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The oral administration of protein therapeutics in solid dosage form is gaining popularity due to its benefits, such as improved medication adherence, convenience, and ease of use for patients compared to traditional parental delivery. However, formulating oral biologics presents challenges related to pH barriers, enzymatic breakdown, and poor bioavailability. Therefore, understanding the interaction between excipients and protein therapeutics in the solid state is crucial for formulation development. In this Letter, we present a case study focused on investigating the role of excipients in protein aggregation during the production of a solid dosage form of a single variable domain on a heavy chain (VHH) protein. We employed solid-state hydrogen–deuterium exchange coupled with mass spectrometry (ssHDX-MS) at both intact protein and peptide levels to assess differences in protein–excipient interactions between two formulations. ssHDX-MS analysis revealed that one formulation effectively prevents protein aggregation during compaction by blocking β-sheets across the VHH protein, thereby preventing β-sheet−β-sheet interactions. Spatial aggregation propensity (SAP) mapping and cosolvent simulation from molecular dynamics (MD) simulation further validated the protein–excipient interaction sites identified through ssHDX-MS. Additionally, the MD simulation demonstrated that the interaction between the VHH protein and excipients involves hydrophilic interactions and/or hydrogen bonding. This novel approach holds significant potential for understanding protein–excipient interactions in the solid state and can guide the formulation and process development of orally delivered protein dosage forms, ultimately enhancing their efficacy and stability.

Graphical Abstract: In this study, we found that exposure to PAHs during pregnancy leads to lower birth weight, with maternal thyroid hormones playing a mediating role.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants that pose a potentially serious threat to maternal and infant health, yet there are few studies on low-dose maternal and infant health. Therefore, this study investigated 2566 mother–infant pairs in Zunyi rural area, southwest China, and used multiple linear regression (MLR) and Bayesian kernel machine regression (BKMR) to reveal the relationship between pre-pregnancy PAHs exposures and neonatal birth outcomes. The results showed that more than 75% of the PAHs metabolite concentrations were above the limit of detection, and the main exposure was to 2-OHNAP (2. 9379 µg/L).The results of the MLR showed that, in both the original and adjusted models, 9-OHFLU and 4-OHPH were associated with lower birth weight, corresponding to β (95% CI) of − 36.684 (− 7.580, − 65.788), − 76.931 (− 22.524, − 131. 338), − 33.254 (− 4.628, − 61.879) and − 65.490 (− 12.073, − 118.906) (95%). 9-OHFLU was associated with loss of birth length, corresponding to β (95% CI) of − 0.094 (− 0.013, − 0.176) and − 0.084 (− 0.003, − 0.164). 9-OHFLU and 4-OHPH were associated with decreased neonatal BMI, corresponding to β (95%) CI) of − 0.104 (− 0.006, − 0.202) and − 0.323 (− 0.139, − 0.507), respectively. The results of the BKMR model showed that in the original model, 1-OHNAP, 1-OHPYR and total PAHs were negatively correlated with birth weight, with the corresponding PIP value of 0.0008, and that, after adjusting the model, total PAHs and 2-0HPH were negatively correlated with birth weight and birth BMI, corresponding to PIP values of 0.0232 and 0.0316, and total PAHs levels were negatively correlated with birth length. In conclusion, exposure of pregnant women to PAHs during pregnancy can have a negative impact on the birth outcomes of their newborns. Therefore, it is recommended that pregnant women with potentially adverse pregnancy outcomes, especially those suffering from gestational malnutrition, pre-eclampsia, or who are substance abusers, should reduce or avoid exposure to PAHs.

The oral delivery of protein therapeutics offers numerous advantages for patients but also presents significant challenges in terms of development. Currently, there is limited knowledge available regarding the stability and shelf life of orally delivered protein therapeutics. In this study, a comprehensive assessment of the stability of an orally delivered solid dosage variable domain of heavy-chain antibody (VHH antibody) drug product was conducted. Four stability related quality attributes that undergo change as a result of thermal and humidity stress were identified. Subsequently, these attributes were modeled using an accelerated stability approach facilitated by ASAPprimesoftware. To the best of our knowledge, this is the first time that this approach has been reported for an antibody drug product. We observed overall good model quality and accurate predictions regarding the protein stability during storage. Notably, we discovered that protein aggregation, formed through a degradation pathway, requires additional adjustments to the modeling method. In summary, the ASAP approach demonstrated promising results in predicting the stability of this complex solid-state protein formulation. This study sheds light on the stability and shelf life of orally delivered protein therapeutics, addressing an important knowledge gap in the field.

AbstractTrypophloeus klimeschiEggers (Coleoptera: Curculionidae: Scolytinae) was first discovered in China in 2003, and it exhibits strong species specificity to Populus albavar. pyramidalisBunge (Salicaceae). To screen plant volatile compounds for monitoring and trapping T. klimeschi, the electroantennogram responses of adult T. klimeschito eight plant volatiles, including nonanal, 2-methylbutanal, decanal, 2-hydroxybenzaldehyde, (Z)-3-hexen-1-ol benzoate, methyl benzoate, methyl salicylate, and geraniol were tested at various concentrations. Behavioural responses of female and male adults to various concentrations of these eight plant volatiles were also determined using a Y-tube olfactometer. We then tested the effectiveness of these compounds as lures for trapping T. klimeschiin the field. Electroantennogram tests showed that T. klimeschipossesses olfactory sensitivity for eight compounds. Additionally, walking T. klimeschiexhibited attraction to low concentrations (≤ 1 μg/μL) of all eight compounds in Y-tube olfactometer. Field experiment results indicated that baits composed of each volatile compound alone were more attractive to greater numbers of T. klimeschithan the control. The methyl benzoate bait was better attracted by T. klimeschithan other tested volatiles. These results suggest that these compounds could be used in attraction of this stem-boring pest. This study could have important implications for the development of an effective semiochemical-based management tool for T. klimeschiin the field.

AbstractBackground:Parkinson’s disease (PD) is a degenerative disorder of the central nervous system mainly affecting the motor system. Presently, there is no effective and safe drug to treat patients with PD. Ginkgo biloba extract (GBE), obtained from leaves of the Ginkgo biloba tree, is a complex mixture of ingredients primarily containing two active components: flavonoids and terpenoids. In this study, we investigated the effects of GBE on A53T α-synuclein transgenic mice, a PD model that has better simulated the progression of PD patients than other models such as the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine–induced PD model. Methods:Fifty α-synuclein A53T transgenic mice were fed and treated with GBE, and locomotor activity was detected by pole test, forced swim test, and wire-hang test. The expression of tyrosine hydroxylase and dopamine transporters was detected using immunohistochemistry. Superoxide dismutase activity, glutathione peroxidase activity, and malondialdehyde expression were detected using an assay kit. Results:Our results show that GBE treatment improved locomotor activity and that superoxide dismutase and glutathione peroxidase inhibited the expression of methane dicarboxylic aldehyde and recovered the expression of tyrosine hydroxylase and dopamine transporters. Conclusions:The GBE treatment improved locomotor activity and inhibited the development of PD in the A53T α-synuclein transgenic mice, which may be partly responsible for decreased oxidative damage and maintain the normal dopamine homeostasis.

•A new generic HILIC method is developed to overcome the hydrolysis issue of pinacol boronate esters during analysis.•The presented method can simultaneously separate boroate esters and the corresponding boronic acids from the hydrolysis.•More than forty boronte esters have been successfully analyzed by this generic method.

Objective This study aimed to determine the relationship between serum testosterone levels and depressive symptoms in an adult male population.Methods We conducted a cross-sectional study of 1166 male participants from Zunyi, Guizhou, China. Each participant completed a questionnaire, a brief clinical exam, and had a fasting blood sample taken. We measured serum testosterone, sex hormone-binding globulin, and luteinizing hormone levels. Multiple linear regression was used to evaluate the effect of demographic factors on the relationship between the depressive symptom score and serum sex hormone levels.Results Mean testosterone, sex hormone-binding globulin, and luteinizing hormone levels were significantly higher in the depressive symptom group than in the non-depressed group. The mean calculated free serum testosterone level and free testosterone index (FTI) were significantly lower in the depressive symptom group than in the non-depressed group. Additionally, the mean FTI was significantly negatively correlated with the Beck Depression Inventory scale score in the multiple linear regression model (95% confidence interval: −3.274 to −0.406).Conclusions Decreased bioactive testosterone levels might be a contributing factor of depression in adult men. The FTI could be the most sensitive biomarker reflecting the level of bioavailable testosterone in patients with depression.