recombinant FSH (FostiRel)

The link between diabetes and male infertility: mechanisms and implications.

Haffez Hesham H, Mosaad Mohamed M, Rezk Ahmed Y AY, Sayed Ahmed A et al.

Diabetes mellitus (DM) is a growing global health crisis affecting male reproductive function, yet the enhanced combined effects of diabetes with pre-existing fertility abnormalities remain poorly understood. This study aims to investigate the individual and combined effects of diabetes and abnormal semen parameters on male reproductive function and the underlying apoptotic mechanisms. Thirty-nine men were enrolled and stratified into two phases: a validation cohort (nondiabetic vs. diabetic; fertile vs. abnormally infertile) and a four-group mechanistic study (normal nondiabetic (n = 10), abnormal nondiabetic (n = 11), normal diabetic (n = 10), and abnormal diabetic (n = 8)). We assessed HbA1c, FSH, LH, testosterone, semen parameters, sperm apoptosis (Annexin V/PI flow cytometry), DNA fragmentation (diphenylamine), and expression of apoptotic markers (caspase-3, cytochrome c, Bax, and Bcl-2) at gene and protein levels. Diabetic patients had significantly higher HbA1c (9.6 ± 2.31% vs. 5.49 ± 0.42%, p < 0.001), elevated FSH and LH, and reduced testosterone. Abnormal infertile patients showed impaired motility and morphology. The abnormal diabetic group had the most severe dysfunction: lowest rapid progressive motility (11.3 ± 3.10%, p < 0.001 vs. control) and highest early apoptosis (58.9 ± 8.79%, p < 0.0001). Protein analysis showed a pro-apoptotic shift with an elevated Bax/Bcl-2 ratio (3.64), increased cytochrome-c, and caspase-3 activation exclusively in this group (p < 0.0001). Diabetes and abnormal semen parameters exert enhanced combined detrimental effects on male fertility via enhanced activation of the intrinsic mitochondrial apoptotic pathway. Diabetic men with pre-existing fertility abnormalities exhibit the most severe phenotype and require prioritized clinical intervention.

Systematic engineering of Pichia pastoris for high-level production of recombinant human granulocyte-macrophage colony-stimulating factor.

Cheng Zhenzhen Z, Gong Keyu K, Song Yuchao Y, Guo Zhenchang Z et al.

Human granulocyte-macrophage colony-stimulating factor (hCSF2) is a clinically important therapeutic glycoprotein with growing market demand, underscoring the need for efficient recombinant production platforms. To enable high-level production of recombinant hCSF2 (rhCSF2), the Pichia pastoris GS115 strain was systematically engineered through multi-copy integration of the expression cassette, screening for suitable secretory signal peptides, and enhancement of protein folding and transport pathways. The combination of multi-copy integration at multiple genomic loci with the combinatorial use of endogenous and exogenous signal peptides proved critical for improving rhCSF2 titers, while reinforcement of the folding and transport machinery further alleviated the bottleneck of protein throughput. Following high-density fermentation in a 3‑L bioreactor, the optimally engineered strain achieved an rhCSF2 titer of 3.4 g/L-markedly exceeding the highest titer previously reported in yeast hosts by an order of magnitude. Importantly, this engineering strategy was successfully extended to a glycoengineered strain SuperMan5, where it enabled production of rhCSF2 with more homogeneous and humanized N‑glycans and a titer of 4.3 g/L under high‑density fermentation condition. Our work demonstrates that the high-yield production of recombinant human therapeutic glycoproteins bearing homogeneous, humanized N-glycans in engineered yeast offers promising prospects.

Herpes zoster recurrence in primary care: Unmeasured residual confounding, the recombinant vaccine era, and external validity for Latin America.

Therán-León Juan Sebastián JS, Hernández-Cañas María Camila MC, Quintero-Arévalo Bárbara Yuliana BY

Podophyllotoxin induces testicular toxicity via the microbiota-gut-testis axis based on the toxicological evidence chain concept.

Shao Yuanyang Y, Wang Yu Y, Dai Yihang Y, Wang Lei L et al.

Podophyllotoxin (PPT), a natural lignan with well-established antitumor efficacy and well-documented ovarian toxicity, was first investigated for its potential testicular toxicity in male Sprague-Dawley rats, following the guidance of the Toxicological Evidence Chain (TEC) framework. Through an integrated approach combining physiological and pathological phenotyping, targeted metabolomics of intestinal contents, serum, and testicular tissues, testicular transcriptomics, and 16S rDNA sequencing of gut microbiota, we systematically delineated the injury evidence chain induced by PPT. Oral administration of PPT (20mg/kg/day for 4 days) elicited marked systemic toxicity, including reduced body weight and food intake, alongside clinical signs such as nasal hemorrhage and diarrhea. Testicular toxicity was evident from decreased testicular weight and organ index, histopathological impairments-including seminiferous tubule distortion, fibrosis, and germ cell apoptosis-and compromised sperm quality. Serum levels of testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were significantly suppressed. Concurrently, colonic injury was observed alongside gut dysbiosis, characterized by a reduction in Lactobacillus and enrichment of Proteus and Escherichia-Shigella. Multi-tissue metabolomics consistently identified disruption of vitamin B6 metabolism, with downregulation of pyridoxine, pyridoxamine, and 4-pyridoxic acid, while transcriptomic analysis revealed suppression of steroidogenic genes (Star, Cyp11a1, Cyp17a1). These findings collectively indicate that PPT induces testicular injury via the microbiota-gut-testis (MGT) axis.