The cover art, created by Yan Zhang and Nan Luo, draws inspiration from the thematic contrasts depicted in the Ne Zha film. The red "Demon Pill," marked with an "X," symbolizes the activity of Xdh enzyme that has been known since 1902, which converts xanthine into the disease-causing compound, uric acid. In contrast, the blue "Spirit Pearl," labeled with a "Y," represents the newly identified function of an Xdh homologue that reduces uric acid to produce yanthine. The biochemistry of this reductive uric acid degradation pathway, along with its potential application in developing engineered probiotics for treating gout and hyperuricemia can be found in loaf031.
Based on current research in neuroscience, systems biology, and clinical medicine, we propose a novel theoretical concept: the “Homeostasis Threshold Deviation (HTD) Theory of Wide-Range Oscillatory Physiological Parameters”. HTD posits that, when the external environment undergoes significant and sustained changes or when visceral signals exhibit long-term abnormalities, central nervous system (CNS) network topologies reset first, establishing a new range of physiological setpoints before peripheral organs adapt. This central reset leads to a deviation in the topological information network structure of central nuclei, resulting in the displacement of the original range of physiological parameters that become challenging to restore. This deviation further triggers passive adaption in peripheral organs, ultimately causing complex multi-organ diseases and severe organ dysfunction. By targeting the CNS threshold shift, HTD provides a novel path for precision medicine. That is, restoring original homeostatic setpoints could enable both early prevention and durable treatment of hypertension and metabolic disorders, achieving a “two birds with one stone” effect or even partially curing related conditions.
Vitellogenins (VITs), the lipoprotein precursors of yolk proteins in Caenorhabditis elegans, are expressed in the intestine, secreted into the pseudocoelom, and ultimately transported into oocytes. However, the mechanism by which VITs are secreted out of the intestine remains unclear. In this study, a candidate RNA interference (RNAi) screen suggested that both the conventional secretion pathway and recycling endosomes (REs) are essential for VIT secretion. In addition to expected conventional secretion, VITs were also found to be synthesized in the intestinal rough endoplasmic reticulum (ER) and then transported to the Golgi apparatus. VIT-2::GFP accumulated in enlarged REs upon depletion of receptor-mediated endocytosis 1 (RME-1), a key protein that facilitates endocytic recycling. Moreover, the number of VIT-2::GFP-containing REs decreased upon inhibition of either ER-to-Golgi trafficking, trans-Golgi-to-endosome trafficking, or endocytosis. These findings suggested that REs are required for intestinal secretion of both newly-synthesized VITs and yolk proteins endocytosed from the pseudocoelom. Moreover, RME-1 was found at the periphery of vitellogenin-containing vesicles (VVs), and this required RAB-10, the upstream regulator of RME-1 in endocytic recycling. RAB-10 was additionally required for the trafficking of VV from the apical/luminal side to the basal/pseudocoelomic side of the intestine. Together, these results identify REs as an intermediate compartment for the secretion of VIT/yolk proteins out of the intestine, suggesting a conserved role for endocytic recycling in the secretion of lipoproteins in mammals, particularly those assembled by apoB-100, a mammalian homolog of VITs.
Junjie Fei, Shuhan Yu, Mingzhe Xu, Yang Liu, Guoqiang Wang, Xueqing Li, Xinyue Yu, Yifan Zhang, Wenhua Zhang, Yang Wang, Mengmeng Niu, Yujun Zhang, Yang Cao, Zhi-Xiong Jim Xiao, Yong Yi·16 Jul 2025
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Energy stress triggers the activation of AMP-activated protein kinase (AMPK) via phosphorylation mediated by liver kinase B1 (LKB1). A pivotal step during this process is the translocation of protein kinase C zeta (PKCζ) to the nucleus, where it facilitates the phosphorylation and subsequent nuclear export of LKB1 to the cytosol. However, the mechanism(s) by which PKCζ translocates to the nucleus remains elusive. Here we demonstrate that energy stress, including glucose starvation or metformin treatment, elevates cellular reactive oxygen species (ROS) that promotes PKCζ nuclear import to promote LKB1 cytoplasmic translocation and subsequent AMPK activation both in vitro and in vivo. Mechanistically, we show that energy stress-induced ROS promotes the S-glutathionylation of PKCζ at Cys48, and enhances PKCζ interaction with karyopherin subunit alpha 2 (KPNA2), a key nuclear transport protein, thereby facilitating PKCζ nuclear translocation and the phosphorylation of LKB1 at Ser428, consequently leading to LKB1 cytoplasmic translocation and activation of AMPK. Importantly, the reduction of ROS significantly augments the high-fat diet-induced lipid accumulation in mouse liver and reduces the hypoglycemic efficacy of metformin in an AMPK-dependent manner. Together, these results establish a critical role of energy stress-induced PKCζ S-glutathionylation in LKB1 cytoplasmic translocation, highlighting the activation of the ROS−PKCζ−KPNA2−LKB1 axis as a vital mechanism for AMPK activation in response to energy stress.
Li-Jie Yang, Qiu-kai Tang, Lei Wang, Yan-Jue Song, Zhen-Yu Xu, Xi-Ni Ma, Yang Liu, Shu-Wen Qian, Qi-Qun Tang, Yan Tang·12 Jul 2025
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Brown adipose tissue (BAT) orchestrates interorgan crosstalk through secreted mediators, including proteins, lipids, and exosomal microRNAs (miRNAs). However, the precise molecular identities and functional contributions of these mediators remain elusive. In this study, we isolated exosomes from BAT and conducted miRNA sequencing, identifying miR-206-3p as a previously unrecognized exosomal miRNA with the potential to alleviate metabolic dysfunction-associated fatty liver disease (MAFLD). In vivo, adipose-specific knockout of miR-206-3p in mice exacerbated obesity-induced MAFLD, glucose intolerance, insulin resistance, and impaired energy expenditure. Mechanistically, BAT-derived miR-206-3p is selectively packaged into exosomes via a BAT-specific “exo motif” and transported to the liver, where it targets the 3’ untranslated regions (3’-UTRs) of glucose-6-phosphate dehydrogenase (G6pd) and transketolase (Tkt), key enzymes in the pentose phosphate pathway (PPP). The PPP generates nicotinamide adenine dinucleotide phosphate (NADPH) and ribulose-5-phosphate (Ru-5-P) to support lipogenesis and nucleotide synthesis. miR-206-3p modulates these processes by decreasing NADPH production to inhibit hepatic lipid synthesis and increasing Ru-5-P availability to promote cell proliferation. Notably, obese individuals exhibit reduced serum exosomal miR-206-3p alongside upregulated hepatic PPP enzymes. Our study reveals that BAT-derived exosomal miR-206-3p serves as a mediator of BAT−liver crosstalk, suggesting its potential as a therapeutic target for obesity-related disorders, particularly MAFLD.
Uric acid (UA) is a key intermediate in purine degradation across diverse organisms, while its accumulation in humans leads to inflammation and gout disease. Aerobic organisms degrade UA via a well-known “oxidative pathway” involving dearomatization of the purine core catalyzed by UA oxidases or dehydrogenases. The ability to degrade UA is also widespread in anaerobic bacteria, including gut bacteria, although the mechanisms are incompletely understood. Here, we report the biochemical characterization of a recently identified UA degradation gene cluster from Escherichia coli, and show that it encodes a “reductive pathway” for UA degradation. In this pathway, UA is first reduced to 2,8-dioxopurine (yanthine) by a xanthine dehydrogenase homolog (XdhD), followed by dearomatization of the purine core catalyzed by a flavin-dependent reductase (YgfK). Stepwise cleavage of the pyrimidine and imidazole rings forms 2,3-diureidopropionate, and stepwise cleavage of the 2- and 3-ureido groups then forms 2,3-diaminopropionate, which is cleaved by a pyridoxal 5’-phosphate-dependent lyase (YgeX) to pyruvate and ammonia. The detection of yanthine in clinical serum samples from healthy individuals and significantly higher levels from gout patients suggests that yanthine is a physiologically relevant circulating metabolite. A probiotic E. coli Nissle strain was engineered for constitutive overexpression of the gene cluster, and oral administration in a uricase-knockout hyperuricemic mouse model significantly reduced the serum UA level and alleviated associated kidney injury, suggesting a potential route towards uricolytic probiotics.
