Relaxin-3 (RLN3) and its native receptor, relaxin family peptide 3 receptor (RXFP3), constitute a newly identified neuropeptide system enriched in mammalian brain. The distribution of RLN3/RXFP3 networks in rat brain and recent experimental studies suggest a role for this system in modulation of arousal, stress, metabolism, and cognition. In order to facilitate exploration of the biology of RLN3/RXFP3 in complementary murine models, this study mapped the neuroanatomical distribution of the RLN3/RXFP3 system in mouse brain. Adult, male wildtype and RLN3 knock-out (KO)/LacZ knock-in (KI) mice were used to map the central distribution of RLN3 gene expression and RLN3-like immunoreactivity (-LI). The distribution of RXFP3 mRNA and protein was determined using [(35)S]-oligonucleotide probes and a radiolabeled RXFP3-selective agonist ([(125)I]-R3/I5), respectively. High densities of neurons expressing RLN3 mRNA, RLN3-associated beta-galactosidase activity and RLN3-LI were detected in the nucleus incertus (or nucleus O), while smaller populations of positive neurons were observed in the pontine raphé, the periaqueductal gray and a region adjacent to the lateral substantia nigra. RLN3-LI was observed in nerve fibers/terminals in nucleus incertus and broadly throughout the pons, midbrain, hypothalamus, thalamus, septum, hippocampus, and neocortex, but was absent in RLN3 KO/LacZ KI mice. This RLN3 neural network overlapped the regional distribution of RXFP3 mRNA and [(125)I]-R3/I5 binding sites in wildtype and RLN3 KO/LacZ KI mice. These findings provide further evidence for the conserved nature of RLN3/RXFP3 systems in mammalian brain and the ability of RLN3/RXFP3 signaling to modulate "behavioral state" and an array of circuits involved in arousal, stress responses, affective state, and cognition.

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Human epidermal growth factor receptor 2 (HER2) regulates cell mitosis, proliferation, and apoptosis. Trastuzumab is a HER2-targeted monoclonal antibody (mAB), which can prolong the overall survival rate of patients with HER2 overexpression in later periods of gastric cancer and breast cancer. Although anti-HER2 monoclonal antibody has a curative effect, adjuvant chemotherapy is still necessary to upgrade the curative effect maximumly. Antibody-drug conjugate (ADC) is a kind of therapeutic drug that contains antigen-specific antibody and cytotoxic payload, which can improve the survival time of tumor patients. To date, there are several HER2-ADC products on the market, for which two anti-HER2 ADC (trastuzumab emtansine and trastuzumab deruxtecan) have been authorized by the FDA for distinct types of HER2-positive carcinoma in the breast. Disitamab vedotin (RC48) is a newly developed ADC drug targeting HER2 that is comprised of hertuzumab coupling monomethyl auristatin E (MMAE) via a cleavable linker. This paper aims to offer a general insight and summary of the mechanism of action and the currently completed and ongoing clinical studies of RC-48 in HER-2 positive solid tumors.

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SjP40 is a major egg antigen of Schistosoma japonicum. In the present study, the authors investigated the effect of SjP40 in vitro on transforming growth factor-β1 (TGF-β1)- stimulated hepatic stellate cells (HSCs). LX-2, an immortalized human HSC line, was treated with purified recombinant SjP40 (rSjP40) in the presence or absence of TGF-β1. Quantitative real-time polymerase chain reaction and western blot analysis were performed to determine messenger ribonucleic acid and protein of fibrogenic genes and TGF-β signaling pathway. The results showed that expression of fibrogenic genes was significantly reduced by rSjP40. Furthermore, rSjP40 also suppressed the TGF-β1-induced upregulation of Smads and ERK proteins. We also found that the effect of rSjP40 on HSCs was similar to SB431542, an inhibitor of type I TGF-β receptor. In conclusion, the data suggest that SjP40 attenuates HSC activation, which might be, at least in part, mediated by inhibiting the TGF-β and ERK signaling pathways.

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Pharmaceutical cocrystal has gained increasing interest due to its ability to modify various physicochemical properties of hydrophobic drugs, especially solubility and dissolution. The temporarily generated supersaturation during the dissolution of cocrystals, usually called “spring and parachute” effect, would favor the oral absorption of poorly soluble drugs. In this study, biopharmaceutics classification system II drug ibuprofen (IBU) was cocrystallized with nicotinamide (NIC) by slow solvent evaporation. An AP-type complexation between IBU and NIC was observed by phase solubility study, and complexation phenomenon was verified by fluorescence quenching method. Reduction of solvation barrier by inserting extremely soluble NIC in the crystal lattice of IBU makes the cocrystal gain a 70-fold higher aqueous solubility than that of original crystalline IBU. A novel mathematic model, considering both the ionization of IBU and the complexation between IBU and NIC, was developed and well-fitted to experimental pH solubility of cocrystal. Surprisingly, instead of common spring and parachute, the prepared IBU-NIC cocrystal demonstrated an initially rapid dissolution followed by a constant high concentration, like a helicopter hovering in the sky, during its nonsink dissolution. Such a result is interpreted with a spring and hover model, which should be ascribed to the enhanced IBU solubility by complexation with the coformer NIC.

As a foundation for regulatory and functional studies of central relaxin family peptide receptor systems, we are mapping the distribution of the different receptors in the brain of rat, mouse, and nonhuman primates, attempting to identify the nature of the receptor-positive neurons in key circuits and establish the complementary distribution of the respective ligands in these species. Here we review progress in mapping RXFP1, RXFP2, and RXFP3 (mRNAs and proteins) and their respective ligands and discuss some of the putative functions for these peptides and receptors that are being explored using receptor-selective agonist and antagonist peptides and receptor and peptide gene deletion mouse strains. Comparative studies reveal an association of RXFP1 and RXFP2 with excitatory neurons but a differential regional or cellular distribution, in contrast to the association of RXFP3 with inhibitory neurons. These studies also reveal differences in the distribution of RXFP1 and RXFP2 in rat and mouse brain, whereas the distribution of RXFP3 is more conserved across these species. Enrichment of RXFP1/2/3 in olfactory, cortical, thalamic, limbic, hypothalamic, midbrain, and pontine circuits suggests a diverse range of modulatory actions for these receptors. For example, experimental evidence in the rat reveals that RXFP1 activation in the amygdala inhibits memory consolidation, RXFP2 activation in striatum produces sniffing behavior, and RXFP3 modulation has effects on feeding and metabolism, the activity of the septohippocampal pathway, and spatial memory. Further studies are now required to reveal additional details of these and other functions linked to relaxin family peptide receptor signaling in mammalian brain and the precise mechanisms involved.