains unclear. We generated brain-specific Tph2 conditional knockout (Tph2-CKO) mice lacking 5-HT and observed reduced follicle numbers and anti-Müllerian hormone (AMH) levels, indicating diminished ovarian reserve (DOR). Mechanistically, Brain-derived 5-HT deficiency suppressed ovarian mTOR signaling, triggering excessive autophagy, mitochondrial dysfunction, and apoptosis. In the hypothalamus, reduced central 5-HT levels downregulated 5-HT receptor 7 (HTR7)-cAMP/PKA signaling, disrupted circadian rhythms, and decreased gonadotropin-releasing hormone (GnRH) expression, impairing hypothalamic-pituitary-ovarian (HPO) axis function. Ovarian follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) levels decreased, ultimately leading to DOR. Thus, 5-HT deficiency in the dorsal raphe nucleus disrupts the HPO axis via HTR7, leading to DOR.

Green tea, a commonly consumed beverage worldwide, is extensively used as dietary supplements for cancer prevention. However, the interaction between green tea and paclitaxel is still unknown. This study aimed to systematically investigate the herb-drug interaction of green tea consumption on the pharmacodynamics and pharmacokinetics of paclitaxel. The ATP assay results indicated that green tea extract (GTE) significantly enhanced the cytotoxicity of paclitaxel in both human and murine breast cancer cells. Further, the 4T-1 tumor model testified that daily green tea consumption could improve the therapeutic effects of paclitaxel on breast carcinoma. The pharmacokinetic profiles revealed that in the group with short-term green tea consumption (0.5 h), there was a more than 55.87% increase in the maximum plasma concentration (C max) of paclitaxel and a 38.49% increase in the area under the plasma concentration curve (AUC). In the long-term green tea consumption group (2 weeks), there was a 23.80% increase in the C max of paclitaxel and a 28.29% increase in the AUC. Moreover, long-term green tea consumption significantly reduced hepatic microsomal protein level. Taken together, green tea consumption enhances the anticancer efficacy and increases the pharmacokinetic profile of paclitaxel, which provides information to study the interaction between herbs and chemotherapy.

Fibroblast activation protein(FAP)is overexpressed in cancer-associated fibroblasts across various cancer types.Numerous radi-olabeled FAP inhibitors(FAPIs)(Fig.S1A)currently under clinical investigation have shown remarkable potential in cancer thera-nostics.

Radioactive prostate-specific membrane antigen (PSMA)-targeting agents are clinically useful for the diagnosis and treatment of patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). Neuroendocrine-differentiated prostate cancer (NEPC), a highly aggressive subtype that is strongly associated with a poor clinical prognosis, may present with reduced PSMA expression and evade detection with PSMA-targeted agents. Several studies have shown elevated uptake of somatostatin receptor 2 (SSTR2) ligands in PSMA-negative NEPC. By combining a SSTR2-targeting peptide, JR11, with previously reported PSMA-targeting ligands, P16-093 and P17-087, [68Ga]Ga-1 and [68Ga]Ga/[177Lu]Lu-2 were designed and synthesized. The cell uptake of [68Ga]Ga-1 was comparable to [68Ga]Ga-P16-093 in PSMA-positive cell lines, while [68Ga]Ga-1 and [68Ga]Ga-2 showed a positive but slightly lower uptake than [68Ga]Ga-DOTA-TATE in SSTR2-positive cell lines. In vivo studies in SSTR2+ or PSMA+ tumor-bearing mice demonstrated that [68Ga]Ga-1 and [68Ga]Ga/[177Lu]Lu-2 showed positive uptake for both SSTR2+ and PSMA+ tumors. These dual-targeting radiotracers are potentially valuable for the diagnosis and radioligand therapy of NEPC.

Prostate-specific membrane antigen (PSMA) overexpressed in prostate cancer cells can serve as a target for imaging and radioligand therapy (RLT). Previously, [68Ga]Ga-P16-093, containing a Ga(III) chelator, N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC), displayed excellent PSMA-targeting properties and showed a high tumor uptake and retention useful for diagnosis in prostate cancer patients. Recently, [177Lu]Lu-PSMA-617 has been approved by the U.S. food and drug administration (FDA) for the treatment of prostate cancer patients. Derivatives of PSMA-093 using AAZTA (6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid), as the chelator, were designed as alternative agents forming complexes with both diagnostic and therapeutic radiometals, such as gallium-68 (log K = 22.18) or lutetium-177 (log K = 21.85). The aim of this study is to evaluate AAZTA-Gly-O-(methylcarboxy)-Tyr-Phe-Lys-NH-CO-NH-Glu (designated as AZ-093, 1) leading to a gallium-68/lutetium-177 theranostic pair as potential PSMA targeting agents. Synthesis of the desired precursor, AZ-093, 1, was effectively accomplished. Labeling with either [68Ga]GaCl3 or [177Lu]LuCl3 in a sodium acetate buffer solution (pH 4-5) at 50 °C in 5 to 15 min produced either [68Ga]Ga-1 or [177Lu]Lu-1 with high yields and excellent radiochemical purities. Results of in vitro binding studies, cell uptake, and retention (using PSMA-positive prostate carcinoma cells line, 22Rv1-FOLH1-oe) were comparable to that of [68Ga]Ga-P16-093 and [177Lu]Lu-PSMA-617, respectively. Specific cellular uptake was determined with or without the competitive blocking agent (2 μM of "cold" PSMA-11). Cellular binding and internalization showed a time-dependent increase over 2 h at 37 °C in the PSMA-positive cells. The cell uptakes were completely blocked by the "cold" PSMA-11 suggesting that they are competing for the same PSMA binding sites. In the mouse model with implanted PSMA-positive tumor cells, both [68Ga]Ga-1 and [177Lu]Lu-1 displayed excellent uptake and retention in the tumor. Results indicate that [68Ga]Ga/[177Lu]Lu-1 (68Ga]Ga/[177Lu]Lu-AZ-093) is potentially useful as PSMA-targeting agent for both diagnosis and radiotherapy of prostate cancer.

Objective: Hydroxychloroquine (HCQ) is an essential drug in the treatment of systemic lupus erythematosus (SLE). This study aimed to detect the concentrations of HCQ and its metabolites from peripheral blood of SLE patients and to investigate the relationship between those concentrations and SLE disease activity.Methods: 176 SLE patients treated with HCQ were enrolled in this study. The concentrations of HCQ and its metabolites in their peripheral blood were measured by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Patients' disease activity was evaluated with the systemic lupus erythematosus disease activity index (SLEDAI). The variables between different concentrations or treatments were statistically analyzed. Linear regression was employed to explore relationships between the concentrations of HCQ and its metabolites with the disease activity.Results: The SLEDAI was lower in patients with higher concentrations of HCQ, desethylhydroxychloroquine (DHCQ), and desethylchloroquine (DCQ) (P = 0.024, P = 0.018, and P = 0.003, respectively). There were no significant differences in SLEDAI and the concentrations of HCQ and its metabolites among groups with different treatments (P > 0.05). After adjusting age, gender, disease duration, HCQ dose adjusted to actual body weight, and glucocorticoid (GC) dose, the SLEDAI was negatively correlated with the concentrations of HCQ, DHCQ, DCQ and bisdesethylchloroquine (BDCQ) (P = 0.007, P = 0.011, P = 0.029, and P = 0.008, respectively). After grouping analysis, in patients treated with HCQ and GC, the SLEDAI was negatively correlated with concentrations of HCQ, DHCQ and BDCQ (P = 0.011, P = 0.035, and P = 0.036, respectively). Conclusions: The concentrations of HCQ and metabolites were correlated with the SLE disease activity after adjusting possible confounding factors, indicating that HCQ and its metabolites might play certain immunoregulatory roles in SLE treatment. Moreover, GC might have a synergistic effect with HCQ. It is helpful in clinical management and follow-up to monitor the concentrations of HCQ and its metabolites in SLE patients.

Photodynamic therapy (PDT) and chemodynamic therapy (CDT) are both promising cancer treatments to inhibit tumor cells by generating highly cytotoxic reactive oxygen species (ROS). Herein, we report a novel tumor microenvironment (TME) stimulus-responsive water-soluble glycosylated photosensitizer (BT-TPE@Fe-Lac), which can serve as a high-efficiency antitumor agent by combining PDT and CDT, based on the coordination of Fe3+ with lactosyl bis(2-pyridylmethyl)amine and an AIE luminogen (benzothiazole-hydroxytetraphenylethene, BT-TPE). BT-TPE@Fe-Lac is stable under physiological conditions and selectively targets HepG2 cells via asialoglycoprotein receptor (ASGPR)-mediated endocytosis. It rapidly dissociates into AIE-active BT-TPE molecules and a lactosyl ferric(iii) complex in the acidic lysosomes of cancer cells. Upon exposure to light, BT-TPE produces O2(center dot)- radicals for type I PDT. The ferric(iii) complex is reduced to an Fe(ii) complex upon depletion of glutathione, which primes the breakdown of endogenous H2O2 within the tumor microenvironment, thus generating highly toxic (OH)-O-center dot for enhanced CDT. Compared with the monotherapy of PDT or CDT, BT-TPE@Fe-Lac can significantly increase the intracellular ROS levels to induce more tumor cell death under low drug doses and hypoxia-dependent conditions. This strategy leverages the unique properties of the TME to optimize therapeutic outcomes, offering a promising approach for the TME-responsive nanoplatform in advanced cancer therapy.

Fibroblast activation protein (FAP), which is overexpressed in cancer-associated fibroblasts (CAFs), represents a promising target for cancer diagnosis and therapy. Hypoxia is a common feature of solid tumors. A bivalent agent, DOTA-NI-FAPI-04 (1), was developed by incorporating hypoxia-sensitive nitroimidazole (NI) into the FAP-targeting agent FAPI-04. Compound 1 exhibited a strong FAP binding affinity with an IC50 of 7.44 nM. Radiolabeled [68Ga]Ga-1 and [177Lu]Lu-1 demonstrated enhanced in vitro cell uptake. In vivo positron emission tomography/computed tomography (PET/CT) imaging showed that [68Ga]Ga-1 displayed significantly higher specific uptake and retention in U87MG tumor-bearing mice compared to [68Ga]Ga-FAPI-04 (SUVavg: 7.87 vs 1.99% ID/mL at 120 min). Biodistribution studies confirmed superior tumor uptake of [68Ga]Ga-1 (48.15 vs 5.72% ID/g at 120 min). Similarly, [177Lu]Lu-1 exhibited higher tumor uptake than [177Lu]Lu-FAPI-04 (50.75 vs 20.48% ID/g at 120 min). These preliminary results suggest that a nitroimidazole-containing bivalent-targeting agent, [68Ga]Ga/[177Lu]Lu-1, is a promising candidate for tumor theranostics.

PurposeThis study aimed to evaluate the use of serum neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in the diagnosis of Alzheimer’s disease (AD) and the differential diagnosis between AD and mild cognitive impairment (MCI).MethodsFrom September 2021 to October 2022, we collected venous blood from patients and healthy individuals who visited our hospital’s Neurology Department, and we isolated serum to detect NfL and GFAP using direct chemiluminescence. The results were analyzed using one-way analysis of variance (ANOVA) analysis and receiver operating characteristic (ROC) curves.ResultsPairwise comparisons among the three groups showed that compared with the health checkup (HC) group, serum NfL and GFAP were increased in both AD and MCI (PNfL < 0.05, PGFAP < 0.01). There were significant differences in GFAP between MCI and AD groups, and the level in AD group was higher (p < 0.01), while there was no difference in NfL. Both serum NfL and serum GFAP levels can independently diagnose AD (p < 0.01). The ROC curve showed that GFAP had a higher diagnostic efficacy, with an area under the ROC curve (AUC) of 0.928. The cut-off values of the two serum markers for the diagnosis of AD were NfL > 40.09 pg./mL and GFAP >31.40 pg./mL. Sensitivity and specificity for NfL in the diagnosis of AD were 59.6 and 76.2%, respectively, and for GFAP, they were 90.4 and 82.1%, respectively. The combined diagnosis of GFAP and NfL improved the diagnostic efficiency (AUC = 0.931, sensitivity = 78.8%, specificity = 92.3%). The cut-off value of GFAP for the differential diagnosis of MCI and AD was 46.05 pg./mL.ConclusionBoth serum NfL and serum GFAP can be used as biomarkers for the diagnosis of AD. Serum GFAP has better diagnostic efficacy and can distinguish AD from MCI. A combined diagnosis can improve diagnostic specificity.

Objective: The aim of this research is to synthesize and evaluate beta-amyloid (A beta) binding probes for early diagnosis of Alzheimer's disease (AD). Methods: We designed and synthesized two new fluorine tag Indanone derivatives (compounds a and b), and then based on the platform of ultra-high-performance liquid chromatography-mass spectrometry for its affinity with beta-amyloid (A beta) protein determination, and use of compounds a and b solution as dyes for AD brain tissue staining in vitro. To evaluate the lipid solubility and stability of the drug, the lipid-water partition coefficient was determined using n-octanol as the lipid phase, and the stability of compound b was tested in vitro to mimic the in vivo environment. Results: Both compounds a and b exhibit high affinity for binding to A beta. The Kd values of compound a for A beta 1-40 and A beta 1-42 were found to be 467.40 +/- 63.26, and 227.57 +/- 19.08 nmol/L, respectively. Similarly, the Kd values of compound b for A beta 1-40 and A beta 1-42 were 438.13 +/- 26.77 and 167.27 +/- 23.70 nmol/L, respectively. In the staining experiment of human brain slices of AD, both compounds a and b were found to bind to A beta plaques, and their staining effect was stronger than positive control (0.1 % ThS). In the lipid-water partition coefficient experiment, compound a and compound b exhibited logP values of 0.84 and 1.85, respectively, indicating good lipid solubility. In the in vitro stability experiment, compound b exhibited a concentration of 74.79 %, 80.47 %, and 70.00 % after incubation in liver, brain homogenate, and blood, respectively. Conclusion: We have successfully designed and synthesized two probes labeled with fluoride that can be used for diagnosing AD. These probes have a high affinity for A beta protein and good lipid solubility. As A contrast agent based on A beta protein, compound b showed greater potential than compound a.

BackgroundThe primary aim of this study is to investigate the correlation between serum levels of fibrinogen-to-prealbumin ratio (FPR) and C-reactive protein-to-prealbumin ratio (CPR) and prognostic outcomes among patients with severe fever with thrombocytopenia syndrome (SFTS). SFTS, characterized by elevated mortality rates, represents a substantial public health challenge as an emerging infectious disease.MethodsThe study included 159 patients with SFTS. Clinical and laboratory data were compared between the survival and death groups. Univariate and multivariate logistic regression analysis were utilized to identify independent risk factors for mortality. The predictive efficacy of FPR and CPR was evaluated using receiver operating characteristic (ROC) curve. Survival analysis was conducted using the Kaplan–Meier curve and the log-rank test was employed for comparison.ResultsThe death group exhibited significantly elevated levels of FPR and CPR compared to the survival group (P < 0.05). Multivariate logistic regression analysis confirmed that both FPR and CPR independently correlated with a poorer prognosis among patients with SFTS. The ROC curve analysis indicated that FPR and CPR had superior predictive capabilities compared to C-reactive protein and fibrinogen. Kaplan–Meier survival analysis demonstrated that patients with SFTS who have FPR > 0.045 (log-rank test; χ2 = 17.370, P < 0.001) or CPR > 0.05 (log-rank test; χ2 = 19.442, P < 0.001) experienced significantly lower survival rates within a 30-day follow-up period.ConclusionElevated levels of FPR and CPR serve as distinct risk factors for mortality among patients with SFTS, indicating their potential to predict an unfavorable prognosis in these patients.

Background: Alzheimer's disease (AD) is one of the most common causes of dementia, affecting many old people. Objectives: By designing and synthesizing intracerebral imaging probes, we try to provide a new solution for early diagnosis of AD. Methods: We designed and synthesized bis-iodine-labeled curcumin, and verified its performance through in vivo and in vitro experiments. Results: In this study, bis-iodine-labeled curcumin (7, BICUR) was synthesized. In the in vitro mass spectrum binding assay, Kd values of BICUR with Aβ1-40 and Aβ1-42 aggregates were 46.29 nM and 64.29 nM, respectively. Aβ plaques in AD brain adjacent sections were positively stained by BICUR, which was similar to some other curcumin derivatives. The LogP value of BICUR was 1.45. In the biodistribution experiment, BICUR showed the highest initial brain uptake (5.87% compared with the blood concentration) two minutes after the tail vein injection and rapid clearance from the mouse brain. In the acute toxicity experiment, BICUR showed low toxicity, and the LD50 was > 100 mg/kg. Moreover, BICUR showed a high stability in vitro (86.68% unchanged BICUR after incubation for 120 min in mouse brain homogenate). Besides, BICUR produced an enhanced CT imaging effect that could be sensitively detected in vitro, but it also showed an obvious differentiation from surrounding tissues after intracerebral injection. Conclusion: All results suggested that BICUR could probably act as a targeted CT imaging agent for Aβ plaques in the brain.

Fibroblast activation protein (FAP) is selectively expressed in tumors and highly important for maintaining the microenvironment in malignant tumors. Radioisotope-labeled FAP inhibitors (FAPIs) were proven to be useful for diagnosis and radionuclide therapy of cancer and are under active clinical investigations. Ga-HBED complex displays a higher in vivo stability constant (log K-GaL: 38.5), compared to that of Ga-DOTA (log K-GaL: 21.3). Such advantage in stability constant suggests that it may be useful for development of alternative FAPI imaging agents. In this study, previously reported [Ga-68]Ga-DOTA-FAPI-02 and-04 were converted to the corresponding [Ga-68]Ga-HBED-CC-FAPI-02 and-04 derivatives ([Ga-68]Ga-4, [Ga-68]Ga-5, [Ga-68]Ga-6, and [Ga-68]Ga-7). It was found that substituting the DOTA chelating group with HBED-CC led to several unique and desirable tumor-targeting properties: (1) robust, fast, and high yield labeling-readily adaptable to a kit formulation; (2) high stabilities in vitro; (3) excellent FAP binding affinities (IC50 ranging between 4 and 7 nM) and improved cell uptake and retention (in HT1080 (FAP+) cells); and (4) excellent selective in vivo tumor uptake in nude mice bearing U87MG tumor. It appeared that Ga(III) chelation with HBED-CC improved the in vivo kinetics favoring higher tumor uptake and retention compared to the corresponding Ga-DOTA complex. Out of the four tested ligands the new [Ga-68]Ga-HBED-CC-FAPI dimer, [Ga-68]Ga-6, displayed the best tumor localization properties, and further studies are warranted to demonstrate that it is an alternative FAP imaging agent for cancer patients.

The ongoing coronavirus disease 2019 (COVID-19) pandemic represents one of the most exigent threats of our lifetime to global public health and economy. As part of the pandemic, from January 10 to March 10, 2020, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) began to spread in Hefei (Anhui Province, China) with a total of 174 confirmed cases of COVID-19. During this period, we were able to gather critical information on the transmission and evolution of pathogens through genomic surveillance. Particularly, the objective of our study was to track putative variants of SARS-CoV-2 circulating in Hefei for the first time and contribute to the global effort toward elucidating the molecular epidemic profile of the virus. Patients who showed symptoms of COVID-19 were routinely tested for SARS-CoV-2 infections via RT-PCR at the First Affiliated Hospital of Anhui Medical University. Whole-genome sequencing was performed on 97 clinical samples collected from 29 confirmed COVID-19 patients. As a result, we identified a local novel single-nucleotide polymorphism site (10,380) harboring a G → T mutation (Gly → Val) in Hefei. Further phylogenetic network analysis with all the sequences of SARS-CoV-2 deposited in GenBank collected in East and Southeast Asia revealed a local subtype of S-type SARS-CoV-2 (a1) harboring a C → T synonymous mutation (Leu) at position 18,060 of ORF1b, likely representing a local SARS-CoV-2 mutation site that is obviously concentrated in Hefei and the Yangtze River Delta region. Moreover, clinical investigation on the inflammatory cytokine profile of the patients suggested that mutations at positions 18,060 (the shared variable site of subtype a1) and 28,253(harboring a C → T synonymous mutation, Phe) were associated with milder immune responses in the patients.

In order to realize the early diagnosis of Alzheimer's disease (AD), we designed and synthesized a series of multi-fluorine labeled indanone derivatives based on indanone which could target β-amyloid (Aβ). Through the in vitro staining experiment and affinity experiment, we selected 7d out, and then evaluated it through other in vivo and in vitro experiments. The staining of AD human brain adjacent sections revealed that compound 7d could bind to Aβ plaques with high affinity. In the in vitro binding assay, 7d showed a balanced affinity with Aβ1-40 (Kd = 367 ± 13) and Aβ1-42 (Kd = 384 ± 56). Also, 7d exhibited a low toxicity (LD50 > 50 mg/kg) and an excellent ability to pass through the blood-brain barrier (Log p = 3.87). The biodistribution experiment in mice showed that 7d reached the highest brain uptake after 1 h of tail vein injection and cleared after 24 h. A low concentration of 7d (1.875 mg/ml) showed a strong imaging ability (19F-weighted mode), and the imaging capability increased with the increasing of concentration. All the results showed that 7d could provide a feasible solution for the early diagnosis of AD under non-radioactive condition.