Targeting phosphatases: From molecule design to clinical trials.

Phosphatase is a kind of enzyme that can dephosphorylate target proteins, which can be divided into serine/threonine phosphatase and tyrosine phosphatase according to its mode of action. Current evidence showed multiple phosphatases were highly correlated with diseases including various cancers, demonstrating them as potential targets. However, currently, targeting phosphatases with small molecules faces many challenges, resulting in no drug approved. In this case, phosphatases are even regarded as "undruggable" targets for a long time. Recently, a variety of strategies have been adopted in the design of small molecule inhibitors targeting phosphatases, leading many of them to enter into the clinical trials. In this review, we classified these inhibitors into 4 types, including (1) molecular glues, (2) small molecules targeting catalytic sites, (3) allosteric inhibition, and (4) bifunctional molecules (proteolysis targeting chimeras, PROTACs). These molecules with diverse strategies prove the feasibility of phosphatases as drug targets. In addition, the combination therapy of phosphatase inhibitors with other drugs has also entered clinical trials, which suggests a broad prospect. Thus, targeting phosphatases with small molecules by different strategies is emerging as a promising way in the modulation of pathogenetic phosphorylation.

Forward or Backward: Lessons Learned from Small Molecule Drugs Approved by FDA from 2012 to 2022.

At every juncture in history, the design and identification of new drugs pose significant challenges. To gain valuable insights for future drug development, we conducted a detailed analysis of New Molecular Entitiy (NME) approved by the Food and Drug Administration (FDA) from 2012 to 2022 and focused on the analysis of first-in-class (FIC) small-molecules from a perspective of a medicinal chemist. We compared the change of numbers between all the FDA-approved NMEs and FIC, which could be more visual to analyze the changing trend of FIC. To get a more visual change of molecular physical properties, we computed the annual average trends in molecular weight for FIC across various therapeutic fields. Furthermore, we consolidated essential information into three comprehensive databases, which covered the indications, canonical SMILES, structural formula, research and development (R&D) institutions, molecular weight, calculated LogP (CLogP), and route of administration on all the small-molecule pharmaceutical. Through the analysis of the database of 11 years of approvals, we forecast the development trend of NME approval in the future.

The impact of two dietary patterns on hyperuricemia in adults: A meta analysis of observational studies.

BACKGROUND: Hyperuricemia (HUA) is a crucial factor contributing to some chronic diseases among adults. In past observational literatures, scholars have debated the effectiveness of dietary pattern on HUA and inconsistencies exist. Given this condition, the study aimed to provide a comparative assessment of the relation between dietary pattern and HUA risk and offer implications to policy makers. METHODS: A systematic research was undertaken in PubMed, Web of Science, Cochrane, Embase, Medicine, ScienceDirect and Medline to identify observational studies examining the effect of dietary pattern on HUA, and search period was from past to January 2022. Meta analysis was applied by using the Stata version 11.0 software. RESULTS: A total of 34,583 adults from 8 observational studies, 45,525 adults from 6 observational studies were included to examine the effectiveness of "healthy" and "meat/western" dietary patterns on HUA risk respectively. The findings suggested that "healthy" dietary pattern significantly decreased the HUA risk (OR = 0.73; 95% CI: 0.61-0.88) both in Eastern countries (OR = 0.79; 95% CI: 0.64-0.98) and Western countries (OR = 0.53; 95% CI: 0.30-0.92) while the "Meat/Western" pattern increased the HUA possibilities (OR = 1.26; 95% CI: 1.17-1.37). Stratified analysis exhibited that "healthy" pattern reduced HUA risk in adults was more effective in cohort study (OR = 0.79; 95% CI: 0.72-0.86). CONCLUSIONS: This study's findings highlighted the potential benefit of healthy dietary pattern in decreasing HUA risk. Accordingly, implementing policy makers of countries should enhance to appeal adults to keep a healthy diet, offer financial support to low-income staff, or provide guidelines for adult's dietary behavior changes. TRIAL REGISTRATION NUMBER: INPLASY: INPLASY202290034.

[Clinical characteristics and pathogens of infancy lower respiratory tract infections in infants with bronchopulmonary dysplasia]. / æ”¯æ°”ç®¡è‚ºå‘è‚²ä¸è‰¯æ‚£å„¿å©´å„¿æœŸä¸‹å‘¼å¸é“æ„ŸæŸ“çš„ä¸´åºŠç‰¹å¾åŠç— åŽŸå­¦åˆ†æž.

OBJECTIVES: To study the clinical characteristics and pathogen features of infants with bronchopulmonary dysplasia (BPD) who were readmitted during infancy due to lower respiratory tract infections. METHODS: A retrospective analysis was conducted on 128 preterm infants with BPD who were admitted for lower respiratory tract infections in Qingdao Women and Children's Hospital from January 2020 to December 2022. An equal number of non-BPD preterm infants admitted during the same period were selected as controls. General information, clinical characteristics, lung function parameters, and respiratory pathogen results were compared between the two groups. RESULTS: Compared with the non-BPD group, the BPD group had a lower gestational age and birth weight, were more likely to experience shortness of breath, wheezing, and cyanosis, and had a longer duration of wheezing relief (P<0.05). Compared with the non-BPD group, the BPD group had lower lung function parameters, including tidal volume per kilogram of body weight, ratio of time to peak tidal expiratory flow to total expiratory time, ratio of volume at peak tidal expiratory flow to expiratory tidal volume, tidal expiratory flow at 25%, 50%, and 75% of tidal volume, and increased respiratory rate (P<0.05). The detection rates of gram-negative bacteria, such as Klebsiella pneumoniae and Acinetobacter baumannii, were higher in the BPD group than in the non-BPD group (P<0.05). CONCLUSIONS: Infants with BPD who develop infancy lower respiratory tract infections require closer attention to the clinical characteristics such as shortness of breath, wheezing, and cyanosis. Lung function is characterized by obstructive changes and small airway dysfunction. Gram-negative bacteria, including Klebsiella pneumoniae and Acinetobacter baumannii, are more likely to be detected as respiratory pathogens.

A hypothalamic novelty signal modulates hippocampal memory.

The ability to recognize information that is incongruous with previous experience is critical for survival. Novelty signals have therefore evolved in the mammalian brain to enhance attention, perception and memory1,2. Although the importance of regions such as the ventral tegmental area3,4 and locus coeruleus5 in broadly signalling novelty is well-established, these diffuse monoaminergic transmitters have yet to be shown to convey specific information on the type of stimuli that drive them. Whether distinct types of novelty, such as contextual and social novelty, are differently processed and routed in the brain is unknown. Here we identify the supramammillary nucleus (SuM) as a novelty hub in the hypothalamus6. The SuM region is unique in that it not only responds broadly to novel stimuli, but also segregates and selectively routes different types of information to discrete cortical targets-the dentate gyrus and CA2 fields of the hippocampus-for the modulation of mnemonic processing. Using a new transgenic mouse line, SuM-Cre, we found that SuM neurons that project to the dentate gyrus are activated by contextual novelty, whereas the SuM-CA2 circuit is preferentially activated by novel social encounters. Circuit-based manipulation showed that divergent novelty channelling in these projections modifies hippocampal contextual or social memory. This content-specific routing of novelty signals represents a previously unknown mechanism that enables the hypothalamus to flexibly modulate select components of cognition.

[Effect of peroxisome proliferator-activated receptor-gamma on proliferation of airway smooth muscle cells in mice with asthma].

OBJECTIVE: To investigate the effects of peroxisome proliferator-activated receptor-gamma (PPARγ) agonist rosiglitazone on the expression of cyclin D1 in lung tissue, and the proliferation of airway smooth muscle cells (ASMCs) in mice with bronchial asthma. METHODS: Thirty clean BALB/c mice were randomly divided into control group (n = 10), asthma group (n = 10), and rosiglitazone treatment group (n = 10). A mouse model of asthma was established by ovalbumin (OVA) sensitization and challenge. The treatment group received rosiglitazone (5 mg/kg) by gavage 1 hour before each challenge and the control group received saline instead of OVA sensitization and challenge. Leukocytes and eosinophils in bronchoalveolar lavage fluid (BALF) were counted under a microscope. Airway structural changes were observed by hematoxylin-eosin staining. Protein and mRNA expression levels of cyclin D1 were measured by immunohistochemical staining and RT-PCR. Perimeter of the basement membrane (Pbm), total bronchial wall area (WAt), airway smooth muscle area (WAm), and number of nuclei in ASMCs (N) were determined using image analysis software, and WAt/Pbm, WAm/Pbm, and N/Pbm were calculated. RESULTS: Compared with the control group, the asthma group showed significant increases in the total number of leukocytes and percentage of eosinophils in BALF, as well as in the mRNA and protein expression of cyclin D1, but changes in these indices were significantly reduced in the rosiglitazone treatment group (P < 0.05). In addition, compared with the control group, the asthma group had significantly increased WAt/Pbm, WAm/Pbm, and N/Pbm, but rosiglitazone significantly decreased these ratios (P < 0.05). CONCLISONS: Rosiglitazone may delay the process of airway remodeling by inhibiting the proliferation of ASMCs, so it can be used for preventing and treating chronic asthma.

[Effects of fasudil on the expression of Rho kinase-1 and airway inflammation in a mouse model of asthma.].

OBJECTIVE: To explore the role of Rho kinase-1 (ROCK-1) in airway inflammation of asthma by observing the effects of fasudil, a specific inhibitor of ROCK-1, on the expression of Rho kinase-1 and airway inflammation in a mouse model of asthma. METHODS: Twenty-four female BALB/c mice were randomly divided into 3 groups (n = 8 each): a control group, an asthmatic group and a treatment group. Mice in the asthmatic and the treatment groups were sensitized by intraperitoneal injection of OVA (25 microg) precipitated with 1 mg of alum in 200 microl of saline on days 1 and 15, and subsequently challenged by nebulization of 2% OVA on days 22-26. Mice in the control group were sensitized with Al(OH)3 saline and challenged with saline instead of OVA. Mice of the treatment group were injected intraperitoneally with fasudil (10 mg/kg) 1 h before each OVA challenge. All the mice were killed 24 h after the final challenge, and bronchoalveolar lavage fluid (BALF) was collected for counting total inflammatory cells and eosinophils (EOS). Cytokines and chemokines in BALF were measured by ELISA. The lung tissue slides were examined histologically. The protein and mRNA expression of ROCK-1 were measured by immunohistochemistry and RT-PCR respectively. RESULTS: (1) OVA challenge in mice of the asthmatic group caused a marked increase in the number of the total cells and eosinophils in BALF (q = 25.909, 35.002, respectively, all P < 0.01). When fasudil was applied, both the total cell counts and the eosinophil numbers were significantly decreased. The total cell number was decreased from (1.45 +/- 0.12) x 10(9)/L to (0.89 +/- 0.09) x 10(9)/L (q = 16.676, P < 0.01), and the number of eosinophils was decreased from (0.52 +/- 0.06) x 10(9)/L to (0.20 +/- 0.04) x 10(9)/L (q = 21.537, P < 0.01). (2) Compared with the control group, OVA challenge in mice of the asthmatic group induced eotaxin, IL-5 and IL-13 release into BALF (q = 18.246, 23.009, 25.826, respectively, all P < 0.01). The eotaxin, IL-5 and IL-13 levels in BALF after OVA challenge were (45 +/- 8) ng/L, (157 +/- 23) ng/L and (429 +/- 46) ng/L, respectively. Application of fasudil resulted in inhibition of the augmented levels of eotaxin, IL-5 and IL-13 in BALF, decreased to (20 +/- 5) ng/L, (57 +/- 14) ng/L and (254 +/- 28) ng/L, respectively (q = 13.119, 17.503, 8.449, respectively, all P < 0.01). (3) Mice in the control group showed no detectable inflammatory response in the lung, whereas OVA-challenged mice induced infiltration of inflammatory cells around airways and blood vessels. The majority of the infiltrated inflammatory cells were eosinophils. Application of fasudil significantly reduced the infiltration of inflammatory cells in the peribronchial areas compared with the asthmatic mice. (4) The expression levels of ROCK-1 mRNA and protein in mice of the asthmatic group (0.67 +/- 0.05 and 1.09 +/- 0.06) were much higher than those of the control group (0.26 +/- 0.05 and 0.87 +/- 0.09) (q = 25.614, 8.156, all P < 0.01). When fasudil was administered, the expression levels of ROCK-1 mRNA and protein were significantly attenuated to 0.35 +/- 0.04 and 0.98 +/- 0.08, compared with those of the asthmatic group (q = 20.379, 4.135, all P < 0.01). (5) The expression level of ROCK-1 mRNA was positively correlated with the number of eosinophils and the levels of eotaxin, IL-5 and IL-13 in BALF (r = 0.709, 0.600, 0.613, 0.650, all P < 0.01). CONCLUSION: Airway inflammation of bronchial asthma was improved by inhibiting expression and activity of ROCK-1 by fasudil, suggesting that ROCK-1 may be involved in asthmatic airway inflammation induced by OVA challenge.